Supplemental Reading for Chapter 1 Basic Principles of Clinical ...

Supplemental Reading for Chapter 1 

Basic Principles of Clinical Pharmacology 

Relevant to Cardiology 

William H. Frishman, MD 

Bourne HR, von Zastrow M: Drug receptors and pharmacodynamics. 

In: Katzung BG, ed. Basic and Clinical 

Pharmacology, 10th ed. New York: McGraw Hill 

2007: 11–33. 

Cardiac surgery patients may have clinically relevant 

changes in the pharmacokinetics of frequently 

used drugs. Drugs Therap Perspect 2009; 25: 

23–26. 

Cheng JWM, Frishman WH, Aronow WS: Updates on 

cytochrome P450-mediated cardiovascular drug 

interactions. Disease-a-Month 2010; 56: 163–179. 

Correia MA: Drug biotransformation. In: Katzung BG, 

ed. Basic and Clinical Pharmacology, 10th ed. New 

York: McGraw Hill 2007: 50–63. 

Fleg JL, Aronow WS, Frishman WH: Cardiovascular drug 

therapy in the elderly: benefits and challenges. Nat 

Rev Cardiol epub October 26, 2010. 

Fleming WW: Mechanisms of drug action. In: Craig 

CR, Stitzel RE, eds. Modern Pharmacology, 6th ed. 

Philadelphia: Lippincott Williams & Wilkins 2004: 

10–19. 

Frishman WH; Fifty years of beta-adrenergic blockade: 

a golden era of clinical medicine and molecular 

pharmacology (commentary). Am J Med 2008; 121: 

933–34. 

Godin DV: Pharmacokinetics: disposition and metabolism 

of drugs. In: Munson PL, Mueller RA, Breese 

GR, eds. Principles of Pharmacology: Basic Concepts 

and Clinical Applications. New York: Chapman & 

Hall, 1995:39–84. 

Holford NHG: Pharmacokinetics and pharmacodynamics: 

Rational dosing and time course of drug action. 

In: Katzung BG, ed. Basic and Clinical Pharmacology, 

10th ed. New York: McGraw Hill 2007: 34–49. 

Hollenberg MD, Severson DL: Pharmacodynamics: drug 

receptors and receptors/mechanisms. In: Munson 

PL, Mueller RA, Breese GR, eds. Principles of Pharmacology: 

Basic Concepts and Clinical Applications. 

New York: Chapman & Hall, 1995:7–37. 

Nierenberg DW, Melmon KL: Introduction to clinical 

pharmacology and rational therapeutics. In: Carruthers 

SG, Hoffman BB, Melmon KL, Nierenberg 

DW, eds. Melmon & Morrelli’s Clinical Pharmacology, 

4th ed. New York: McGraw Hill, 2000:3. 

Opie LH, Frishman WH: Drug interactions. In: Fuster 

V, Alexander RW, O’Rourke RA, et al., eds. Hurst’s 

The Heart, 10th ed. New York: McGraw Hill, 

2000:2251. 

Pea F, Pavan F, Furlanut M: Clinical relevance of pharmacokinetics 

and pharmacokinetics in cardiac critical 

care patients. Clin Pharmacokinet 2008; 47: 449–62. 

Rang HP, Dale MM, Ritter HM, Gardner P: Pharmacology. 

New York, Churchill Livingstone, 1995.Sokol 

SI, Cheng-Lai A, Frishman WH, Kaza CS: Cardiovascular 

drug therapy in patients with hepatic diseases 

and patients with congestive heart failure. J 

Clin Pharmacol 40:11, 2000. 

Roden DM: Drug-induced prolongation of the QT interval. 

NEJM 2004; 350: 1013–22. 

Schwartz SL, Wellstein A, Woosley RL: Significance of 

pharmacokinetic principles. In Singh BN, Dzau 

VJ, Vanhoutte PM, Woosley RL (eds): Cardiovascular 

Pharmacology and Therapeutics. New York: 

Churchill Livingstone 1994; 15–29. 

Sokol SI, Cheng A, Frishman WH, Kaza CS. Cardiovascular 

drug therapy in patients with hepatic diseases 

and patients with congestive heart failure. J Clin 

Pharmacol 2000; 40: 11–30. 

Tracy TS: Drug absorption and distribution. In Craig 

CR, Stizel RE (eds): Modern Pharmacology 6th ed. 

New York: Lippincott Williams & Wilkins 2004; 

20–33. 

Cardiovascular Pharmacotherapeutics, 3rd ed, Abridged and Updated. © 2012 William H. Frishman and Domenic A. Sica, eds. Cardiotext 

Publishing, ISBN: 978-1-935395-52-2. 

1-1

1-2 Cardiovascular Pharmacotherapeutics 

Tracy TS: Metabolism and excretion of drugs. In Craig 

CR, Stizel RE (eds): Modern Pharmacology 6th ed. 

New York: Lippincott Williams & Wilkins 2004; 

34–47. 

Tracy TS: Pharmacokinetics. In Craig CR, Stizel RE (eds): 

Modern Pharmacology 6th ed. New York: Lippincott 

Williams & Wilkins 2004; 48–55.

References for Chapter 5 

Alpha- and Beta-Adrenergic 

Blocking Drugs 


1. Ahlquist RP: Study of the adrenotropic receptors. 

Am J Physiol 153:486, 1948. 

2. Lands AM, Luduena FP, Buzzo HJ: Differentiation 

of receptor systems responsive to isoproterenol. 

Life Sci 6:2241, 1967. 

3. Emorine LJ, Marullo S, Briend-Sutren M-M, et al: 

Molecular characterization of the human b 3 -adrenergic 

receptor. Science 245:1118, 1989. 

4. Berthelsen S, Pettinger WA: A functional basis for 

classification of alpha-adrenergic receptors. Life Sci 

21:596, 1977. 

5. Berecek KH, Carey RM: Adrenergic and dopaminergic 

receptors and actions. In Izzo JL Jr, Sica 

DA, Black HR: Hypertension Primer 4th ed. Dallas: 

American Heart Assn 2008: 39. 

6. Sutherland EW, Robinson GA, Butcher RW: Some 

aspects of the biological role of adenosine 3ʹ5ʹ-monophosphate 

(cyclic AMP). Circulation 37:279– 

306, 1968. 

7. Insel PA: Adrenergic receptors: evolving concepts 

and clinical implications. N Engl J Med 334:580, 

1996. 

8. Lefkowitz RJ, Caron MG: Adrenergic receptors: 

models for the study of receptors coupled to guanine 

nucleotide regulatory proteins. J Biol Chem 

263:4993–4996, 1988. 

9. Benovic JL, Bouvier M, Caron MG, Lefkowitz RJ: 

Regulation of adenyl cyclase-coupled beta-adrenergic 

receptors. Annu Rev Cell Biol 4:405–428, 1988. 

10. Lefkowitz RJ: Seven transmembrane receptors: 

something old, something new. Acta Physiol 190: 

9-19, 2007. 

11. Watanabe AM: Recent advances in knowledge 

about beta-adrenergic receptors: application to 

clinical cardiology. J Am Coll Cardiol 1:82–89, 

1983. 

12. Frishman WH, Charlap S: a-Adrenergic blockers. 

Med Clin North Am 72:427, 1988. 

13. Pool JL: a-Adrenoceptor antagonists. In Izzo JL Jr, 

Sica DA, Black HR: Hypertension Primer 4th ed. 

Dallas: American Heart Assn 2008: 450. 

14. Katz AM, Hager WD, Mesineo FC, et al: Cellular 

actions and pharmacology of the calcium channel 

blocking drugs. Am J Med 77:2, 1984. 

15. Ribner HS, Bresnahan D, Hsieh AM: Acute hemodynamic 

responses to vasodilation therapy in 

congestive heart failure. Prog Cardiovasc Dis 25:1, 

1982. 

16. Neaton JD, Grimm RH, Prineas RI, et al for the 

Treatment of Mild Hypertension Study Research 

Group: treatment of mild hypertension study: final 

results. JAMA 270:713, 1993. 

17. Materson BJ, Reda DJ, Cushman WC, et al: Singledrug 

therapy for hypertension in men. A comparison 

of six antihypertensives with placebo. N Engl J 

Med 328:914, 1994. 

18. Davis BR, Cutler JA, Gordon DJ, et al, for the ALL- 

HAT Research Group: Rationale and design for the 

Antihypertensive and Lipid Lowering Treatment to 

Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 

9:342, 1996. 

19. The ALLHAT Off\hskip.1pticers and Coordinators 

for the ALLHAT Collaborative Research Group: 

Major cardiovascular events in hypertensive patients 

randomized to doxazosin vs chlorthalidone. 

The Antihypertensive and Lipid-Lowering Treatment 

to Prevent Heart Attack Trial (ALLHAT). 

JAMA 283:1967, 2000. 

20. Frishman WH: Update in cardiology. Ann Intern 

Med 135:439, 2001. 

21. Davis BR, Cutler JA, Furberg CD, et al: Relationship 

of antihypertensive treatment regimens and change 



5-1


in blood pressure to risk for heart failure in hypertensive 

patients randomly assigned to doxazosin or 

chlorthalidone: Further analyses from the antihypertensive 

and lipid-lowering treatment to prevent 

Heart Attack Trial. Ann Intern Med 137:313, 2002. 

22. Frishman WH, Patel K: Lipid-lowering drugs. In: 

Frishman WH, Sonnenblick EH, eds. Cardiovascular 

Pharmacotherapeutics. New York: McGraw- 

Hill, 1997:399. 

23. Hachamovitch R, Strom JA, Sonnenblick EH, Frishman 

WH: Left ventricular hypertrophy in hypertension 

and the effects of anti-hypertensive 

drug therapy. Curr Probl Cardiol 13:371, l988. 

24. Black HR, Keck M, Meredith P, et al: Controlledrelease 

doxazosin as combination therapy in hypertension: 

the GATES study. J Clin Hypertens 8: 

159-66, 2006. 

25. Gould L, Reddy CVR: Phentolamine. Am Heart J 

92:392, 1976. 

26. Majid PA, Sharma B, Taylor SH: Phentolamine for 

vasodilator treatment of severe heart failure. Lancet 

2:719, 1971. 

27. Gregorini L, Marco J, Palombo C, et al: Postischemic 

left ventricular dysfunction is abolished by 

alpha-adrenergic blocking agents. J Am Coll Cardiol 

31:992, 1998. 

28. Packer M: Vasodilator and inotropic therapy for severe 

chronic heart failure: passion and skepticism. J 

Am Coll Cardiol 2:841, 1983. 

29. Cohn JN, Archibald DG, Ziesche S, et al: Effect of 

vasodilator therapy on mortality in chronic congestive 

heart failure: results of a Veterans Administration 

Cooperative Study (V-Heft). N Engl J Med 

314:1547, 1986. 

30. Elkayam U, Bitar F: Effects of nitrates and hydralazine 

in heart failure: clinical evidence before the 

African American Heart Failure Trial. Am J Cardiol 

96(7B): 37i, 2005. 

31. Kukin ML, Kalman J, Mannino M, et al: Combined 

alpha-beta blockade (doxazosin plus metoprolol) 

compared with beta blockade alone in chronic congestive 

heart failure. Am J Cardiol 77:486, 1996. 

32. Kern MJ: Appreciating a adrenergic receptors and 

their role in ischemic left ventricular dysfunction. 

Circulation 99:468, 1999. 

33. Baumgart D, Haude M, Gorge G, et al: Augmented 

a adrenergic constriction of atherosclerotic human 

coronary arteries. Circulation 99:2090, 1999. 

34. Heusch G: Emerging importance of alpha-adrenergic 

coronary vasoconstriction in acute coronary 

syndromes and its genetic background (editorial 

comment). J Am Coll Cardiol 41:195,2003 

35. Orlick AE, Ricci DR, Cipriano PR, et al: The contribution 

of alpha-adrenergic tone to resting coronary 

vascular resistance in man. J Clin Invest 62:459, 

1978. 

36. Winniford MD, Flipchuk N, Hillis DL: Alphaadrenergic 

blockade for variant angina: a longterm 

double-blind randomized trial. Circulation 

67:1185, 1983. 

37. Corr PB, Shayman JA, Kramer JB, et al: Increased a 

-adrenergic receptors in ischemic cat myocardium: 

a potential mediator of electrophysiologic derangements. 

J Clin Invest 67:1232, 1981. 

38. Young WF, Sheps SG: Management of pheochromocytoma. 

In Izzo JL Jr., Sica DA, Black HR (eds): 

Hypertension Primer 4th ed. Dallas: American 

Heart Assn 2008; 571. 

39. Honston MC, Thompson WL, Robertson D: Shock. 

Arch Intern Med 144:1433, 1984. 

40. Fein SA, Frishman WH: The pathophysiology and 

management of pulmonary hypertension. Cardiol 

Clin 5:563, 1987. 

41. Cohen ML, Kronzon I: Adverse hemodynamic effects 

of phentolamine in primary pulmonary hypertension. 

Ann Intern Med 95:591, 1981. 

42. Henderson WR, Shelhamer JH, Reingold DB, et al: 

Alpha-adrenergic hyperresponsiveness in asthma. 

N Engl J Med 300:642, 1979. 

43. Barnes PJ, Wilson NM, Vickers H: Prazosin, an 

alpha 1 -adrenoceptor antagonist, partially inhibits 

exercise-induced asthma. J Allergy Clin Immunol 

68:411,1981. 

44. Hedlund H, Andersson KE, Ek A: Effects of prazosin 

in patients with benign prostatic obstruction. J 

Urol 130:275, 1983. 

45. Narayan P, Lowe FC: The effects of tamsulosin on 

vital signs in two multicenter, placebo-controlled 

studies. Cardiovasc Rev Rep 21:494, 2000. 

46. Alfuzosin (Uroxatral) – another alpha 1 -blocker for 

benign prostatic hyperplasia. The Medical Letter 46 

(Issue 1173): 1, 2004. 

47. Frishman WH: b-Adrenoceptor antagonists: new 

drugs and new indications. N Engl J Med 305:500– 

506, 1981. 

48. Frishman WH: Clinical Pharmacology of the b-Adrenoceptor 

Blocking Drugs, 2nd ed. Norwalk, CT: 

Appleton-Century-Crofts, 1984. 

49. Frishman WH: b-Adrenergic blockers. Med Clin 

North Am 72:37–81, 1988. 

50. Frishman WH: b-Adrenergic blockers: 50-year historical 

perspective. Am J Therap 15: 565,2008. 

51. Frishman WH: Fifty years of beta-adrenergic 

blockade: a golden era in clinical medicine and 

molecular pharmacology (commentary). Am J Med 

121:933,2008. 

52 Frishman WH, Furberg CD, Friedewald WT: b- 

Adrenergic blockade for survivors of acute myo-

cardial infarction. N Engl J Med 310:30–837, 1984. 

53. TIMI Study Group: Comparison of invasive and 

conservative strategies after treatment with intravenous 

tissue-type plasminogen activator in acute 

myocardial infarction: results of the thrombolysis 

in myocardial infarction (TIMI) trial phase II. N 

Engl J Med 320: 618–627, 1989. 

54. Frishman WH: Carvedilol. N Engl J Med 339:1759, 

1998. 

55. MERIT-HF Study Group: Effect of metoprolol 

CR/XL in chronic heart failure: Metoprolol CR/ 

XL Randomised Intervention Trial in Congestive 

Heart Failure (MERIT-HF). Lancet 353:2001, 1999. 

56. Lefkowitz RJ: A magnificent time with the “magnificent 

seven” transmembrane spanning receptors. 

Circ Res 92: 342,2003. 

57. Frielle T, Daniel KW, Caron MG, Lefkowitz RJ: 

Structural basis of b-adrenergic receptor subtype 

specificity studied with chimeric b1/b2-adrenergic 

receptors. Proc Natl Acad Sci USA 85: 9494,1988. 

58. Dixon RA, Kobilka BK, Strader DJ, et al: Cloning of 

the gene and cDNA for mammalian b-adrenergic 

receptor and homology with rhodopsin. Nature 

321: 75,1986. 

59. Rasmussen SGF, Choi H-J, Rosenbaum DM, et al: 

Crystal structure of the human b 2 adrenergic Gprotein-coupled 

receptor. Nature 450: 383,2007. 

60. Lefkowitz RJ: The superfamily of heptahelical receptors. 

Nature Cell Biol 2: E133,2000. 

61. Lefkowitz RJ, Rajagopal K, Whalen EJ. New roles 

for b-arrestins in cell signaling: not just for seventransmembrane 

receptors. Molec Cell 24: 643,2006. 

62. Cruickshank JM, Prichard BNC: Beta-Blockers in 

Clinical Practice, 2nd ed. Edinburgh: Churchill 

Livingstone, 1994:1055. 

63. Koch-Weser J: Metoprolol. N Engl J Med 301:698, 

1979. 

64. Frishman WH: Atenolol and timolol, two new 

systemic adrenoceptor antagonists. N Engl J Med 

306:1456, 1982. 

65. Frishman WH: Nadolol: A new b-adrenoceptor 

antagonist. N Engl J Med 305:678, 1981. 

66. Frishman WH: Pindolol: A new b-adrenoceptor 

antagonist with partial agonist activity. N Engl J 

Med 308:940, 1983. 

67. Frishman WH, Covey S: Penbutolol and carteolol: 

two new beta-adrenergic blockers with partial agonism. 

J Clin Pharmacol 30:412, 1990. 

68. Frishman WH, Tepper D, Lazar E, Behrmann D: 

Betaxolol: a new long-acting b 1 -selective adrenergic 

blocker. J Clin Pharmacol 30:699, 1990. 

69. Frishman WH, Cheng-Lai A, Chen J, eds. Current 

Cardiovascular Drugs, 3rd ed. Philadelphia: Current 

Medicine, 2000:120. 

References to Chapter 5 5-3 

69a. Sule SS, Frishman WH: Nebivolol. New therapy 

update. Cardiol in Rev 14: 259, 2006. 

69b. Somberg JC, Preston RA, Ranade V, Molnar J: Developing 

a safe intravenous sotalol dosing regimen. 

Am J Therap 17: 365, 2010. 

69c. Kamp O, Metra M, Bugatti S, et al: Nebivolol. 

Haemodynamic effects and clinical significance 

of combined b-blockade and nitric oxide release. 

Drugs 70: 41, 2010 

70. Frishman W: Clinical pharmacology of the new beta-adrenergic 

blocking drugs. Part I: Pharmacokinetic 

and pharmacodynamic properties. Am Heart 

J 97:663, 1979. 

71. Conolly ME, Kersting F, Dollery CT: The clinical 

pharmacology of beta-adrenoceptor blocking 

drugs. Prog Cardiovasc Dis 19:203, 1976. 

72. Singh BN, Deedwania P, Nademanee K, et al: Sotalol: 

a review of its pharmacodynamic and pharmacokinetic 

properties and therapeutic use. Drugs 

34:311, 1987. 

73. Morgan T: Clinical pharmacokinetics and pharmacodynamics 

of carvedilol. Clin Pharmacokinet 

26:335, 1994. 

74. Opie LH, Yusuf S: Beta-blocking agents. In: Opie 

LH, Gersh BJ, eds. Drugs for the Heart, 5th ed. 

Philadelphia:Saunders, 2001:1. 

75. Frishman W, Jacob H, Eisenberg E, Ribner H: 

Clinical pharmacology of the new beta-adrenergic 

blocking drugs. Part VIII: Self-poisoning with beta-adrenoceptor 

blocking drugs: recognition and 

management. Am Heart J 98:798, 1979. 

76. Lands AM, Arnold A, McAuliff JP, et al: Differentiation 

of receptor systems activated by sympathomimetic 

amine. Nature 214: 597,1967. 

77. Frishman WH: Alpha- and beta-adrenergic blocking 

drugs. In Frishman WH, Sonnenblick EH, Sica 

DA (eds): Cardiovascular Pharmacotherapeutics 

2nd ed. New York : McGraw Hill 2003: 67. 

78. Wright P: Untoward effect associated with practolol 

administration: oculomucocutaneous syndrome. 

Br Med J 1: 595,1975. 

79. Frishman WH: a- and b-adrenergic blocking 

drugs. In Frishman WH, Sonnenblick EH, Sica DA 

(eds): Cardiovascular Pharmacotherapeutics Manual 

2nd ed. New York: McGraw Hill 2005; 19. 

80. Frishman WH Clinical differences between betaadrenergic 

blocking agents: implications for therapeutic 

substitution. Am Heart J 113: 1190,1987. 

81. Xamoterol in Severe Heart Failure Study Group: 

Xamoterol in severe heart failure. Lancet 336: 

1,1990. 

82. Frishman W, Halprin S. Clinical pharmacology of 

the new beta-adrenergic blocking drugs. Part VII: 

new horizons in beta-adrenoceptor blocking thera-


py: labetalol. Am Heart J 1979; 98: 660. 

83. Frishman WH, Sica DA: b-Adrenergic blockers. In, 

Izzo JL, Jr., Sica D, Black HR, Eds.: Hypertension 

Primer, 4th ed.: The Essentials of High Blood Pressure. 

Philadelphia: Wolters Kluwer/Lippincott Williams 

& Wilkins, 2008: p 446-450. 

84. Wisler JW, DeWire SM, Whalen EJ, et al: A unique 

mechanism of b-blocker action: carvedilol stimulates 

b-arrestin signaling. Proc Natl Acad Sci 104: 

16657, 2007. 

85. Waal Manning HJ: Hypertension: which betablocker? 

Drugs 12: 412, 1976. 

86. Frishman WH, Lazar EJ, Gorodokin G: Pharmacokinetic 

optimization of therapy with beta-adrenergic 

blocking agents. Clin Pharmacokinet 20:311, 

1991. 

87. Frishman WH, Alwarshetty M: Beta-adrenergic 

blockers in systemic hypertension: pharmacokinetic 

considerations related to the JNC-VI and 

WHO-ISH current guidelines. Clin Pharmacokinet 

42:505,2002. 

88. Frishman WH, Teicher M: Long-acting propranolol. 

Cardiovasc Rev Rep 4:100, 1983. 

89. Halkin H, Vered I, Saginer A, Rabinowitz B: Oncedaily 

administration of sustained release propranolol 

capsules in the treatment of angina pectoris. Eur 


90. Abrahamsson B, Lucker P, Olofsson, et al: The relationship 

between metoprolol plasma concentration 

and beta 1 -blockade in healthy subjects: a study on 

conventional metoprolol and metoprolol CR/ZOK 

formulations. J Clin Pharmacol 30:S46, 1990. 

91. Sandberg A, Blomqvist I, Jonsson UE, Lundborg 

P: Pharmacokinetic and pharmacodynamic properties 

of a new controlled-release formulation of 

metoprolol: a comparison with conventional tablets. 

Eur J Clin Pharmacol 33(Suppl):S9, 1988. 

92. Frishman WH, Murthy VS, Strom JA: Ultra-short 

acting b-adrenergic blockers. Med Clin North Am 

72:359, 1988. 

93. Murthy VF, Frishman WH: Controlled beta-receptor 

blockade with esmolol and flestolol. Pharmacotherapy 

8:168, 1988. 

94. Parker JO, Porter A, Parker JD: Propranolol in angina 

pectoris: comparison of long-acting and standard 

formulation propranolol. Circulation 65:1351, 

1982. 

95. Matier WL, Patil G: Esprolol hydrochloride. A new 

beta adrenergic antagonist with a rapid onset of effect. 

Heart Dis 2:146, 2000. 

96. Reid JL: Nebivolol: the role of nitric oxide in hypertension—concluding 

remarks. J Cardiovasc Pharmacol 

38(Suppl 3):S37, 2001. 

97. Tzemos N, Lim PO, MacDonald TM: Nebivolol 

reverses endothelial dysfunction in essential hypertension. 

A randomized, double-blind, crossover 

study. Circulation 104:511, 2001. 

98. Frishman WH: Acebutolol. Cardiovasc Rev Rep 

6:979, 1985. 

99. Wurzelmann J, Frishman W, Aronson M, et al: 

Neuropsychiatric effects of antihypertensive drugs 

in the old old. Cardiol Clin 5:689, 1987. 

100. Carney RM, Rich MW, te Velde AJE, et al: Prevalence 

of major depressive disorders in patients 

receiving b-blocker therapy versus other medications. 

Am J Med 83:223, 1987. 

101. Kostis JB, Rosen RC: Central nervous system effects 

of b-adrenergic blocking drugs: the role of 

ancillary properties. Circulation 75:204, 1987. 

102. Cruickshank JM, Prichard BNC: Beta-blockers in 

Clinical Practice, 2nd ed. Edinburgh: Churchill Livingstone, 

1994:277. 

103. Ward SA, Walle T, Walle UK, et al: Propranolol’s 

metabolism is determined by both mephenytoin 

and debrisoquin hydroxylase activities. Clin Pharmacol 

Ther 45:72, 1989. 

104. Fujimaki M: Oxidation of the R(+) and S(–) carvedilol 

by rat liver microsome. Evidence for stereoselective 

oxidation and characterization of the 

cytochrome P450 isozymes involved. Drug Metab 

Dispos 22:700, 1994. 

105. Panton LB, Guillen GJ, Williams L, et al: The lack 

of effect of aerobic exercise training on propranolol 

pharmacokinetics in young and elderly adults. J 


106. McAlister FA, Wiebe N, Ezekowitz JA, et al: Metaanalysis: 

b-Blocker dose, heart rate reduction, and 

death in patients with heart failure. Ann Intern Med 

150: 784, 2009. 

107. Cohn JN: Nitroprusside and dissecting aneurysm 

of aorta (correspondence). N Engl J Med 295:567, 

1976. 

108. Cohen LS, Braunwald E: Amelioration of angina 

pectoris in idiopathic hypertrophic subaortic stenosis 

with beta-adrenergic blockade. Circulation 

35:847-851, 1967. 

109. Turner JRB: Propranolol in the treatment of digitalis-induced 

and digitalis-resistant tachycardia. 

Am J Cardiol 18:450, 1966. 

110. Winkle RA, Lopes MG, Goodman DS, et al: Propranolol 

for patients with mitral valve prolapse. 

Am Heart J 93:422, 1970. 

111. Krahn AD, Yee R, Chauhan V, et al: Beta blockers 

normalize QT hysteresis in long QT syndrome. Am 

Heart J 143:528, 2002. 

112. Kornbluth A, Frishman WH, Ackerman M: Beta-adrenergic 

blockade in children. Cardiol Clin 

5:629, 1987.

113. Meister SG, Engel TR, Feitosa GS, et al: Propranolol 

in mitral stenosis during sinus rhythm. Am 

Heart J 94:685, 1977. 

114. Svedberg K, Hjalmarson A, Waagstein F, Wallentin 

I: Beneficial effects of long-term beta-blockade 

in congestive cardiomyopathy. Br Heart J 44:117, 

1980. 

115. Sullebarger JT, Liang C-s: Beta-adrenergic receptor 

stimulation and inhibition in chronic congestive 

heart failure. Heart Failure 7:154, 1991. 

116. Kraus ML, Gottlieb LD, Horwitz RI, Anscher M: 

Randomized clinical trial of atenolol in patients 

with alcohol withdrawal. N Engl J Med 313:905, 

1985. 

117. Weber RB, Reinmuth OM: The treatment of migraine 

with propranolol. Neurology (NY) 22:366, 

1972. 

118. Young RR, Growdon JH, Shahani BT: Beta-adrenergic 

mechanisms in action tremor. N Engl J Med 

293:950, 1975. 

119. Frishman WH, Razin A, Swencionis C, Sonnenblick 

EH: Beta-adrenoceptor blockade in anxiety 

states: a new approach to therapy. Update. Cardiovasc 

Rev Rep (Classics of the Decade Series) 

13(2):8, 1992. 

120. Ingbar SH: The role of antiadrenergic agents in the 

management of thyrotoxicosis. Cardiovasc Rev Rep 

2:683, 1981. 

121. Caro JF, Castro JH, Glennon JA: Effect of longterm 

propranolol administration on parathyroid 

hormone and calcium concentration in primary 

hyperparathyroidism. Ann Intern Med 91:740, 

1979. 

122. Lebrec D, Poynard T, Hillon P, Benhamou J-P: Propranolol 

for prevention of recurrent gastrointestinal 

bleeding in patients with cirrhosis. N Engl J 

Med 305:1371, 1981. 

123. Herndon DN, Hart DW, Wolf SE, et al: Reversal of 

catabolism by beta-blockade after severe burns. N 

Engl J Med 345:1223, 2001. 

124. SHEP Cooperative Research Group: Prevention of 

stroke by antihypertensive drug treatment in older 

persons with isolated systolic hypertension: final 

results of Systolic Hypertension in the Elderly Program 

(SHEP). JAMA 265:3255, 1991. 

125. Kostis JB, Berge KG, Davis BR, et al: Effect of atenolol 

and resperine on selected events in the Systolic 

Hypertension in the Elderly Program (SHEP). Am 

J Hypertens 8:1147, 1995. 

126. Dahlof B, Lindholm LH, Hansson L, et al: Morbidity 

and mortality in the Swedish Trial in Old Patients 

with Hypertension (STOP Hypertension). 

JAMA 289: 2560,2003. 

127. The Seventh Report of the Joint National Com- 


mittee on Detection, Evaluation and Treatment of 

High Blood Pressure (JNC 7 report). Arch Intern 

Med 153:154, 1993. 

128. Messerli FH, Grossman E, Goldbourt U: Are b 

blockers eff\hskip.1pticacious as first-line therapy 

for hypertension in the elderly? JAMA 279:1903, 

1998. 

129. Cutler JA, Davis BR: Should b blockers and diuretics 

remain as first-line therapy for hypertension? 

Circulation 117: 2691,2008. 

130. Lindholm LH, Carlberg B, Samuelsson O: Should b 

blockers remain first choice in the treatment of primary 

hypertension? A meta-analysis. Lancet 366: 

1545, 2005. 

131. Lindholm LH, Ibsen H, Devereux RB, et al: Cardiovascular 

morbidity and mortality in patients 

with diabetes in the Losartan Intervention for Endpoint 

reduction in hypertension study (LIFE), a 

randomised trial against atenolol. Lancet 359:1004, 

2002. 

132. Gress TW, Nieto J, Shahar E, et al for the Atherosclerosis 

Risk in Communities Study: Hypertension 

and anti-hypertensive therapy as risk factors 

for type 2 diabetes mellitus. N Engl J Med 342: 

905,2000. 

133. Sowers JR, Bakris GL: Antihypertensive therapy 

and the risk of type 2 diabetes mellitus (editorial). 

N Engl J Med 342: 969,2000. 

134. Sarafidis P, Bogojevic Z, Basta E, et al: Comparative 

efficacy of two different b blockers on 24hour 

blood pressure control. J Clin Hypertens 10: 

112,2008. 

135. Bakris GL, Fonseca V, Katholi RE, et al for the 

GEMINI Investigators: Metabolic effects of carvedilol 

vs metoprolol in patients with type 2 diabetes 

mellitus and hypertension: a randomized 

controlled trial. JAMA 292: 2227,2004. 

136. Ram CVS: b blockers in hypertension: truths 

and half-truths (editorial). J Clin Hypertens 10: 

516,2008. 

137. Weber MA, Bakris GL, Giles TD, Messerli FH: b 

blockers in the treatment of hypertension: new 

data, new directions. J Clin Hypertens 10: 234,2008. 

138. Chrysant SG, Chrysant GS, Dimas B: Current and 

future status of beta blockers in the treatment of 

hypertension. Clin Cardiol 31: 249,2008. 

139. Saunders E, Weir MR, Kong BW, et al: A comparison 

of the efficacy and safety of a b-blocker, a calcium 

channel blocker, and a converting enzyme 

inhibitor in hypertensive blacks. Arch Intern Med 

150:1707, 1990. 

139a. Frohlich ED: Hyperdynamic Circulation and hypertension. 

Postgrad Med 52:68-74, 1972. 

140. Blumenfeld ID, Sealey JE, Manner SJ, et al: b-


Adrenergic receptor blockade as a therapeutic 

approach for suppressing the renin-angiotensinaldosterone 

system in normotensive and hypertensive 

subjects. Am J Hypertens 12:451, 1999. 

141. Myers MG, Lewis PJ, Reid JL, Dollery CT: Brain 

concentration of propranolol in relation to hypotension 

effects in the rabbit with observations on 

brain propranolol levels in man. J Pharmacol Exp 

Ther 192:327, 1975. 

142. Prichard BNC: Propranolol as an antihypertensive 

agent. Am Heart J 79:128-133, 1979. 

143. Imhof PR: Characterization of beta-blockers as 

antihypertensive agents in the light of human 

pharmacology studies, In: Schweizer W, ed. Beta- 

Blockers—Present Status and Future Prospects. 

Bern: Huber, l974:40-50. 

144. Langer SZ: Presynaptic receptors and their role in 

the regulation of transmitter release. Br J Pharmacol 

60:481, 1977. 

145. Berthelsen S, Pettinger WA: A functional basis for 

classification of b-adrenergic receptors. Life Sci 

2l:595, 1977. 

146. Yamaguchi N, de Champlain J, Nadeau RL: Regulation 

of norepinephrine release from cardiac sympathetic 

fibers in the dog by presynaptic a- and 

b-receptors. Circ Res 41:108, 1976. 

147. Stjarne L, Brundin J: b-Adrenoceptors facilitate 

noradrenaline secretion from human vasoconstrictor 

nerves. Acta Physiol Scand 97:88, 1976. 

148. Majewski HJ, McCulloch MW, Rand MJ, Story DF: 

Adrenaline activation of prejunctional b-adrenoceptors 

in guinea pig atria. Br J Pharmacol 71:435, 

1980. 

149. Savolainen A, Keto P, Poutanen V-P, et al: Effects of 

angiotensin converting enzyme inhibition versus 

b-adrenergic blockade on aortic stiffness in essential 

hypertension. J Cardiovasc Pharmacol 27:99, 

1996. 

150. Waal HJ: Hypotensive action of propranolol. Clin 

Pharmacol Ther 7:588-598, 1966. 

151. Rahn KH, Hawlina A, Kersting F, Peanz G: Studies 

on the antihypertensive action of the optical 

isomers of propranolol in man. Naunyn Schmiedebergs 

Arch Pharmacol 286:319-, 1974. 

152. Pickering TG, Gribbin B, Petersen ES, et al: Effects 

of autonomic blockade on the baroreflex in man at 

rest and during exercise. Circ Res 30:177, 1972. 

153. Kato N, Sugiyama T, Morita H, et al: Association 

analysis of beta 2 -adrenergic receptor polymorphisms 

with hypertension in Japanese. Hypertension 

37:286, 2001. 

154. Bray MS, Krushkal J, Li L, et al: Positional genomic 

analysis identifies the beta 2 -adrenergic receptor 

gene as a susceptibility locus for human hyperten- 

sion. Circulation 101:2877, 2000. 

155. Bengtsson K, Melander O, Orho-Melander M, et 

al: Polymorphism in the beta 1 -adrenergic receptor 

gene and hypertension. Circulation 104:187, 2001. 

156. Jia H, Hingorani AD, Sharma P, et al: Association 

of the G s α gene with essential hypertension and response 

to b blockade. Hypertension 34:8, 1999. 

157. Sonnenblick EH, Ross J Jr, Braunwald E: Oxygen 

consumption of the heart: newer concepts of its 

multifactorial determination. Am J Cardiol 22:328- 

336, 1968. 

158. Sonnenblick EH, Skelton CL: Myocardial energetics: 

basic principles and clinical implications. N 

Engl J Med 285:668-675, 1971. 

159. Black JW, Stephenson JS: Pharmacology of a new 

adrenergic beta-receptor blocking compound 

(Nethalide). Lancet 2:311-314, 1962. 

160. Frishman WH: Beta-adrenergic blockade in the 

treatment of coronary artery disease. In: Hurst JW, 

ed. Clinical Essays on the Heart, Vol 2. New York: 

McGraw-Hill, l983:25. 

161. Billinger M, Seiler C, Fleisch M, et al: Do betaadrenergic 

blocking agents increase coronary flow 

reserve? J Am Coll Cardiol 38:1866, 2001. 

162. Frishman WH, Gabor R, Pepine C, Cavusoglu E: 

Heart rate reduction in the treatment of chronic 

stable angina pectoris: experience with a sinus 

node inhibitor. Am Heart J 131:204, 1996. 

163. Brouwer J, Viersma JW, van Veldhuisen DJ, et al: 

Usefulness of heart rate variability in predicting 

drug efficacy (metoprolol vs diltiazem) in patients 

with stable angina pectoris. Am J Cardiol 76:759, 

1995. 

164. Ardissino D, Savonitto S, Egstrup K, et al: Selection 

of medical treatment in stable angina pectoris: 

results of the International Multicenter Angina Exercise 

(IMAGE) study. J Am Coll Cardiol 25:1516, 

1995. 

165. Frishman W, Pepine CJ, Weiss R, Baiker WM for 

the Zatebradine Study Group: Addition of zatebradine, 

a direct sinus node inhibitor, provides no 

greater exercise tolerance benef\hskip.1ptit in patients 

with angina pectoris taking extended-release 

nifedipine: results of a multicenter, randomized, 

double-blind, placebo-controlled, parallel group 

study. J Am Coll Cardiol 26:305, 1995. 

166. Parratt JR, Grayson J: Myocardial vascular reactivity 

after b-adrenergic blockade. Lancet 1:338-340, 

1966. 

167. Becker LC, Fortuin NJ, Pitt B: Effects of ischemia 

and anti-anginal drugs on the distribution of radioactive 

microspheres in the canine left ventricle. 

Circ Res 28:263-269, 1971. 

168. Wolfson S, Gorlin R: Cardiovascular pharmacolo-

gy of propranolol in man. Circulation 40:501, 1969. 

169. Barrett AM: A comparison of the effect of (+) propranolol 

and (+) propranolol in anesthetized dogs: 

b-receptor blocking and hemodynamic action. J 

Pharm Pharmacol 21:241, 1969. 

170. Bjorntorp P: Treatment of angina pectoris with beta-adrenergic 

blockade: mode of action. Acta Med 

Scand 184:259, 1968. 

171. Fihn SD, Williams SV, Daley J, Gibbons RJ: Guidelines 

for the management of patients with chronic 

stable angina: treatment. Ann Intern Med 135:616, 

2001. 

172. Haim M, Shotan A, Boyko V, et al for the Bezafibrate 

Infarction Prevention (BIP) Study Group: 

effect of beta blocker therapy in patients with coronary 

artery disease in New York Heart Association 

classes II and III. Am J Cardiol 81:1455, 1998. 

173. Heidenreich PA, McDonald KM, Hastie T, et al: 

Meta-analysis of trials comparing b blockers, calcium 

antagonists, and nitrates for stable angina. 

JAMA 281:1927, 1999. 

174. Marie PY, Danchin N, Branly F, et al: Effects of 

medical therapy on outcome assessment using 

exercise thallium-201 single photon emission 

computer tomography imaging. Evidence from a 

protective effect of beta-blocking antianginal medications. 

J Am Coll Cardiol 34:113, 1999. 

175. Task Force of the European Society of Cardiology: 

management of stable angina pectoris. Recommendations 

of the Task Force of the European Society 

of Cardiology. Eur Heart J 18:394, 1997. 

176. Gibbons RJ, Chatterjee K, Daley J, et al: ACC/ 

AHA/ACP-ASIM guidelines for the management 

of patients with chronic stable angina: Executive 

summary and recommendations. A report of 

the American College of Cardiology/American 

Heart Association Task Force on Practice Guidelines 

(Committee on Management of Patients with 

Chronic Stable Angina). Circulation 99:2829, 1999. 

177. Frishman WH, Smithen C, Befler B, et al: Non-invasive 

assessment of clinical response to oral propranolol. 

Am J Cardiol 35:635, 1975. 

178. Gauri AJ, Raxwal VK, Roux L, et al: Effects of chronotropic 

incompetence and b blocker use on the 

exercise treadmill test in men. Am Heart J 142:136, 

2001. 

179. Robinson BF: The mode of action of beta-antagonists 

in angina pectoris. Postgrad Med J 47:4l, 1971. 

180. Packer M: Combined beta-adrenergic and calcium-entry 

blockade in angina pectoris. N Engl J 

Med 320:709, 1989. 

181. Weiner DA, Klein MD: Calcium antagonists for the 

treatment of angina pectoris. In: Weiner DA, Frishman 

WH, eds. Therapy of Angina Pectoris. New 


York: Marcel Dekker, 1986:45-204. 

182. Weiner DA: Calcium channel blockers. Med Clin 

North Am 72:83, 1988. 

183. Frishman WH, Charlap S, Farham J, et al: Combination 

propranolol and bepridil therapy in stable 

angina pectoris. Am J Cardiol 55:43C, 1985. 

184. Schwarz ER, Klues HG, vom Dahl J, et al: Functional, 

angiographic and intracoronary Doppler 

flow characteristics in symptomatic patients with 

myocardial bridging: effect of short-term intravenous 

beta-blocker medication. J Am Coll Cardiol 

27:1637, 1996. 

185. ACC/AHA 2002 Guidelines Update for the Management 

of Patients with Unstable Angina and 

Non-ST-Segment Elevation Myocardial Infarction. 

www.acc.org/clinical/guidelines/unstable.pdf 

2002. 

186. Doo Y-C, Kim D-M, Oh D-J, et al: Effect of beta 

blockers on expression of interleukin-6 and Creactive 

protein in patients with unstable angina 

pectoris. Am J Cardiol 88:422, 2001. 

186a. Rangel C, Shu RG, Lazar LD, et al: b-Blockers for 

Chest pain associated with recent cocaine use. Arch 

Intern Med 170: 874, 2010. 

187. Jenkins NP, Keevil BG, Hutchinson IV, Brooks NH: 

Beta-blockers are associated with lower C-reactive 

protein concentrations in patients with coronary 

artery disease. Am J Med 112:269, 2002. 

188. Miura D, Frishman WH, Dangman KH: Class II 

drugs. In: Dangman KH, Miura D, eds. Basic and 

Clinical Electrophysiology and Pharmacology of the 

Heart. New York: Marcel Dekker,1991:665-676. 

189. Nademanee K, Taylor R, Bailey WE, et al: Treating 

electrical storm. Sympathetic blockade versus 

advanced cardiac life support-guided therapy. Circulation 

102:742, 2000. 

190. Xu X, Zhang M, Kyker K, et al: Ischemic inactivation 

of G protein-coupled receptor kinase and 

altered desensitization of canine cardiac b-adrenergic 

receptors. Circulation 102:2535, 2000. 

191. Tisdale JE, Sun H, Zhao H, et al: Antifibrillatory 

effect of esmolol alone and in combination with lidocaine. 

J Cardiovasc Pharmacol 27:376, 1996. 

192. Cavusoglu E, Frishman WH: Sotalol: a new b-adrenergic 

blocker for ventricular arrhythmias. Prog 

Cardiovasc Dis 37:423, 1995. 

193. Anderson JL, Prystowsky EN: Sotalol: an important 

new antiarrhythmic. Am Heart J 137:388, 1999. 

194. Kühlkamp V, Mewis C, Mermi J, et al: Suppression 

of sustained ventricular tachyarrhythmias: a comparison 

of d,l-sotalol with no antiarrhythmic drug 

treatment. J Am Coll Cardiol 33:46, 1999. 

195. Pacifico A, Hohnloser SH, Williams JH, et al for the 

d,l-Sotalol Implantable Cardioverter-Defibrillator


Study Group: prevention of implantable defibrillator 

shocks by treatment with sotalol. N Engl J Med 

340:1855, 1999. 

196. Mewis C, Kühlkamp V, Mermi J, et al: Long-term 

reproducibility of electrophysiologically guided 

therapy with sotalol in patients with ventricular 

tachyarrhythmias. J Am Coll Cardiol 33:1989, 1999. 

197. Lai L-P, Lin J-L, Lien W-P, et al: Intravenous sotalol 

decreases transthoracic cardioversion energy requirement 

for chronic atrial fibrillation in humans: 

assessment of the electrophysiological effects by biatrial 

basket electrodes. J Am Coll Cardiol 35:1434, 

2000. 

198. Southworth MR, Zarembski D, Viana M, Bauman 

J: Comparison of sotalol versus quinidine for maintenance 

of normal sinus rhythm in patients with 

chronic atrial fibrillation. Am J Cardiol 83:1629, 

1999. 

199. Tse H-F, Lau C-P, Ayers GM: Incidence and modes 

of onset of early reinitiation of atrial fibrillation 

after successful internal cardioversion, and its prevention 

by intravenous sotalol. Heart 82:319, 1999. 

200. Gomes JA, Ip J, Santoni-Rugiu F, et al: Oral d,l sotalol 

reduces the incidence of postoperative atrial 

fibrillation in coronary artery bypass surgery patients: 

a randomized, double-bind, placebo-controlled 


201. Benditt DG, Williams JH, Deering TF, et al for the 

d,l Sotalol Atrial Fibrillation/Flutter Study Group: 

Maintenance of sinus rhythm with oral d,l sotalol 

therapy in patients with symptomatic atrial fibrillation 

and/or atrial flutter. Am J Cardiol 84:270, 1999. 

202. Bellandi F, Simonetti I, Leoncini M, et al: Longterm 

efficacy and safety of propafenone and sotalol 

for the maintenance of sinus rhythm after conversion 

of recurrent symptomatic atrial fibrillation. 

Am J Cardiol 88:640, 2001. 

203. Amato Vincenzo de Paola A, Horta Veloso H, for 

the SOCESP Investigators: efficacy and safety of sotalol 

versus quinidine for the maintenance of sinus 

rhythm after conversion of atrial fibrillation. Am J 

Cardiol 84:1033, 1999. 

204. Kochiadakis GE, Igoumenidis NE, Marketous ME, 

et al: Low dose amiodarone and sotalol in the treatment 

of recurrent, symptomatic atrial fibrillation: 

a comparative, placebo controlled study. Heart 

84:251, 2000. 

205. Waldo AL, Camm AJ, deRuyter H, et al for the 

SWORD Investigators: effect of d-sotalol on mortality 

in patients with left ventricular dysfunction 

after recent and remote myocardial infarction. Lancet 

348:7, 1996. 

206. Pratt CM, Camm AJ, Cooper W, et al for the 

SWORD Investigators: mortality in the Survival 

with Oral D-Sotalol (SWORD) Trial: Why did patients 

die? Am J Cardiol 81:869, 1998. 

207. Lehmann MH, Hardy S, Archibald D, MacNeil DJ: 

JTc prolongation with d,l sotalol in women versus 

men. Am J Cardiol 83:354, 1999. 

208. Chung MK, Schweikert RA, Wilkoff BL, et al: Is 

hospital admission for initiation of anti-arrhythmic 

therapy with sotalol for atrial arrhythmias 

required? Yield of in-hospital monitoring and prediction 

of risk for significant arrhythmia complications. 


209. Barbey JT, Sale ME, Woosley RL, et al: Pharmacokinetic, 

pharmacodynamic, and safety evaluation 

of an accelerated dose titration regimen of sotalol 

in healthy middle-aged subjects. Clin Pharmacol 

Ther 66:91, 1999. 

210. Kühlkamp V, Schirdewan A, Stangl K, et al: Use of 

metoprolol CR/XL to maintain sinus rhythm after 

conversion from persistent atrial fibrillation: a randomized, 

double-blind, placebo-controlled study. J 


211. Page RL: Beta blockers for atrial fibrillation: must 

we consider asymptomatic arrhythmias? J Am Coll 

Cardiol 36:147, 2000. 

212. Farshi R, Kistner D, Sarma JSM, et al: Ventricular 

rate control in chronic atrial fibrillation during daily 

activity and programmed exercise: a crossover 

open-label study of five drug regimens. J Am Coll 

Cardiol 33:304, 1999. 

213. Sager PT: Modulation of antiarrhythmic drug effects 

by beta-adrenergic sympathetic stimulation. 

Am J Cardiol 82:20I, 1998. 

214. Boutitie F, Boissel J-P, Connolly SJ, et al and the 

EMIAT and CAMIAT Investigators: Amiodarone 

interaction with b blockers. Analysis of the merged 

EMIAT (European Myocardial Infarct Amiodarone 

Trial) and CAMIAT (Canadian Amiodarone 

Myocardial Infarction Trial) databases. Circulation 

99:2268, 1999. 

215. Antz M, Cappato R, Kuck K-H: Metoprolol versus 

sotalol in the treatment of sustained ventricular 

tachycardia. J Cardiovasc Pharmacol 26:627, 1995. 

216. Pitzalia MV, Mastropasqua F, Massari F, et al: Holter-guided 

identification of premature ventricular 

contractions susceptible to suppression by b blockers. 

Am Heart J 131:508, 1996. 

217. Reiter MJ, Reiffel JA: Importance of beta blockade 

in the therapy of serious ventricular arrhythmias. 

Am J Cardiol 82:9I, 1998. 

218. Exner DV, Reiffel JA, Epstein AE, et al and the 

AVID Investigators: beta blocker use and survival 

in patients with ventricular fibrillation or symptomatic 

ventricular tachycardia: the Antiarrhythmics 

versus Implantable Defibrillators (AVID)

trial. J Am Coll Cardiol 34:325, 1999. 

219. Frishman WH, Cavusoglu E: b-Adrenergic blockers 

and their role in the therapy of arrhythmias. In: 

Podrid PJ, Kowey PR, eds. Cardiac Arrhythmias: 

Mechanisms, Diagnosis and Management. Baltimore: 

Williams & Wilkins, 1995:421-433. 

220. Ryden L, Ariniego R, Arnman K, et al: A doubleblind 

trial of metoprolol in acute myocardial infarction: 

effects on ventricular tachyarrhythmias. 

N Engl J Med 308:614-618, 1983. 

221. Lichstein E, Morganroth J, Harrist R, et al for the 

BHAT Study Group: Effect of propranolol on ventricular 

arrhythmia—the Beta Blocker Heart Attack 

Trial Experience. Circulation 67:I5, 1983. 

222. Szabo BM, Crijn HJGM, Wiesfeld ACP, et al: Predictors 

of mortality in patients with sustained ventricular 

tachycardias or ventricular fibrillation and 

depressed left ventricular function: importance of 

b blockade. Am Heart J 130:281, 1995. 

223. Mason JW for the Electrophysiologic Study Versus 

Electrocardiographic Monitoring (ESVEM): a 

comparison of seven antiarrhythmic drugs in patients 

with ventricular tachyarrhythmias. N Engl J 

Med 329:452, 1993. 

224. Kennedy HL, Brooks MM, Barker AH, et al: Beta 

blocker therapy in the Cardiac Arrhythmia Suppression 

Trial. Am J Cardiol 74:674, 1994. 

225. Steinbeck G, Andresen D, Bach P, et al: A comparison 

of electrophysiologically guided antiarrhythmic 

drug therapy with beta blocker therapy in 

patients with symptomatic, sustained ventricular 

tachyarrhythmias. N Engl J Med 327:987, 1992. 

226. Chiale PA, Rosenbaum MB, Elizari MV, et al: High 

prevalence of antibodies against beta 1 - and beta 2 - 

adrenoceptors in patients with primary electrical 

cardiac abnormalities. J Am Coll Cardiol 26:864, 

1995. 

227. Iwata M, Yoshikawa T, Baba A, et al: Autoantibodies 

against the second extracellular loop of 

beta 1 -adrenergic receptors predict ventricular 

tachycardia and sudden death in patients with idiopathic 

dilated cardiomyopathy. J Am Coll Cardiol 

37:418, 2001. 

228. Braunwald E, Muller JE, Kloner RA, Maroko P: 

Role of beta-adrenergic blockade in the therapy 

of patients with myocardial infarction. Am J Med 

74:113-123, 1983. 

229. Abrams J, Frishman W, Weitz J, Opie L: Pharmacologic 

options for treatment of ischemic disease. 

In: Antman E, ed. Cardiovascular Therapeutics. A 

Companion to Braunwald’s Heart Disease, 2nd ed. 

Philadelphia: Saunders, 2002:97. 

230. Boissel-J-P, Leizorovicz A, Picolet H, et al for the 

APSI Investigators: secondary prevention after 


high risk myocardial infarction with low-dose acebutolol. 

Am J Cardiol 66:251, 1990. 

231. Parks KC, Forman DE, Wei JY: Utility of betablockade 

treatment for older postinfarction patients. 

J Am Geriatr Soc 43:751, 1995. 

232. Freemantle N, Cleland J, Young P, et al: b blockade 

after myocardial infarction: systematic review and 

meta regression analysis. BMJ 318:1730, 1999. 

233. Furberg CD, Hawkins CM, Lichstein E: Effect of 

propranolol in post-infarction patients with mechanical 

or electrical complications. Circulation 

69:761, 1984. 

234. Frishman WH: Role of b-adrenergic blockade. In: 

Fuster V, Ross R, Topol EJ, eds. Atherosclerosis and 

Coronary Artery Disease. New York: Lippincott, 

1996:1205. 

235. Frishman WH: Secondary prevention of myocardial 

infarction: the roles of b-adrenergic blockers, 

calcium-channel blockers, angiotensin converting 

enzyme inhibitors, and aspirin. In: Willich SN, 

Muller JE, eds. Triggering of Acute Coronary Syndromes. 

The Netherlands: Kluwer, 1996:367. 

236. Frishman WH, Skolnick AE, Miller KP: Secondary 

prevention post infarction: The role of betaadrenergic 

blockers, calcium-channel blockers, 

and aspirin. In: Gersh B, Rahimtoola S, eds. Acute 

Myocardial Infarction, 2nd ed. New York: Chapman 

& Hall, 1996: 766. 

237. Kendall MJ, Lynch KP, Hjalmarson A, Kjekshus J: 

b-Blockers and sudden cardiac death. Ann Intern 

Med 123:358, 1995. 

238. Tuininga YS, Crijns HJGM, Brouwer J, et al: Evaluation 

of importance of central effects of atenolol 

and metoprolol measured by heart rate variability 

during mental performance tasks, physical exercise, 

and daily life in stable postinfarct patients. 


239. Gottlieb SS, McCarter RJ: Comparative effects of 

three beta blockers (atenolol, metoprolol, and propranolol) 

on survival after acute myocardial infarction. 

Am J Cardiol 87:823, 2001. 

240. b Blockers are best antiarrhythmics for reducing 

post-MI mortality. Drugs Ther Perspect 17:5, 2001. 

241. Frishman WH, Lazar EJ: Reduction of mortality, 

sudden death and non-fatal reinfarction with beta-adrenergic 

blockers in survivors of acute myocardial 

infarction: a new hypothesis regarding the 

cardioprotective action of beta-adrenergic blockade. 

Am J Cardiol 66:66G, 1990. 

242. Williams MJA, Low CJS, Wilkins GT, Stewart 

RAH: Randomised comparison of the effects of 

nicardipine and esmolol on coronary artery wall 

stress: implications for the risk of plaque rupture. 

Heart 84:377, 2000.


243. Dargie HJ: Effect of carvedilol on outcome after 

myocardial infarction in patients with left ventricular 

dysfunction: the CAPRICORN randomized 

trial. Lancet 357: 1385,2001. 

244. Coreg CR (carvedilol phosphate) extended release 

capsules (package insert). Research Triangle Park, 

NC: GlaxoSmithKlein, 2007. 

245. International Collaborative Study Group: Reduction 

of infarct size with the early use of timolol in 

acute myocardial infarction. N Engl J Med 310:9- 

15, 1984. 

246. Hjalmarson A, Elmfeldt D, Herlitz J, et al: Effect 

of mortality of metoprolol in acute myocardial infarction. 

A double-blind randomised trial. Lancet 

2:823-827, 1981. 

247. MIAMI Trial Research Group: Metoprolol in acute 

myocardial infarction (MIAMI): a randomized 

placebo-controlled international trial. Eur Heart J 

6:199-226, 1985. 

248. ISIS-I collaborative Group: Randomized trial of 

intravenous atenolol among 16,027 cases of suspected 

acute myocardial infarction: ISIS-I. Lancet 

2: 57, 1986. 

249. Muller J, Roberts R, Stone P, et al: Failure of propranolol 

administration to limit infarct size in 

patients with acute myocardial infarction (abstr). 

Circulation 68 (Suppl. III):III294, 1983. 

250. Barron HV, Rundle AC, Gore JM, et al for the Participants 

in the National Registry of Myocardial 

Infarction-2. Intracranial hemorrhage rates and effect 

of immediate beta-blocker use in patients with 

acute myocardial infarction treated with tissue 

plasminogen activators. Am J Cardiol 85:294, 2000. 

251. Pfisterer M, Cox JL, Granger CB, et al for the 

GUSTO-I Investigators: atenolol use and clinical 

outcomes after thrombolysis for acute myocardial 

infarction: the GUSTO-I experience. J Am Coll 

Cardiol 32:634, 1998. 

252. Phillips BG, Yim JM, Brown EJ Jr, et al: Pharmacologic 

profile of survivors of acute myocardial 

infarction at United States academic hospitals. Am 

Heart J 131:872, 1996. 

253. Ayanian JZ, Hauptman PJ, Guadagnoli E, et al: 

Knowledge and practices of generalist and specialist 

physicians regarding drug therapy for acute 

myocardial infarction. N Engl J Med 331:1136, 

1994. 

254. Soumerai SB, McLaughlin TJ, Spiegelman D, et al: 

Adverse outcomes of underuse of beta blockers in 

elderly survivors of acute myocardial infarction. 

JAMA 277:115, 1997. 

255. Grand DA, Newcomer LN, Frieburger A, Tian H: 

Cardiologist’s practice compared with practice 

guidelines: use of beta blockade after acute myo- 

cardial infarction. J Am Coll Cardiol 26:1432, 1995. 

256. Phillips KA, Shlipak MG, Coxson P, et al: Health 

and economic benefits of increased b blocker use 

following myocardial infarction. JAMA 284:2748, 

2000. 

257. Chen J, Radford MJ, Wang Y, et al: Effectiveness of 

beta blocker therapy after acute myocardial infarction 

in elderly patients with chronic obstructive 

pulmonary disease or asthma. J Am Coll Cardiol 

37:1950, 2001. 

258. Aronow WS, Ahn C: Effect of beta blockers on incidence 

of new coronary events in older persons 

with prior myocardial infarction and diabetes mellitus. 

Am J Cardiol 87:780, 2001. 

259. Rochon PA, Tu JV, Anderson GM, et al: Rate of 

heart failure and 1-year survival for older people 

receiving low-dose b blocker therapy after myocardial 

infarction. Lancet 356:639, 2000. 

260. Barron HV, Viskin S: Dispelling the myths surrounding 

the use of beta blockers in patients after 

acute myocardial infarction. Prev Cardiol 3:13, 

1998. 

261. Krumholz HM, Radford MJ, Wang Y, et al: National 

use and effectiveness of b blockers for the 

treatment of elderly patients after acute myocardial 

infarction. National Cooperative Cardiovascular 

Project. JAMA 280:623, 1998. 

262. Krumholz HM, Radford MJ, Wang Y, et al: Early b 

blocker therapy for acute myocardial infarction in 

elderly patients. Ann Intern Med 131:648, 1999. 

263. Chen J, Marciniak TA, Radford MJ, et al: Beta 

blocker therapy for secondary prevention of myocardial 

infarction in elderly diabetic patients. J Am 

Coll Cardiol 34:1388, 1999. 

264. Gottlieb SS, McCarter RJ, Vogel RA: Effect of beta 

blockade on mortality among high-risk and lowrisk 

patients after myocardial infarction. N Engl J 

Med 339:489, 1998. 

265. Heller DA, Ahern FM, Kozak M: Changes in rates 

of b blocker use between 1994 and 1997 among elderly 

survivors of acute myocardial infarction. Am 

Heart J 140:663, 2000. 

266. Chen J, Radford MJ, Wang Y, et al: Are b blockers 

effective in elderly patients who undergo coronary 

revascularization after acute myocardial infarction? 


267. The CAPRICORN Investigators: Effect of carvedilol 

on outcome after myocardial infarction in 

patients with left ventricular dysfunction: the 

CAPRICORN randomised trial. Lancet 357:1385, 

2001. 

268. Bradley EH, Holmboe ES, Matterna JA, et al: A 

qualitative study of increasing b blocker use after 

myocardial infarction. Why do some hospitals suc-

ceed? JAMA 285:2604, 2001. 

269. Soumerai SB, McLaughlin TJ, Gurwitz JH, et al: Effect 

of local medical opinion leaders on quality of 

care for acute myocardial infarction: a randomized 

controlled trial. JAMA 279:1358, 1998. 

270. Sarasin FP, Maschiangelo M-L, Schaller M-D, et 

al: Successful implementation of guidelines for encouraging 

the use of beta blockers in patients after 

acute myocardial infarction. Am J Med 106:499, 

1999. 

271. Barron HV, Viskin S, Lumdstrom RJ, et al: b 

Blocker dosages and mortality after myocardial 

infarction. Data from a large health maintenance 

organization. Arch Intern Med 158:449, 1998. 

272. Gardtman M, Dellborg M, Brunnhage C, et al: 

Effect of intravenous metoprolol before hospital 

admission on Chest pain in suspected acute myocardial 

infarction. Am Heart J 137:821, 1999. 

273. Frishman WH, Teicher M: Antianginal drug therapy 

for silent myocardial ischemia. Med Clin North 

Am 72:185-196, 1988. 

274. Andrews TC, Fenton T, Toyosaki N, et al for the 

Angina and Silent Ischemia Study Group (ASIS): 

subsets of ambulatory myocardial ischemia based 

on heart rate activity. Circadian distribution and 

response to anti-ischemic medication. Circulation 

88:92, 1993. 

275. Rogers WJ, Bourassa MG, Andrews TC, et al: Asymptomatic 

Cardiac Ischemia Pilot (ACIP) Study: 

Outcome at 1 year for patients with asymptomatic 

cardiac ischemia randomized to medical therapy or 

revascularization. J Am Coll Cardiol 26:594, 1995 

276. Pepine CJ, Cohn PF, Deedwania PC, et al for the 

ASIST (Atenolol/ Silent Ischemia Study) Study 

Group: effects of treatment on outcome in mildly 

symptomatic patients with ischemia during daily 

life. Circulation 90:762, 1994. 

277. Portegies MCM, Sijbring P, Gobel EJA, et al: Efficacy 

of metoprolol and diltiazem in treating silent 

myocardial ischemia. Am J Cardiol 74:1095, 1994. 

278. von Arnim T for the TIBBS Investigators: prognostic 

significance of transient ischemic episodes: 

response to treatment shows improves prognosis. J 


279. Madjlessi-Simon T, Mary-Krause M, Fillette F, et 

al: Persistent transient myocardial ischemia despite 

beta-adrenergic blockade predicts a higher risk of 

adverse cardiac events in patients with coronary artery 

disease. J Am Coll Cardiol 27:1586, 1996. 

280. Engelhardt S, Bohm M, Erdmann E, Lohse MJ: 

Analysis of beta-adrenergic receptor mRNA levels 

in human ventricular biopsy specimens by quantitative 

polymerase chain reactions: progressive 

reduction of beta 1 -adrenergic receptor mRNA in 


heart failure. J Am Coll Cardiol 27:146, 1996. 

281. De Mello WC: Impaired regulation of cell communication 

by b-adrenergic receptor activation in the 

failing heart. Hypertension 27:265, 1996. 

282. Wu J-R, Chang H-R, Huang T-Y, et al: Reduction 

in lymphocyte b-adrenergic density in infants and 

children with heart failure secondary to congenital 

heart failure. Am J Cardiol 22:120, 1996. 

283. Akhter SA, Eckhart AD, Rockman HA, et al: In 

vivo inhibition of elevated myocardial b-adrenergic 

receptor kinase activity in hybrid transgenic 

mice restores normal b-adrenergic signaling and 

function. Circulation 100:648, 1999. 

284. Cho M-C, Rao M, Koch WJ, et al: Enhanced contractility 

and decreased b-adrenergic receptor 

kinase-1 in mice lacking endogenous norepinephrine 

and epinephrine. Circulation 99:2702, 1999. 

285. Moniotte S, Kobzik L, Feron O, et al: Upregulation 

of beta 3 adrenoceptors and altered contractile response 

to inotropic amines in human failing myocardium. 

Circulation 103:1649, 2001. 

286. Sackner-Bernstein JD, Mancini DM: Rationale for 

treatment of patients with chronic heart failure 

with adrenergic blockade. JAMA 274:1462, 1995. 

287. LeJemtel TH, Sonnenblick EH, Frishman WH: Diagnosis 

and management of heart failure. In: Fuster 

V, Alexander RW, O’Rourke RA, eds. Hurst’s The 

Heart, 10th ed. New York: McGraw-Hill, 2000:687. 

288. White DC, Hata JA, Shah AS, et al: Preservation of 

myocardial b-adrenergic receptor signaling delays 

the development of heart failure after myocardial 

infarction. Proc Natl Acad Sci USA 97:5428, 2000. 

289. Manning BS, Shotwell K, Mao L, et al: Physiological 

induction of a b-adrenergic receptor kinase 

inhibitor transgene preserves b-adrenergic responsiveness 

in pressure-overload cardiac hypertrophy. 

Circulation 102:2751, 2000. 

290. Shad AS, White DC, Emani S, et al: In vivo ventricular 

gene delivery of a b-adrenergic receptor 

kinase inhibitor to the failing heart reverses cardiac 

dysfunction. Circulation 103:1311, 2001. 

291. Podlowski S, Luther HP, Morwinski R, et al: Agonistic 

anti-beta 1 -adrenergic receptor autoantibodies 

from cardiomyopathy patients reduces the 

beta 1 -adrenergic receptor expression in neonatal 

rat cardiomyocytes. Circulation 98:2470, 1998. 

292. Francis GS, Goldsmith SR, Cohn JN: Relationship 

of exercise capacity to resting left ventricular performance 

and basal plasma norepinephrine levels 

in patients with congestive heart failure. Am Heart 

J 104:725, 1982. 

293. Viquerat CE, Daly P, Swedberg K, et al: Endogenous 

catecholamine levels in congestive heart 

failure: relation to severity of hemodynamic abnor-


mality. Am J Med 78:455, 1985. 

294. Stanek B, Frey B, Hulsmann M, et al: Prognostic 

evaluation of neurohumoral plasma levels before 

and during beta blocker therapy in advanced left 

ventricular dysfunction. J Am Coll Cardiol 38:436, 

2001. 

295. Frishman WH: Multifactorial actions of b-adrenergic 

blocking drugs in ischemic heart disease. Circulation 

67(Suppl I):I-11, 1983. 

296. Daley PA, Sole MJ: Myocardial catecholamines and 

the pathophysiology of heart failure. Circulation 

82(Suppl I):I-35, 1990. 

297. Henderson EB, Kahn JK, Corbett JR, et al: Abnormal 

I123 metaiodobenzylguanidine myocardial 

washout and distribution may reflect myocardial 

adrenergic derangement in patients with congestive 

heart failure. Circulation 78:1192, 1988. 

298. Cruikshank JM, Neil-Dwyer G, Degaute JP, et al: 

Reduction of stress/catecholamine induced cardiac 

necrosis by beta I-selective blockade. Lancet 2:585, 

1987. 

299. Pauletto P, Vescove G, Scannapieco G, et al: Cardioprotection 

by beta blockers: molecular and 

structural aspects in experimental hypertension. 

Drugs Exp Clin Res 16(3):1055, 1990. 

300. Shizukuda Y, Buttrick PM, Geenen DL, et al: b- 

Adrenergic stimulation causes cardiocyte apoptosis: 

influence of tachycardia and hypertrophy. Am J 

Physiol 275:H961, 1998. 

301. Iwai-Kanai E, Hasegawa K, Araki M, et al: a- and 

b-adrenergic pathways differentially regulate cell 

type-specific apoptosis in rat cardiac myocytes. 


302. Podrid PJ, Fuchs T, Candinas R: Role of the sympathetic 

nervous system in the genesis of ventricular 

arrhythmias. Circulation 82 (Suppl I):I-103, 1990. 

303. Wit AL, Cranefield PF: Triggered and automatic 

activity in the canine coronary sinus. Circ Res 

41:433, 1977. 

304. Engelmeier RS, O’Connell JB, Walsh R, et al: Improvement 

in symptoms and exercise tolerance 

by metoprolol in patients with dilated cardiomyopathy: 

a double-blind, randomized, placebo-controlled 

trial. Circulation 72:536, 1985. 

305. Waagstein F, Bristow MR, Swedberg K, et al: Beneficial 

effects of metoprolol in idiopathic dilated 

cardiomyopathy. Lancet 342:1441, 1993. 

306. Olsen SL, Gilbert EM, Renlund DG, et al: Carvedilol 

improves left ventricular function and symptoms 

in chronic heart failure: a double-blind 

randomized study. J Am Coll Cardiol 25:1225, 

1995. 

307. Metra M, Nardi M, Giubbini R, Dei Cas L: Effects 

of short- and long-term carvedilol administration 

on rest and exercise hemodynamic variables, exercise 

capacity, and clinical conditions in patients 

with idiopathic dilated cardiomyopathy. J Am Coll 

Cardiol 24:1678, 1994. 

308. Krum H, Sackner-Bernstein J, Goldsmith RL, et 

al: Double-blind, placebo-controlled study of the 

long-term efficacy of carvedilol in patients with 

severe chronic heart failure. Circulation 92:1499, 

1995. 

309. Australia-New Zealand Heart Failure Research 

Collaborative Group: Effects of carvedilol, a vasodilator-b 

blocker, in patients with congestive heart 

failure due to ischemic heart disease. Circulation 

92:212, 1995. 

310. Eichhorn EJ, McGhie AA, Bendotto JB, et al: Effects 

of bucindolol on neurohormonal activation in 

congestive heart failure. Am J Cardiol 67:67, 1991. 

311. Leizorovicz A, Lechat P, Cucherat M, Bugnard F: 

Bisoproprolol for the treatment of chronic heart 

failure: a meta analysis on individual data of two 

placebo-controlled studies—CIBIS and CIBIS II. 

Am Heart J 143:301, 2002. 

312. Goldstein S: Benefits of b-blocker therapy for heart 

failure. Weighing the evidence. Arch Intern Med 

162: 641, 2002. 

313. Farrell MH, Foody JM, Krumholz HM: b-blockers 

in heart failure: clinical applications. JAMA 287: 

890, 2002. 

314. Packer M, Coats AJS, Fowler MB, et al for the 

Carvedilol Prospective Randomized Cumulative 

Survival Study Group: Effect of carvedilol on survival 

in severe chronic heart failure. N Engl J Med 

344: 1651, 2001. 

315. Packer M, Bristow MR, Cohn N, et al: Effect of 

carvedilol on morbidity and mortality in chronic 

heart failure. N Engl J Med 334:1349-1355, 1996. 

316. Joglar JA, Acusta AP, Shusterman NH, et al: Effect 

of carvedilol on survival and hemodynamics 

in patients with atrial fibrillation and left ventricular 

dysfunction: retrospective analysis of the U.S. 

Carvedilol Heart Failure Trials Program. Am Heart 

J 142:498, 2001. 

317. Fowler MB, Vera-Llonch M, Oster G, et al for the 

U.S. Carvedilol Heart Failure Study Group: influence 

of carvedilol on hospitalizations in heart failure: 

incidence, resource utilization and costs. J Am 

Coll Cardiol 37:1692, 2001. 

318. Yancy CW, Fowler MB, Colucci WS, et al for the 

U.S. Carvedilol Heart Failure Study Group: Race 

and the response to adrenergic blockade with 

carvedilol in patients with chronic heart failure. N 

Engl J Med 344:1358, 2001. 

319. Kumar A, Choudhary G, Antonio C, et al: Carvedilol 

titration in patients with congestive heart

failure receiving inotropic therapy. Am Heart J 

142:512, 2001. 

320. CIBIS-II Investigators and Committee: The Cardiac 

Insufficiency Bisoprolol Study II (CIBIS II): a 

randomized trial. Lancet 353: 9, 1999. 

321. Hjalmarson A, Goldstein S, Fagerberg B, et al: for 

the MERIT-HF Study Group: Effects of controlledrelease 

metoprolol on total mortality, hospitalizations, 

and well-being in patients with heart failure. 

The Metoprolol CR/XL Randomized Intervention 

Trial in Congestive Heart Failure (MERIT-HF). 

JAMA 283:1295, 2000. 

322. Prakash A, Markham A: Metoprolol. A review of its 

use in chronic heart failure. Drugs 60:647, 2000. 

323. Ghali JK, Piña IL, Gottlieb SS, et al: Metoprolol CR/ 

XL in female patients with heart failure. Analysis 

of the experience in Metoprolol Extended-release 

Randomized Intervention Trial in Heart Failure 

(MERIT-HF). Circulation 105:1585, 2002. 

324. Gottlieb SS, Fisher ML, Kjekshus J, et al: Tolerability 

of b-blocker initiation and titration in the 

Metoprolol CR/XL Randomized Intervention Trial 

in Congestive Heart Failure (MERIT-HF). Circulation 

105:1182, 2002. 

325. The Beta Blocker Evaluation of Survival Trial Investigators: 

a trial of the beta blocker bucindolol 

in patients with advanced chronic heart failure. N 

Engl J Med 344: 1659, 2001. 

326. Remme WJ, Torp-Pedersen C, Cleland JG, et al: 

Carvedilol protects better against vascular events 

than metoprolol in heart failure results from COM- 

ET. J Am Coll Cardiol 49: 963, 2007. 

327. Flather MD, Shibata MC, Coats AJ, et al: Randomized 

trial to determine the effects of nebivolol on 

mortality and cardiovascular hospital admissions 

in elderly patients with heart failure (SENIORS). 

Eur Heart J 26:215,2005. 

328. van Veldhuisen DJ, Cohen-Solal A, Bohm M, et 

al on behalf of the SENIORS Investigators: Beta 

blockade with nebivolol in elderly heart failure patients 

with impaired and preserved left ventricular 

ejection fraction. Data from SENIORS (Study of 

Effects of Nebivolol Intervention on Outcomes and 

Rehospitalization in Seniors with Heart Failure). J 

Am Coll Cardiol 53: 2150, 2009. 

329. Hernandez AF, Hammill BG, O’Connor CM, et al: 

Clinical effectiveness of beta blockers in heart failure. 

Findings from the OPTIMIZE-HF (Organized 

Program to Initiate Lifesaving Treatment in Hospitalized 

Patients with Heart Failure) registry. J Am 

Coll Cardiol 53: 184,2009. 

330. Gilbert EM, Sandoval A, Larrabee P, et al: Lisinopril 

lowers cardiac adrenergic drive and increases 

beta-receptor density in the failing human heart. 



331 Whyte K, Jones CR, Howie CA, et al: Haemodynamic, 

metabolic, and lymphocyte beta 2-adrenoceptor 

changes following chronic beta-adrenoceptor antagonism. 

Eur Heart J 32:237, 1987. 

332. Lowes BD, Gilbert EM, Abraham MT, et al: Myocardial 

gene expression in dilated cardiomyopathy 

treated with beta blocking agents. N Engl J Med 

346:1357, 2002. 

333. Luchner A, Burnett JC Jr, Jougasaki M, et al: Augmentation 

of the cardiac natriuretic peptides by 

beta-receptor antagonism: evidence from a population-based 


334. Floras J, Jones J, Hassan O, Sleight P: Effects of 

acute and chronic beta-adrenergic blockade on 

baroreflex sensitivity (abstr). J Am Coll Cardiol 

11:148A, 1988. 

335. Shimoyama H, Sabbah HN, Rosman H, et al: Effect 

of b blockade on left atrial contribution to ventricular 

f\hskip.1ptilling in dogs with moderate heart 

failure. Am Heart J 131:772, 1996. 

336. Kubo H, Margulies KB, Piacentino V, et al: Patients 

with end-stage congestive heart failure treated with 

b-adrenergic receptor antagonists have improved 

ventricular myocyte calcium regulatory protein 

abundance. Circulation 104:1012, 2001. 

337. Reiken S, Gaburjakova M, Gaburjakova J, et al. b- 

Adrenergic receptor blockers restore cardiac calcium 

release channel (ryanodine receptor) structure 

and function in heart failure. Circulation 104:2843, 

2001. 

338. Doi M, Yano M, Kabayashi S, et al: Propranolol 

prevents the development of heart failure by restoring 

FKBP 12.6-mediated stabilization by ryanodine 

receptor. Circulation 105:1374, 2002. 

339. Jonas M, Reicher-Reiss H, Boyko V, et al: Usefulness 

of beta blocker therapy in patients with noninsulin 

dependent diabetes mellitus and coronary 

artery disease. Am J Cardiol 27:1233, 1996. 

340. Swan DA, Bell B, Oakley CM, Goodwin J: Analysis 

of symptomatic course and prognosis and treatment 

of hypertrophic obstructive cardiomyopathy. 

Br Heart J 33:671, 1971. 

341. Hubner PJB, Ziady GM, Lane GK, et al: Doubleblind 

trial of propranolol and practolol in hypertrophic 

cardiomyopathy. Br Heart J 35:116, 1973. 

342. Epstein SE, Henry WL, Clark CE, et al: Asymmetric 

septal hypertrophy. Ann Intern Med 81:650, 

1974. 

343. Jeresaty RM: Mitral valve prolapse syndrome. Prog 


344. Slater EE, DeSanctis RW: Dissection of the aorta. 


345. Rios AS, Silber EN, Bavishi N, et al: Effect of long-


term b blockade on aortic root compliance in patients 

with Marfan syndrome. Am Heart J 137:1057, 

1999. 

346. Rossi-Foulkes R, Roman MJ, Rosen SE, et al: Phenotypic 

features and impact of beta blocker or calcium 

antagonist therapy on aortic lumen size in the 

Marfan Syndrome. Am J Cardiol 83:1364, 1999. 

346a. Ong K-T, Perdu J, DeBacker J, et al: Effect of celiprolol 

on prevention of cardiovascualr events in 

vascular Ehlers-Danlos syndrome: a prospective 

randomised, open, blinded-endpoints trial. Lancet 

376: 1476, 2010. 

347. Shimizu W, Antzelevitch C: Differential effects of 

beta-adrenergic agonists and antagonists in LQT1, 

LQT2 and LQT3 models of the long QT syndrome. 


348. Moss AJ, Zareba W, Hall WJ, et al: Effectiveness 

and limitations of b blocker therapy in congenital 

long QT syndrome. Circulation 101:616, 2000. 

349. Dorostkar PC, Eldar M, Belhassen B, Scheinman 

MM: Long-term follow-up of patients with long 

QT syndrome treated with b blockers and continuous 

pacing. Circulation 100:2431, 1999. 

350. Hedblad B, Wikstrand J, Janson L, et al: Low-dose 

metoprolol CR/XL and fluvastatin slow progression 

of carotid intima-media thickness. Main results 

from the b Blocker Cholesterol-Lowering 

Asymptomatic Plaque Study (BCAPS). Circulation 

103:1721, 2001. 

351. Sipahi I, Tuzcu EM, Wolski KE, et al: b Blockers and 

progression of coronary atherosclerosis: pooled 

analysis of 4 intravascular ultrasonography trials. 

Ann Intern Med 147: 10,2007. 

352. Magsino CH Jr, Hamouda W, Bapna V, et al: Nadolol 

inhibits reactive oxygen species generation by 

leukocytes and linoleic acid oxidation. Am J Cardiol 

86:443, 2000. 

353. The Propranolol Aneurysm Trial Investigators: 

propranolol for small abdominal aortic aneurysms: 

results of a randomized trial. J Vasc Surg 35:72, 

2002. 

354. Mahanonda N, Bhuripanyo K, Kangkagate C, et 

al: Randomized, double-blind, placebo-controlled 

trial of oral atenolol in patients with unexplained 

syncope and positive upright tilt table test results. 

Am Heart J 130:1250, 1995. 

355. Cox MM, Perlman BA, Mayor MR, et al: Acute and 

long-term beta-adrenergic blockade for patients 

with neurocardiogenic syncope. J Am Coll Cardiol 

26:1293, 1995. 

356. Iskos D, Dutton J, Scheinman MM, Lurie KG: Usefulness 

of pindolol in neurocardiogenic syncope. 

Am J Cardiol 82:1121, 1998. 

357. Madrid AH, Ortego J, Rebollo JG, et al: Lack of 

efficacy of atenolol for the prevention of neurally 

mediated syncope in a highly symptomatic population: 

a prospective, double-blind, randomized and 

placebo-controlled study. J Am Coll Cardiol 37:554, 

2001. 

358. Harte B, Jaffer AK: Perioperative beta-blockers 

in noncardiac surgery: evolution of the evidence. 

Cleveland Clinic J Med 75: 513,2008. 

359. Mangano DT, Layug EL, Wallace A, Tateo I: Effect 

of atenolol on mortality and cardiovascular morbidity 

after noncardiac surgery. Multicenter study 

of perioprative ischemia research group. N Engl J 

Med 335:1713, 1996. 

360. Poldermans D, Boersma E, Bax JJ, et al for the 

Dutch Echocardiographic Cardiac Risk Evaluation 

Applying Stress Echocardiography Study Group: 

the effect of bisoprolol on peri-operative mortality 

and myocardial infarction in high-risk patients undergoing 

vascular surgery. N Engl J Med 341:1789, 

1999. 

361. Shojania KG, Duncan BW, McDonald KM, et al: 

Making health care safer: A critical analysis of 

patient safety practices. Evid Rep Technol Assess 

(Summ) 43: 1,2003. 

362. National Quality Forum: Safe practices for better 

healthcare – 2006 update. Washington, DC: National 

Quality Forum, 2006. 

363. POISE Study Group: Effects of extended-release 

metoprolol succinate in patients undergoing noncardiac 

surgery (POISE Trial): a randomized, controlled 

trial. Lancet 371; 1839,2008. 

364. Fleisher LA, Poldermans D: Perioperative b blockade: 

where do we go from here? (commentary). 

Lancet 371: 1813,2008. 

364a. Chopra V, Eagle KA: Perioperative b-blockers for 

cardiac risk reduction. Time for clarity (commentary). 

JAMA 303: 551, 2010. 

365. Fleisher LA, Beckman JA, Buller CE, et al: 2009 

ACCF/AHA focused update on perioperative beta 

blockade. A report of the American College of Cardiology 

Foundation/American Heart Association 

Task Force on Practice Guidelines. J Am Coll Cardiol 

54: e13, 2009. 

366. Poldermans D, Bax JJ, Boersma E, et al: Guidelines 

for pre-operative cardiac risk assessment and 

peri-operative cardiac management in non-cardiac 

surgery: The Task Force for Preoperative Cardiac 

Risk Assessment and Perioperative Cardiac Management 

in Non-cardiac surgery of the European 

Society of Cardiology (ESC) and endorsed by the 

European Society of Anaesthesiology (ESA). Eur J 

Anaesthesiol 27: 92, 2010. 

367. Han JA, Frishman WH, Sun SW, et al: Cardiovascular 

and respiratory considerations with pharma-

cotherapy of glaucoma and ocular hypertension. 

Cardiol in Rev 16: 95,2008. 

368. Gluud LL, Klingenberg S, Nikolova D, Gluud C: 

Banding ligation versus beta blockers as primary 

prophylaxis in esophageal varices: systematic review 

of randomized trials. Am J Gastroenterol 102: 

2842,2007. 

369. Groszmann RJ, Garcia-Tsao G, Bosch J, et al for the 

Portal Hypertension Collaborative Group: Betablockers 

to prevent gastroesophageal varices in patients 

with cirrhosis. N Engl J Med 353: 2254, 2005. 

370. Provencher S, Herve P Jais X, et al: Deleterious 

effects of b-blockers on exercise capacity and hemodynamics 

in patients with portopulmonary hypertension. 

Gastroenterol 130:120,2006. 

370a. Rutten FH, Zuithoff NPA, Hak E, et al: b-blockers 

may reduce mortality and risk of exacerbations in 

patients with chronic obstructive pulmonary disease. 

Arch Intern Med 170: 880, 2010. 

371. Kornbluth A, Frishman WH, Ackerman B. Betaadrenergic 

blockade in children. Cardiol Clin 

5:629,1987. 

372. Schlienger RG, Kraenzlin ME, Jick SS, Meier CR: 

Use of b blockers and risk of fractures. JAMA 292: 

1326, 2004. 

372a. Ackland GL, Yao ST, Rudiger A, et al: Cardioprotection, 

attenuated systemic inflammation, and 

survival benefit of b 1 -adrenoceptor blockade in severe 

sepsis in rats. Crit Care Med 38: 388, 2010. 

373. Friedman LM: How do the various beta-blockers 

compare in type, frequency and severity of their 

adverse effects? Circulation 67(Suppl l):89, 1983. 

374. Frishman W, Silverman R, Strom J, et al: Clinical 

pharmacology of the new beta-adrenoceptor 

blocking drugs. Part IV. Adverse effects: choosing 

a b-adrenoceptor blocker. Am Heart J 98:256, 1979. 

375. Frishman WH: Beta-adrenergic receptor blockers: 

adverse effects and drug interactions. Hypertension 

11(Suppl II):1121, 1988. 

376. Frishman WH, Kostis J: The signif\hskip.1pticance 

of intrinsic sympathomimetic activity in beta-adrenoceptor 

blocking drugs: update. Cardiovasc Rev 

Rep (Classics of the Decade Series) 12(12):46, 1991. 

377. Jondeau G, Neuder Y, Eicher JC, et al for the B- 

CONVINCED Investigators: B-CONVINCED: 

Beta blocker Continuation vs interruption in patients 

with congestive heart failure hospitalized for 

a decompensation episode. Eur Heart J 30: 2186, 

2009. 

378. Frishman W, Kostis J, Strom J, et al: Clinical pharmacology 

of the new beta-adrenergic blocking 

drugs. Part VI. A comparison of pindolol and 

propranolol in treatment of patients with angina 

pectoris: the role of intrinsic sympathomimetic ac- 


tivity. Am Heart J 98:526, 1979. 

379. Giudicelli JF, Lhoste F: b-Adrenoceptor blockade 

and atrioventricular conduction in dogs: role of 

intrinsic sympathomimetic activity. Br J Clin Pharmacol 

13(Suppl 2):167, 1982. 

380. Frishman WH: Beta-adrenergic blocker withdrawal. 

Am J Cardiol 59: 26F,1987. 

381. Frishman WH, Klein N, Strom J, et al: Comparative 

effects of abrupt propranolol and verapamil withdrawal 

in angina pectoris. Am J Cardiol 50:1191, 

1982. 

382. Morimoto S-i, Shimizu K, Yamada K, et al: Can b 

blocker therapy be withdrawn from patients with 

dilated cardiomyopathy? Am Heart J 137:456, 1999. 

383. George RB, Manocha K, Burford JG, et al: Effects 

of labetalol in hypertensive patients with chronic 

obstructive pulmonary disease. Chest 83:457, 1983. 

384. Olenchock BA, Fonarow GG, Pan W, et al: Current 

use of beta blockers in patients with reactive airway 

disease who are hospitalized with acute coronary 

syndromes. Am J Cardiol 103: 295, 2009. 

385. Benson MK, Berrill WT, Cruickshank JM, et al: A 

comparison of four adrenoceptor antagonists in 

patients with asthma. Br J Clin Pharmacol 5:415, 

1978. 

386. Frohlich ED, Tarazi RC, Dustan HP: Peripheral arterial 

insufficiency: a complication of beta-adrenergic 

blocking therapy. JAMA 208:2471, 1969. 

387. Lundvall J, Jarhult J: Beta-adrenergic dilator component 

of the sympathetic vascular response in 

skeletal muscle. Acta Physiol Scand 96: 180, 1976. 

388. Simpson FO: b-Adrenergic receptor blocking 

drugs in hypertension. Drugs 7:85, 1974. 

389. Radack K, Deck C: b-Adrenergic blocker therapy 

does not worsen intermittent claudication in subjects 

with peripheral arterial disease. Arch Intern 

Med 151:1769, 1991. 

390. Thadani U, Whitsett TL: Beta-adrenergic blockers 

and intermittent claudication. Arch Intern Med 

151:1705, 1991. 

391. Hiatt WR, Stoll S, Nies A: Effect of beta-adrenergic 

blockers on the peripheral Circulation in patients 

with peripheral vascular disease. Circulation 

72:1226, 1985. 

392. Reveno WS, Rosenbaum H: Propranolol and hypoglycaemia. 

(letter to editor). Lancet 1:920, 1968. 

393. Allison SP, Chamberlain MI, Miller JE: Effects of 

propranolol on blood sugar, insulin and free fatty 

acids. Diabetologia 5:339, 1969. 

394. Sharma AM, Pischon T, Hardt S, et al: b-Adrenergic 

receptor blockers and weight gain. A systematic 

analysis. Hypertension 37:250, 2001. 

395. Deacon SP, Barnett D: Comparison of atenolol and 

propranolol during insulin-induced hypoglycae-


mia BMJ 2:272, 1976. 

396. Lloyd-Mostyn RH, Oram S: Modification by propranolol 

of cardiovascular effects of induced hypoglycaemia. 

Lancet 1:1213, 1975. 

397. Fogari R, Zoppi A, Corradi L, et al: b Blocker effects 

on plasma lipids during prolonged treatment 

of hypertensive patients with hypercholesterolemia. 


398. Dimmitt SB, Williams PD, Croft KD, Beilin LJ: Effects 

of b-blockers on the concentration and oxidizability 

of plasma lipids. Clin Sci 94:573, 1998. 

399. Perez-Stable EJ, Halliday R, Gardiner PS, et al: The 

effects of propranolol on cognitive function and 

quality of life: a randomized trial among patients 

with diastolic hypertension. Am J Med 108:359, 

2000. 

400. Jacob H, Brandt LJ, Farkas P, Frishman WH: Betaadrenergic 

blockade and the gastrointestinal system. 

Am J Med 74:1042, 1983. 

401. Stephen SA: Unwanted effects of propranolol. Am J 

Cardiol 18:463, 1966. 

402. Lydakis C, Lip GYH, Beevers M, Beevers DG: 

Atenolol and fetal growth in pregnancies complicated 

by hypertension. Am J Hypertens 12:541, 

1999. 

403. Bailey R, Neale TJ: Rapid clonidine withdrawal 

with blood pressure overshoot exaggerated by beta-blockade. 

BMJ 1:942, 1976. 

404. Agabiti-Rosei E, Brown JJ, Lever AF, et al: Treatment 

of phaeochromocytoma and clonidine 

withdrawal hypertension with labetalol. Br J Clin 

Pharmacol 3(Suppl 3):809, 1976. 

405. Wright P; Untoward effect associated with practolol 

administration: oculomucocutaneous syndrome. 

BMJ 1:595, 1975. 

406. Blaufarb I, Pfeifer TM, Frishman WH: b Blockers: 

drug interactions of clinical significance. Drug 

Safety 13(6):359, 1995. 

407. Opie LH, Frishman WH: Adverse cardiovascular 

drug interactions and complications. In: Fuster 


Heart, 10th ed. New York: McGraw-Hill, 2001:2251.


Central and Peripheral Sympatholytics 

Lawrence R. Krakoff, MD 


1. Hoffman BB: Therapy of Hypertension. In Brunton 

LL, Lazo JS, Parker KL (eds): Goodman & Gilman’s 

The Pharmacological Basis of Therapeutics, 11th ed. 

NY: McGraw-Hill, 2006: 845. 

2. Drugs for hypertension. Med Lett 43:17, 2001. 

3. Materson BJ: Central and peripheral sympatholytics. 

In: Izzo JL, Sica DA, Black HR, eds. Hypertension 

Primer, 4th ed. Dallas: American Heart 

Association 2008: 453. 

4. Frishman WH, Sinatra ST, Moizuddin M: Herbal 

approach to cardiac disease. In Frishman WH, 

Weintraub MI, Micozzi MS (ed): Complementary 

and Integrative Therapies for Cardiovascular Disease. 

St. Louis: Elsevier/Mosby 2005: 86. 

5. Chobanian AV: Shattuck Lecture. The hypertension 

paradox – more uncontrolled disease despite 

improved therapy. N Engl J Med 361: 878, 2009. 

6. Grossman E, Messerli FH, Goldbourt U: Carcinogenicity 

of antihypertensive therapy. Curr Hypertens 

Rep 4:195, 2002. 

7. Kronig B, Pittrow DB, Kirch W, et al: Different concepts 

in first-line treatment of essential hypertension. 

Comparison of a low-dose reserpine-thiazide 

combination with nitrendipine monotherapy. German 

Reserpine in Hypertension Study Group. Hypertension 

29:651, 2001. 



persons with isolated systolic hypertension: Final 

results of the Systolic Hypertension in the Elderly 

Program SHEP. JAMA 265:3255, 1991. 

9. Eland IA, van Puijenbroek EP Sturkenboom MJ, et 

al: Drug-associated acute pancreatitis: 21 years of 

spontaneous reporting in The Netherlands. Am J 

Gastroenterol 94:2417, 1999. 

10. Frishman WH, Schlocke SJ, Awad K, Tejani N: 

Pathophysiology and medical management of systemic 

hypertension in pregnancy. Cardiol in Rev 

13: 274, 2005. 

11. Hypertension Detection and Follow-up Program: 

Cooperative Group. Five-year findings of the Hypertension 

Detection and Follow-up Program: I. 

Reduction in mortality of persons with high blood 

pressure, including mild hypertension. JAMA 

242:2562, 1979. 

12. Mitchell A, Bührmann S, Opazo Saez A, et al: 

Clonidine lowers blood pressure by reducing 

vascular resistance and cardiac output in young, 

healthy males. Cardiovasc Drugs Ther 19: 5, 2005. 

13. Brahmbhatt R, Baggaley P, Hockings B: Normalization 

of blood pressure in a patient with severe 

orthostatic hypotension and supine hypertension 

using clonidine. Hypertension 37:E24, 2001. 

14. Frye CB, Vance MA: Hypertensive crisis and myocardial 

infarction following massive clonidine 

overdose. Ann Pharmacother 34:611, 2000. 

15. Bravo EL, Tarazi RC, Fouad FM, et al: Clonidinesuppression 

test: A useful aid in the diagnosis of 

pheochromocytoma. N Engl J Med 305:623, 1981. 

16. Hui TP, Krakoff LR, Felton K, Yeager K: Diuretic 

treatment alters clonidine suppression of plasma 

norepinephrine. Hypertension 8:272, 1986. 

17. Bravo EL, Gifford RW Jr: Pheochromocytoma: 

Diagnosis, localization and management. N Engl J 

Med 311:1298, 1984. 

18. Grossman E, Goldstein DS, Hoffman A, Keiser HR: 

Glucogan and clonidine testing in the diagnosis of 

pheochromocytoma. Hypertension 17:733, 1991. 

19. Manelli M, Ianni L, Cilotti A, Conti A: Pheochromocytoma 

in Italy: A multicentric retrospective 

study. Eur J Endocrinol 141:619, 2001. 

20. Makino Y, Kawano Y, Okuda N, et al: Autonomic 



6-1


function in hypertensive patients with neurovascular 

compression of the ventrolateral medulla oblongata. 

J Hypertens 17:1257, 2001. 

21. Roche WJ, Nwofia C, Gittler M, et al: Catecholamine-induced 

hypertension in lumbosacral paraplegia: 

Five case reports. Arch Phys Med Rehabil 

81:222, 2000. 

21a. Guanfacine extended-release (Intuniv) for ADHD. 

Med Ltr 52: 82, 2010. 


therapy for hypertension in men: A comparison 

of six antihypertensive agents with placebo. N 

Engl J Med 328:914, 1993. 

23. Materson BJ, Reda DJ, Cushman WC, Henderson 

WG: Results of combination anti-hypertensive 

therapy after failure of each of the components. 

Department of Veterans Affairs Cooperative Study 

Group on Anti-hypertensive Agents. J Hum Hypertens 

9:791, 1995. 

24. Mansoor GA, Frishman WH: Comprehensive 

management of hypertensive emergencies and urgencies. 

Heart Dis 4: 358, 2002. 

25. Dziedzic SW, Elijovich F, Felton K, et al: Effect of 

guanabenz on blood pressure responses to posture 

and exercise. Clin Pharm Ther 33:151, 1983. 

26. Danchin N, Genton P, Atlas P, et al: Comparative 

effects of atenolol and clonidine on polygraphically 

recorded sleep in hypertensive men: A randomized, 

double-blind, crossover study. Int J Clin Pharmacol 

Ther 33:52, 1995. 

27. Issa FG: Effect of clonidine in obstructive sleep apnea. 

Am Rev Respir Dis 145:435, 1992. 

28. Robege JR, Kimball ET, Warren J: Clonidine and 

sleep apnea syndrome interaction: Antagonism 

with yohimbine. J Emerg Med 16:727, 2001. 

29. White WB, Gilbert JC: Transdermal clonidine in a 

patient with resistant hypertension and malabsorption. 

N Engl J Med 313: 1418, 1985. 

30. Murphy M, Carmichael AJ: Transdermal drug delivery 

systems and skin sensitivity reactions. Incidence 

and management. Am J Clin Dermatol 1:361, 

2000. 

31. Manolis AJ, Olympios C, Sifaki M, et al: Combined 

sympathetic suppression and angiotensin-converting 

enzyme inhibition in congestive heart failure. 

Hypertension 29:525, 2001. 

32. Manolis AJ, Olympios C, Sifaki M, et al: Suppressing 

sympathetic activation in congestive heart 

failure: A new therapeutic strategy. Hypertension 

26:719, 1995. 

33. Azevedo ER, Newton GE, Parker JD: Cardiac and 

systemic sympathetic activity in response to clonidine 

in human heart failure. J Am Coll Cardiol 

33:186, 1999. 

34. Grassi G, Turri C, Seravalle G, et al: Effects of 

chronic clonidine administration on sympathetic 

nerve traffic and baroreflex function in heart failure. 


35. Gavras I, Manolis AJ, Gavras H: The alpha 2 -adrenergic 

receptors in hypertension and heart failure: 

Experimental and clinical studies. J Hypertens 

19:2115, 2001. 

36. Aggarwal A, Esler MD, Socratous F, Kaye DM: Evidence 

for functional presynaptic alpha-2 adrenoceptors 

and their down-regulation in human heart 

failure. J Am Coll Cardiol 37:1246, 2001. 

37. Simpson CS, Ghali WA, Sanfilippo AJ, et al: Clinical 

assessment of clonidine in the treatment of 

new-onset rapid atrial fibrillation: A prospective, 

randomized clinical trial. Am Heart J 142:300, 

2001. 

38. Ernsberger P, Haxhiu MA: The l1-imidazolinebinding 

site is a functional receptor mediating vasodepression 

via the ventral medulla. Am J Physiol 

273: R1572, 1997. 

39. Fenton C, Keating GM, Lyseng-Williamson KA: 

Moxonidine: a review of its use in essential hypertension. 

Drugs 66: 477, 2006. 

40. Mobini R, Fu M, Jansson PA, et al: Influence of 

central inhibition of sympathetic nervous activity 

on myocardial metabolism in chronic heart failure: 

acute effects of the imidazoline I1-receptor agonist 

moxonidine. Clin Sci 110: 329, 2006. 

41. Pöyhönen-alho MK, Manhem K, Katzman P, et al: 

Central sympatholytic therapy has anti-inflammatory 

properties in hypertensive postmenopausal 

women. J Hypertens 26: 2445, 2008. 

42. Krakoff LR, Garbowit D: Adeno-medullary hypertension: 

a review of syndromes, patho-physiology, 

diagnosis and treatment. Clin Chem 37: 49, 1991. 

43. Pacak K, Linehan WM, Eisenhofer G, et al. Recent 

advances in genetics, diagnosis, localization, and 

treatment of pheochromocytoma. Ann Intern Med 

134:315, 2001. 

44. Krakoff LR: History of hypertension. In Hypertension: 

Principles and Practice (ed by EJ Battegay, GL 

Yip, GL Bakris. New York: Taylor & Francis 2005: 3. 

45. Taler SJ: Treatment of pregnant hypertensive patients. 

In: Izzo JL Jr, Sica DA, Black HR, eds. Hypertension 

Primer, 4th ed. Dallas: American Heart 

Association, 2008:536. 

46. Abalos E, Duley L, Steyn DW, Henderson-Smart 

DJ: Antihypertensive drug therapy for mild to 

moderate hypertension during pregnancy (Cochrane 

Review). The Cochrane Library, 2007. 

47. Magee LA, Duley L: Oral beta-blockers for mild 

to moderate hypertension during pregnancy (Cochrane 

Review). The Cochrane Library 2003.

48. Fahlke C, Berggren U, Balldin J: Cardiovascular 

responses to clonidine in alcohol withdrawal: Are 

they related to psychopathology and mental wellbeing? 

Alcohol 1:231, 2000. 

49. Adinoff B: Double-blind study of alprazolam, diazepam, 

clonidine, and placebo in the alcohol withdrawal 

syndrome: Preliminary findings. Alcohol 

Clin Exp Res 18:873, 1994. 


50. Frishman W: Smoking cessation pharmacotherapy. 

Ther Adv Cardiovasc Dis 3: 287, 2009. 

51. Wijeysundera DN, Naik JS, Beattie S: Alpha-2 adrenergic 

agonists to prevent perioperative cardiovascular 

complications: a meta-analysis. Am J Med 

114: 742, 2003.


Cholinergic and Anticholinergic Drugs 


B. Robert Meyer, MD 

1. Hoffman BB, Taylor P: Neurotransmission: The autonomic 

and somatic motor nervous systems. In: 

Hardman JG, Limbird LE, eds. Goodman & Gilman’s 

The Pharmacological Basis of Therapeutics, 

10th ed. New York: McGraw-Hill, 2001:115. 

2. Dale HH: The action of certain esters and ethers of 

choline, and their relation to muscarine. J Pharmacol 

Exp Ther 6:147, 1914. 

3. Caulfield MP: Muscarinic receptors: Characterization, 

coupling and function. Pharmacol Ther 

58:319, 1993. 

4. Bonner TI, Buckley NJ, Young AC, Brann MR: 

Identification of a family of muscarinic receptor 

genes. Science 237:527, 1987. 

5. Hammer R, Berrie CP, Birdsall NJ, et al: Pirenzepine 

distinguishes between different subclasses of 

muscarinic receptors. Nature 283: 90, 1980. 

6. Levine RR, Birdsall NJM, eds: Symposium: Subtypes 

of muscarinic receptors: V. Life Sci 52:405, 

1993. 

7. Levine RR, ed: Symposium: Subtypes of muscarinic 

receptors: VI. Life Sci 56:801, 1995. 

8. Oberhauser V, Schwertfeger E, Rutz T, et al: Acetylcholine 

release in human heart atrium. Influence of 

muscarinic autoreceptors, diabetes, and age. Circulation 

103:1638, 2001. 

9. Brodde OE, Michel MC: Adrenergic and muscarinic 

receptors in the human heart. Pharmacol Rev 

51:651, 1999. 

10. Landzberg JS, Parker JD, Gautheir DF, Colucci WS: 

Effects of intracoronary acetylcholine and atropine 

on basal and dobutamine stimulated left ventricular 

contractility. Circulation 89:164, 1994. 

11. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: 

Physiology, pathophysiology, and pharmacology. 

Pharmacol Rev 43:109, 1991. 

12. Furchgott RF: The role of endothelium in the responses 

of vascular smooth muscle to drugs. Annu 

Rev Pharmacol Toxicol 24:175, 1984. 

13 Tio RA, Monnink SHJ, Amoroso G, et al: Safety 

evaluation of routine intracoronary acetylcholine 

infusion in patients undergoing a first diagnostic 

coronary angiogram. J Investig Med 50:133, 2002. 

14. Goyal RK: Identification, localization, and classification 

of muscarinic receptor subtypes in the gut. 

Life Sci 43:2209, 1988. 

15. Wein AJ: Practical uropharmacology. Urol Clin 

North Am 18:269, 1991. 

16. Eglen RM, Choppin A, Dillon MP, Hegde S: Muscarinic 

receptor ligands and their therapeutic potential. 

Curr Opin Chem Biol 3:426, 1999. 

17. Taylor P: Anticholinesterase agents. In: Hardman 

JG, Limbird LE, eds. Goodman & Gilman’s The 

Pharmacological Basis of Therapeutics, 10th ed. 

New York: McGraw-Hill, 2001:175. 

18. Morris RB, Cronnelly R, Miller RD, et al: Pharmacokinetics 

of edrophonium and neostigmine 

when antagonizing d-tubocurarine neuromuscular 

blockade in man. Anaesthesiology 54:399, 1981. 

19. Morris RB, Cronnelly R, Miller RD, et al: Pharmacokinetics 

of edrophonium in anephric and renal 

transplant patients. Br J Anaesth 53:399, 1981. 

20. American Society of Hospital Pharmacists: AHFS 

Drug Information 1994. Bethesda MD: American 

Hospital Formulary Service, American Society of 

Hospital Pharmacists, 1994. 

21. McCarthy GH, Mirackhur RK, Maddineni VR, 

McCoy EP: Dose-responses for edrophonium during 

antagonism of vecuronium block in young and 

older adult patients. Anaesthesia 50:503, 1995. 

22. Kiajima T, Ishii K, Ogata H: Edrophonium as an 

antagonist of vercuronium-induced neuromuscu- 



7-1


lar block in the elderly. Anaesthesia 50:359, 1995. 

23. Lurie KG, Dutton J, Mangat R, et al: Evaluation of 

edrophonium as a provocative agent for vasovagal 

syncope during head-up tilt-table testing. Am J 

Cardiol 72:1286, 1993. 

24. Medow MS, Stewart JM, Sanyal S, et al: Pathophysiology, 

diagnosis and treatment of orthostatic hypotension 

and vasovagal syncope. Cardiol in Rev 16: 

4, 2008. 

25. Rokkas T, Anggiansah A, McCullagh M, Owen 

WJ: Acid perfusion and edrophonium provocation 

tests in patients with Chest pain of undetermined 

etiology. Dig Dis Sci 37:1212, 1992. 

26. Hofer S, Eisenbach C, Lukic IK, et al: Pharmacologic 

cholinesterase inhibition iproves survival in 

experimental sepsis. Crit Care Med 36: 404-408, 

2008. 

27. Drachman DB: Myasthenia gravia. N Engl J Med 

330: 1797, 1994. 

28. Birks J: Cholinestease inhibitors for Alzheimer’s 

disease. Cochrane Database Syst Rev 1: CD005593, 

2006. 

29. Gill SS, Anderson GM, Fischer HD, et al: Syncope 

and its consequences in patients with dementia receiving 

cholinesterase inhibitors. Arch Intern Med 

169: 867-873, 2009. 

30. Brown JH, Taylor P: Muscarinic receptor agonists 

and antagonists. In: Hardman JG, Limbird LE, eds. 

Goodman & Gilman’s The Pharmacological Basis 

of Therapeutics, 10th ed. New York: McGraw-Hill, 

2001:155. 

31. Zhou HH, Adedoyin A, Wood AJ: Differing effect 

of atropine on heart rate in Chinese and white subjects. 

Clin Pharm Ther 52:120, 1992. 

32. Marine JE, Watanabe MA, Smith TW, Monahan 

KM: Effects of atropine on heart rate turbulence. 

Am J Cardiol 89:767, 2002. 

33. Wellstein A, Pitschener HF: Complex dose-response 

curves of atropine in man explained by different 

functions of M1 and M2 cholinoreceptors. 

Naunyn Schmiedebergs Arch Pharmacol 338:861, 

1988. 

34. Pican E, Mathias W, Pingitore A, et al: Safety and 

tolerability of dobutamine-atropine stress echocardiography: 

A prospective, multicentre study. Lancet 

344:1190, 1994. 

35. Poldermans D, Fioretti PM, Boersma E: Safety of 

dobutamine-atropine stress echocardiography in 

patients with suspected or proven coronary artery 

disease. Am J Cardiol 73:456, 1994. 

36. McNeill AJ, Fioretti PM, El-Said SM, et al: Enhanced 

sensitivity for detection of coronary artery 

disease by addition of atropine to dobutamine 

stress echocardiography. Am J Cardiol 70:41, 1992. 

37. Poldermans D, Fioretti PM, Boersma E: Dobutamine-atropine 

stress echocardiography in elderly 

patients unable to perform an exercise test: Hemodynamic 

characteristics, safety, and prognostic 

value. Arch Intern Med 154:2681, 1994. 

38. Meisner JS, Shirani J, Alaeddini J, et al: Use of pharmaceuticals 

in noninvasive cardiovascular diagnosis. 

Heart Dis 4:315, 2002. 

39. van Noord JA, Bantje TA, Eland ME, et al: A randomised 

controlled comparison of tiotropium and 

ipratropium in the treatment of chronic obstructive 

pulmonary disease. The Dutch Tiotropium 

Study Group. Thorax 55:289, 2000. 

40. Chapman KR: The role of anticholinergic bronchodilators 

in adult asthma and chronic obstructive 

pulmonary disease. Lung 168(Suppl): 295, 1990. 

41. Gross NJ: Ipratropium bromide. N Engl J Med 

319:486, 1988. 

42. Ogale SS, Lee TA, Au DH, et al: Cardiovascular 

events associated with ipratropium bromide in 

COPD. Chest 137: 13, 2010. 

43. Celli B, Decramer M, Leimer I, et al: Cardiovascular 

safety of tiotropium in patients with COPD. 

Chest 137: 20, 2010. 

44. Salpeter SR: Do inhaled anticholinergics increase 

or decrease the risk of major cardiovascular 

events? A synthesis of the available evidence. Drugs 

69:2025, 2009. 

45. Wilkinson JA: Side effects of transdermal scopolamine. 

J Emerg Med 5:389, 1987. 

46. Ziskind AA: Transdermal scopolamine-induced 

psychosis. Postgrad Med 84:73, 1988. 

47. Hall RCW, Hall RCW, chapman MJ: Anticholinergic 

syndrome: presentations, etiological agents, differential 

diagnosis, and treatment. Clin Geriatr 17: 

22, 2009. 

48. LaRovere MT, DeFerrari GM: New potential uses 

for transdermal scopolamine (hyoscine). Drugs 

50:769, 1995.


Calcium Channel Blockers 


Domenic A. Sica, MD 

8. Calcium Channel Blockers 

1. Keefe D, Frishman WH: Clinical pharmacology of 

the calcium-channel blocking drugs. In: Packer M, 

Frishman WH, eds. Calcium Channel Antagonists 

in Cardiovascular Disease. Norwalk, CT: Appleton- 

Century-Crofts, 1984:3. 

2. Braunwald E: Mechanism of action of calciumchannel 

blocking agents. N Engl J Med 307:16l8, 

1983. 

3. Frishman WH, Sonnenblick EH: Beta-adrenergic 

blocking drugs and calcium channel blockers. In: 

Alexander RW, Schlant RC, Fuster V, eds. Hurst’s 

The Heart, 9th ed. New York: McGraw Hill, 1998: 

1583. 

4. Weir MR: Calcium antagonists. In Izzo JL Jr., Sica 

DA, Black HR (eds): Hypertension Primer 4th ed. 

Dallas, American Heart Assn 2008: 465. 

5. Frishman WH, Cheng-Lai A, Nawarskas J, eds. 

Current Cardiovascular Drugs, 4th ed. Philadelphia: 

Current Medicine, 2005. 

6. Malhotra HS, Plosker GL: Barnidipine. Drugs 

61:989, 2001. 

7. Tomoda F, Takata M, Kagitani S, et al: Effects of a 

novel calcium antagonist, benidipine hydrochloride, 

on platelet responsiveness to mental stress in 

patients with essential hypertension. J Cardiovasc 

Pharmacol 34:248, 1999. 

8. Sakata K, Shirotani M, Yoshida H, et al: Effects of 

amlodipine and cilnidipine on cardiac sympathetic 

nervous system and neurohormonal status in essential 

hypertension. Hypertension 33:1447, 1999. 

9. Sánchez M, Sobrino J, Ribera L, et al: Long-acting 

lacidipine versus short-acting nifedipine in the 

treatment of asymptomatic acute blood pressure 

increase. J Cardiovasc Pharmacol 33:479, 1999. 

10. Casiglia E, Mazza A, Tikhonoff V, et al: Therapeutic 

profile of manidipine and lercanidipine in hypertensive 

patients. Adv Therap 21: 357, 2004. 

11. Ohashi N, Mitamura H, Ogawa S: Development 

of newer calcium channel antagonists. Therapeutic 

potential of efonidipine in preventing electrical 

remodeling during atrial fibrillation. Drugs 69: 21, 

2009. 

12. Lindner E: Phenyl-propyl-diphenyl-prophyl-amin, 

a new substance with a dilating action in the coronary 

vessels. Arzneim Forsch 10:569, 1960. 

13. Haas H, Hartfelder G: A-Isopropyl-a(N-methyl- 

N-homoveratryl)-y aminopropyl)-3,4-dimethoxyphenyl-acetonitrol, 

a substance with vasodilating 

properties. Arzneim Forsch 12:549, 1962. 

14. Fleckenstein A, Kammermeier H, Doring H, et al: 

On the action mechanism of new coronary dilators 

with oxygen sparing myocardial effects—Prenylamin 

and Iproveratril. Z Kreislauf Forsch 56:716, 

839, 1967. 

15. Fleckenstein A: Control of myocardial sbolism by 

verapamil: Sites of action and therapeutic effects. 

Arzneim Forsch 20:1317, 1970. 

16. Singh BN, Vaughan-Williams EM: A fourth class 

of antidysrhythmic action? Effect of verapamil on 

ouabain toxicity, on atrial and ventricular intracellular 

potentials, and on other features of cardiac 

function. Cardiovasc Res 6:109, 1972. 

17. Vaughan Williams EM: Classification of antiarrhythmic 

drugs. In: Sande E, Flensted-Jensen E, 

Olsen KH, eds. Symposium on Cardiac Arrhythmias. 

Elsinor, Denmark: AB Astra, 1979:449. 

18. Ge W, Ren J: Combined L-/T-type calcium channel 

blockers. Ready for prime time. Hypertension 53: 

592, 2009. 

19. de Curzon OP, Ghaleh B, Hittinger L, et al: Beneficial 

effects of the T- and L-type calcium channel 



8-1


antagonist, mibefradil, against exercise-induced 

myocardial stunning in dogs. J Cardiovasc Pharmacol 

35:240, 2000. 

20. Schwartz A, Matlib A, Balwierczak J, Lathrop DA: 

Pharmacology of calcium antagonists. Am J Cardiol 

55:3C, 1985. 

21. Dhein S, Salameh A, Berkels R, Klaus W: Dual 

mode of action of dihydropyridine calcium antagonists. 

A role for nitric oxide. Drugs 58:397, 1999. 

22. Kitakaze M, Asanuma H, Takashima S, et al: Nifedipine-induced 

coronary vasodilation in ischemic 

hearts is attributable to bradykinin- and NO-dependent 

mechanisms in dogs. Circulation 101:311, 

2000. 

23. Taddei S, Virdis A, Ghiadoni L, et al: Restoration 

of nitric oxide availability after calcium antagonist 

treatment in essential hypertension. Hypertension 

37:943, 2001. 

24. Wei C, Burnett JC Jr: Inhibition by calcium antagonism 

of circulating and renal endothelin in 

experimental congestive heart failure. Am J Physiol 

278:H263, 2000. 

25. Ikeda U, Hojo Y, Ueno S, et al: Amlodipine inhibits 

expression of matrix metalloproteinase-1 and 

its inhibitor in human vascular endothelial cells. J 

Cardiovasc Pharmacol 35:887, 2000. 

26. van Breeman C, Mangel A, Fahim M, et al: Selectivity 

of calcium antagonistic action in vascular 

smooth muscle. Am J Cardiol 49:507, 1982. 

27. Millard RW, Lathrop DA, Grupp G, et al: Differential 

cardiovascular effects of calcium channel 

blocking agents: Potential mechanisms. Am J Cardiol 

49:499, 1982. 

28. Fleckenstein A: Specific pharmacology of calcium 

in myocardium, cardiac pacemakers, and vascular 

smooth muscle. Annu Rev Pharmacol Toxicol 

17:149, 1977. 

29. Henry PD, Borda L, Schuchleib R: Chronotropic 

and inotropic effects of vasodilators. In: Lichtlen 

PR, Kimura E, Taira N, eds. International Adalat 

Panel Discussion: New Experimental and Clinical 

Results. Amsterdam: Exerpta Medica, 1979:14–21. 

30. Cohn JN, Franciosa JA: Vasodilatory therapy of 

cardiac failure. N Engl J Med 297:27, 1977. 

31. Himori N, Ono H, Taira N: Simultaneous assessment 

of effects of coronary vasodilators on the 

coronary blood flow and the myocardial contractility 

by using the blood perfused canine papillary 

muscle. Jpn J Pharmacol 26:427, 1976. 

32. Singh BN, Hecht HS, Nademanee K, et al: Electrophysiologic 

and hemodynamic effects of slow 

channel blocking drugs. Prog Cardiovasc Dis 

25:103, 1982. 

33. Ellrodt G, Chew CYC, Singh BN: Therapeutic im- 

plications of slow channel blockade in cardiocirculatory 

disorders. Circulation 62:669, 1980. 

34. Landau AJ, Gentilucci M, Cavusoglu E, Frishman 

WH: Calcium antagonists for the treatment of congestive 

heart failure. Coron Artery Dis 5:37, 1994. 

35. Veniant M, Clozel JP, Hess P, et al: Hemodynamic 

profile of RO 40-5967 in conscious rats: Comparison 

with diltiazem, verapamil and amlodipine. J 

Cardiovasc Pharmacol 18 (Suppl 10):S55, 1991. 

36. Frishman WH, LeJemtel T: Electropharmacology 

of the slow channel inhibitors in the management 

of cardiac arrhythmias: verapamil. Pace 5:402, 

1982. 

37. Singh BN, Nademanee K, Baky S: Calcium antagonists. 

Drugs 25:125, 1983. 

38. Nayler WG, Poole-Wilson PH: Calcium antagonists: 

Definition and mode of action. Basic Res 

Cardiol 76:1, 1981. 

39. Yamaguchi I, Obayashi K, Mandel WJ: Electrophysiologic 

effects of verapamil. Cardiovasc Res 

12:597, 1978. 

40. Singh BN, Collet J, Chew CYC: New perspectives 

in the pharmacologic therapy of cardiac arrhythmias. 

Prog Cardiovasc Dis 22:243, 1980. 

41. Wit A, Cranefield P: The effects of verapamil on the 

sinoatrial andatrioventricular nodes of the rabbit 

and the mechanisms by which it arrests reentrant 

AV nodal tachycardia. Circ Res 35:413, 1974. 

42. Findling R, Frishman W, Javed MT, et al: Calcium 

channel blockers and the gastrointestinal tract. Am 

J Ther 3:383, 1996. 

43. Schoen RE, Frishman WH, Shamoon H: Hormonal 

and metabolic effects of calcium-channel antagonists 

in man. Am J Med 84:492, 1988. 

44. Shamoon H, Baylor P, Kamobosos D, et al: Influence 

of oral verapamil on glucoregulatory hormones 

in man. J Clin Endocrinol Metabol 60:536, 

1985. 

45. Frishman WH, Klein N, Strom J, et al: Comparative 

effects of abrupt withdrawal of propranolol and 

verapamil in angina pectoris. Am J Cardiol 50:1191, 

1982. 

46. Mehta JL: Influence of calcium-channel blockers 

on platelet function and arachidonic acid metabolism. 

Am J Cardiol 55:158B, 1985. 

47. Sanguigni V, Gallu M, Sciarra L, et al: Effect of amlodipine 

on exercise-induced platelet activation in 

patients affected by chronic stable angina. Clin Cardiol 

22:575, 1999. 

48. Kates R: Calcium antagonists—pharmacokinetic 

properties. Drug 25:113, 1983. 

49. Frishman WH, Stroh JA, Greenberg SM, et al: Calcium-channel 

blockers in systemic hypertension. 

Curr Prob Cardiol 12:287, 1987.

50. Katz B, Rosenberg A, Frishman WH: Controlledrelease 

drug delivery systems in cardiovascular 

medicine. Am Heart J 129:359, 1995. 

51. Plosker GL, Faulds D: Nisoldipine coat-core. Drugs 

52:232, 1996. 

52. White WB: A chronotherapeutic approach to the 

management of hypertension. Am J Hypertens 

9:29S, 1996. 

53. Frishman WH, Kirstein E, Klein M, et al: Clinical 

relevance of verapamil plasma levels in stable angina 

pectoris. Am J Cardiol 50:1180, 1982. 

54. Frishman WH, Charlap S, Kimmel B, et al: Diltiazem 

compared to nifedipine and combination 

treatment in patients with stable angina: Effects 

on angina, exercise tolerance and the ambulatory 

ECG. Circulation 77:774, 1988. 

55. Sica DA, Gehr TWB: Calcium-channel blockers 

and the cytochrome P450 system. In: Epstein M, 

ed: Calcium Antagonists in Clinical Medicine, 3rd 

ed. Philadelphia: Hanley and Belfus, 2002:93. 

56. Sica DA, Gehr TWB: Calcium-channel blockers 

and end-stage renal disease. In: Epstein M, ed. 

Calcium Antagonists in Clinical Medicine, 3rd ed. 

Philadelphia: Hanley and Belfus, 2002:701. 

57. Singh BN, Chew CYC, Josephson MA, et al: Hemodynamic 

mechanisms underlying the antianginal 

actions of verapamil. Am J Cardiol 50:886, 1982. 

58. Opie LH: Calcium channel antagonists in the treatment 

of coronary artery disease: Fundamental 

pharmacological properties relevant to clinical use. 

Prog Cardiovasc Dis 38(4):273, 1996. 

59. Pepine CJ, Lambert CR: Usefulness of nicardipine 

for angina pectoris. Am J Cardiol 59:13J, 1987. 

60. Scheidt S, Frishman WH, Packer M, et al: Longterm 

effectiveness of verapamil in stable and unstable 

angina pectoris: One year follow-up of patients 

treated-controlled double-blind randomized clinical 

trials. Am J Cardiol 50:1185, 1982. 

61. Opie LH: Calcium channel antagonists in the management 

of anginal syndromes: Changing concepts 

in relation to the role of coronary vasospasm. Prog 


62. Frishman WH, Klein NA, Strom JA, et al: Superiority 

of verapamil to propranolol in stable angina 

pectoris—a double-blind, randomized crossover 

trial. Circulation 65(Suppl I):151, 1982. 

63. Frishman WH, Klein N, Klein P, et al: Comparison 

of oral propranolol and verapamil for combined 

systemic hypertension and angina pectoris: A placebo-controlled 

double-blind randomized crossover 

trial. Am J Cardiol 50:1164, 1982. 

64. Frishman WH, Charlap S: Calcium-channel blockers 

for combined systemic hypertension and myocardial 

ischemia. Circulation 75:V154, 1988. 


65. Abrams J, Frishman WH, Bates SM, et al: Pharmacologic 

options for treatment of ischemic disease. 

In: Antman EM, ed. Cardiovascular Therapeutics, 

3rd ed. Philadelphia: Saunders, 2007: 77. 

66. Kizer JR, Kimmel SE: Epidemiologic review of the 

calcium channel blocker drugs. An up-to-date perspective 

on the proposed hazards. Arch Intern Med 

161:1145, 2001. 

67. Stone PH, Gibson RS, Glasser SP, et al: Comparison 

of propranolol, diltiazem, and nifedipine in the 

treatment of ambulatory ischemia in patients with 

stable angina: Differential effects on ambulatory 

ischemia, exercise performance, and anginal symptoms. 


68. Frishman WH, Glasser S, Stone P, et al: Comparison 

of controlled-onset extended-release verapamil 

to amlodipine and amlodipine plus atenolol on exercise 

performance and ambulatory ischemia in 

patients with chronic stable angina pectoris. Am J 

Cardiol 83:507, 1999. 

69. Johnson SM, Mauritson DR, Willerson JT, et al: A 

controlled trial of verapamil for Prinzmetal’s variant 

angina. N Engl J Med 304:862, 1981. 

70. Antman E, Muller JE, Goldberg S, et al: Nifedipine 

therapy for coronary artery spasm experience in 

127 patients. N Engl J Med 302:1269, 1980. 

71. Schroeder JS, Feldman RL, Giles TD, et al: Multiclinic 

controlled trial of diltiazem for Prinzmetals 

angina. Am J Med 72:227, 1982. 

72. Chahine RA, Feldman RL, Giles TD, et al: Randomized 

placebo controlled trial of amlodipine 

in vasospastic angina. J Am Coll Cardiol 21:1365, 

1993. 

73. Parodi O, Simonetti I, LAbbate A, et al: Comparative 

effectiveness of verapamil and propranolol in 

angina at rest. Am J Cardiol 50:923, 1982. 

74. Johnson SM, Mauritson DR, Willerson JT, et al: 

Comparison of verapamil and nifedipine in the 

treatment of variant angina pectoris: preliminary 

observations in 10 patients. Am J Cardiol 47:1295, 

1981. 

75. Gerstenblith G, Ouyang P, Achuff S, et al: Nifedipine 

in unstable angina: a double-blind randomized 

trial. N Engl J Med 306:885, 1982. 

76. Anderson JL, Adams CD, Antman EM et al. ACC/ 

AHA 2007 guidelines for the management of patients 

with unstable angina/non-ST-segment elevation 

myocardial infarction: a report of the 

American College of Cardiology/American Heart 

Association Task Force on Practice Guidelines 

(Writing committee to revise the 2002 guidelines 

for the management of patients with unstable angina/non-ST-elevation 

myocardial infarction) 

developed in collaboration with the American


College of Emergency Physicians, the Society for 

Cardiovascular Angiography and Interventions, 

and the Society of Thoracic Surgeons endorsed 

by the American Association of Cardiovascular 

and Pulmonary Rehabilitation and the Society for 

Academic Emergency Medicine. J Am Coll Cardiol 

2007; 50: 1–157. 

77. Pehrsson SK, Ringqvist I, Ekdahl S, et al: Monotherapy 

with amlodipine or atenolol versus their 

combination in stable angina pectoris. Clin Cardiol 

23:763, 2000. 

78. Emanuelsson H, Egstrup K, Nikus K, et al: Antianginal 

efficacy of the combination of felodipinemetoprolol 

10/100 mg compared with each drug 

alone in patients with stable effort-induced angina 

pectoris: A multicenter parallel group study. Am 

Heart J 137:854, 1999. 

79. Packer M, Leon MB, Bonow RO, et al: Hemodynamic 

and clinical effects of combined therapy 

with verapamil and propranolol in ischemic heart 

disease. Am J Cardiol 50:903, 1982. 

80. Packer M, Frishman WH: Calcium channel antagonists 

in perspective. In: Packer M, Frishman 

WH, eds. Calcium Channel Antagonists in Cardiovascular 

Disease. Norwalk, CT: Appleton-Century- 

Crofts, 1984:xvii. 

81. Gabrielli A, Gallagher J, Caruso LJ, et al: Diltiazem 

to treat sinus tachycardia in critically ill patients. A 

four-year experience. Crit Care Med 29: 1874, 2000. 

82. Hemels MEW, Van Noord T, Crijns HJGM, et al: 

Verapamil versus digoxin and acute versus routine 

serial cardioversion for the improvement of 

rhythm control for persistent atrial fibrillation. J 


83. Pandozi C, Bianconi L, Calo L, et al: Postcardioversion 

atrial electrophysiologic changes induced 

by oral verapamil in patients with persistent atrial 

fibrillation. J Am Coll Cardiol 36:2234, 2000. 

84. Pritchett ELC: Management of atrial fibrillation. N 

Engl J Med 326:1264, 1992. 

85. Klein HO, Pauzner H, DiSegni E, et al: The beneficial 

effects of verapamil in chronic atrial fibrillation. 


86. Klein HO, Kaplinsky E: Comparative effectiveness 

of verapamil and digoxin in atrial fibrillation. Am J 

Cardiol 50:894, 1982. 

87. De Simone A, Stabile G, Vitale DF, et al: Pretreatment 

with verapamil in patients with persistent or 

chronic atrial fibrillation who underwent electrical 

cardioversion. J Am Coll Cardiol 34:810, 1999. 

88. Amar D, Roistacher N, Rusch VW, et al: Effects of 

diltiazem prophylaxis on the incidence and clinical 

outcome of atrial arrhythmias after thoracic surgery. 

J Thorac Cardiovasc Surg 120:790, 2000. 

89. Krikler DM, Spurrell RAJ: Verapamil in the treatment 

of paroxysmal supraventricular tachycardia. 

Postgrad Med J 50:447, 1974. 

90. Singh BN, Nademanee D, Baky S: Calcium antagonists: 

Uses in the treatment of cardiac arrhythmias. 

Drugs 25:125, 1983. 

91. Hartel G, Hartikainen M: Comparison of verapamil 

and practolol in paroxysmal supraventricular 

tachycardia. Eur J Cardiol 4:87, 1976. 

92. Mauritson DR, Winniford MD, Walker WS, et al: 

Oral verapamil for paroxysmal supraventricular 

tachycardia: A long term, double-blind, randomized 

trial. Ann Intern Med 96:409, 1982. 

93. Matsuyama E, Konishi T, Okazaki H, et al: Effects 

of verapamil on accessory pathway properties and 

induction of circus movement tachycardia in patients 

with the Wolff-Parkinson-White syndrome. 


94. Gotsman M, Lewis B, Bakst A, et al: Verapamil 

in life-threatening tachyarrhythmias. S Afr Med J 

46:2017, 1972. 

95. Aiba T, Shimizu W, Inagaki M, et al: Cellular and 

ionic mechanism for drug-induced long QT syndrome 

and effectiveness of verapamil. J Am Coll 

Cardiol 45: 300, 2005. 

96. Carrasco HA, Fuenmayor A, Barboza J, et al: Effect 

of verapamil on normal sino-atrial node dysfunction 

and on sick sinus syndrome. Am Heart J 

96:760, 1978. 

97. Frishman WH, Stroh JA, Greenberg SM, et al: Calcium-channel 

blockers in systemic hypertension. 


98. Frishman WH, Zawada ET, Smith LK, et al: A comparative 

study of diltiazem and hydrochlorothiazide 

as initial medical therapy for mild to moderate 

hypertension. Am J Cardiol 59:615, 1987. 


therapy for hypertension in men: A comparison 


Engl J Med 328:914, 1993. 

100. Frishman WH, Garofalo JL, Rothschild A, et al: 

Multicenter comparison of the nifedipine gastrointestinal 

system and long-acting propranolol in 

patients with mild to moderate systemic hypertension 

receiving diuretics: A preliminary experience. 

Am J Med 83:15, 1987. 

101. Johnson BF, Frishman WH, Brobyn R, et al: A randomized 

placebo controlled, double-blind comparison 

of amlodipine and atenolol in patients 

with essential hypertension. Am J Hypertens 5:727, 

1992. 

102. Charlap S, Kimmel B, Laifer L, et al: Twice daily 

nicardipine in the treatment of patients with mild 

to moderate hypertension. J Clin Hypertens 2:271,

1986. 

103. Todd PA, Faulds D: Felodipine: A review of the 

pharmacology and therapeutic use of the extended-release 

formulation in cardiovascular disorders. 

Drugs 44:251, 1992. 

104. Hamilton BP: Treatment of essential hypertension 

with PN 200-110 (isradipine). Am J Cardiol 59:141, 

1987. 

105. Basile JN: Treatment of the elderly hypertensive: 

systolic hypertension. In Izzo JL Jr., Sica DA, Black 

HR (eds): Hypertension Primer 4th ed. Dallas, 

American Heart Assn, 2008, 485. 

105a. Fleg JL, Aronow WS, Frishman WH: Cardiovascular 

drug therapy in the elderly: benefits and challenges. 

Nat Rev Cardiol 2010 in press. 

106. Staessen JA, Fagard R, Thijs L, et al: Randomized 

double-blind comparison of placebo and active 

treatment for older patients with isolated systolic 

hypertension. Lancet 350:757, 1997. 

107. Forette F, Seux M-L, Staeseen JA, et al: Prevention 

of dementia in randomized double-blind, placebocontrolled 

systolic hypertension in Europe (SYST- 

EUR). Lancet 352:1347, 1998. 

108. The Seventh Report of the Joint National Committee 

on Detection, Evaluation and Treatment of 

High Blood Pressure (JNC-VII). JAMA 289: 2560, 

2003. 

109. Wang JG, Staessen JA, Gong L, et al: Chinese trial 

on Isolated Systolic Hypertension in the Elderly. 

Systolic Hypertension in China (SYST-CHINA) 

Collaborative Group. Arch Intern Med 160:211, 

2000. 

110. Black HR, Elliott WJ, Weber MA, et al for the Stage 

I Systolic Hypertension (SISH) Study Group: Oneyear 

study of felodipine or placebo for stage 1 isolated 

systolic hypertension. Hypertension 38:1118, 

2001. 

111. Grimm RH Jr., Black H, Rowen R, et al: Amlodipine 

versus chlorthalidoneversus placebo in the 

treatment of stage I isolated systolic hypertension. 

Am J Hypertens 15:31, 2002. 



with Hypertension (STOP-Hypertension). 

Lancet 338:1281, 1991. 

113. Hansson L, Lindholm LH, Ekbom I, et al: Randomized 

trial of old and new antihypertensive drugs 

in elderly patients: Cardiovascular mortality and 

morbidity in the Swedish Trial of Old Patients with 

Hypertension-2 Study. Lancet 354:1751, 1999. 

114. Brown MJ, Palmer CR, Castaigne A, et al: Morbidity 

and mortality in patients randomized to doubleblind 

treatment with long-acting calcium channel 

blocker or diuretic in the International Nifedipine 


GITS Study: Intervention as a Goal in Hypertension 

Treatment (INSIGHT). Lancet 356:366, 2000. 

115. Hansson L, Hedner T, Lund-Johansen P, et al: 

Randomized trial of effects of calcium antagonists 

compared with diuretics and beta blockers on 

cardiovascular morbidity and mortality in hypertension: 

The Nordic Diltiazem (NORDIL) Study. 

Lancet 356:359, 2000. 

116. Randomized double-blind comparison of a calcium 

antagonist and a diuretic in elderly hypertensives. 

National Intervention Cooperative Study in 

Elderly Hypertensives Study Group. Hypertension 

34:1129, 1999. 

117. Hansson L, Zanchetti A, Carruthers SG, et al: Effects 

of intensive blood-pressure lowering and 

low-dose aspirin in patients with hypertension: 

Principal results from the Hypertension Optimal 

Treatment (HOT) randomized trial. Lancet 

351:1755, 1998. 

118. ALLHAT Officers and Coordinators: Major outcomes 

in high-risk hypertensive patients randomized 

to angiotensin converting enzyme inhibitor 

therapy or calcium channel blocker vs diuretic: The 

Antihypertensive and Lipid-Lowering Treatment 

to Prevent Heart Attack Trial (ALLHAT). JAMA 

288: 2981, 2002. 

119. Black HR, Elliott WJ, Neaton JD, et al: Rationale 

and design for the Controlled Onset Verapamil 

Investigation of Cardiovascular Endpoints (CON- 

VINCE). Control Clin Trials 19:370, 1998. 



and the effects of antihypertensive drug 

therapy. Curr Probl Cardiol 13(6):371, 1988. 

121. Sica DA: Combination calcium channel blocker 

therapy in the treatment of hypertension. J Clin 

Hypertens 3:322, 2001. 

122. Frishman WH, Ram CVS, McMahon FG, et al: 

Comparison of amlodipine and benazepril monotherapy 

to combination therapy in patients with 

systemic hypertension: A randomized, doubleblind, 

placebo-controlled, parallel group study. J 


123. Messerli F, Frishman WH, Elliott W, and the Trandolapril 

Study Group: Additive effects of verapamil 

and trandolapril in the treatment of hypertension. 

J Hypertens 11(3 Pt 1):322, 1998. 

124. Plosker GL, Robinson DM: Amlodipine/valsartan. 

Fixed-dose combination in hypertension. Drugs 

68: 373, 2008. 

125. Sanford M, Keam SJ: Olmesartan medoxomil/amlodipine. 

Drugs 69: 717, 2009. 

126. Frishman WH, Hainer JW, Sugg J, and M-FACT 

Study Group: A factorial study of combination


hypertension treatment with metoprolol succinate 

extended-release and felodipine extended-release. 

Results of the metoprolol succinate-felodipine antihypertension 

combination trial (M-FACT). Am J 

Hypertens 19:388, 2006. 

127. Jamerson K, Weber M, Bakris G, et al: Benazepril 

plus amlodipine or hydrochlorothiazide for hypertension 

in high-risk patients. N Engl J Med 359: 

2417, 2008. 

128. Chobanian AV: The hypertension paradox – more 

uncontrolled disease despite improved therapy. N 

Engl J Med 361: 878, 2009. 

129. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et 

al: A calcium antagonist vs a non-calcium antagonist 

hypertension treatment strategy for patients 

with coronary artery disease: the International 

Verapamil-Trandolapril Study (INVEST): a randomized 

controlled trial. JAMA 290: 2805, 2003. 

130. Dahlof B, Sever PS, Poulter NR, et al: Prevention 

of cardiovascular events with an antihypertensive 

regimen of amlodipine adding perindopril as required 

versus atenolol adding bendroflumethiazide 

as required, in the Anglo-Scandinavian Cardiac 

Outcomes Trial-Blood Pressure Lowering Arm 

(ASCOT-BPLA): a multicentre randomised, controlled 

trial. Lancet 36: 895, 2005. 

131. Zing W, Ferguson RK, Vlasses PH: Calcium antagonists 

in elderly and black hypertensive patients: 

Therapeutic controversies. Arch Intern Med 

151:2154, 1991. 

132. Kloner RA, Sowers JR, DiBona GF, et al for the 

Amlodipine Cardiovascular Community Trial 

Study Group: Sex- and age-related antihypertensive 

effects of amlodipine. Am J Cardiol 77:713, 

1996. 

133. Buhler FR, Hulthen UL, Kiowski W, et al: Greater 

anti-hypertensive efficacy of the calcium channel 

inhibitor verapamil in older and low renin patients. 

Clin Sci 63:439S, 1982. 

134. Brozena SC, Johnson MR, Ventura H, et al: Effectiveness 

and safety of diltiazem or lisinopril in 

treatment of hypertension after heart transplantation. 


135. Tuomilehto J, Rastenyte D, Birkenhager WH, et al: 

Effects of calcium-channel blockade in older patients 

with diabetes and systolic hypertension. Systolic 

Hypertension in Europe Trial Investigators. N 

Engl J Med 340:677, 1999. 

136. Estacio RO, Jeffers BW, H iatt WR, et al: The effect 

of nisoldipine as compared with enalapril on 

cardiovascular outcomes in patients with non-insulin-dependent 

diabetes and hypertension. N Engl 

J Med 338:645, 1998. 

137. Tatti P, Pahor M, Byington RP, et al: Outcome re- 

sults of the Fosinopril Versus Amlodipine Cardiovascular 

Events Randomized Trial (FACET) in 

patients with hypertension and NIDDM. Diabetes 

Care 21:597, 1998. 

138. Opie LH, Schall R: Evidence-based evaluation of 

calcium channel blockersfor hypertension. J Am 

Coll Card 39:315, 2002. 

139. Pahor M, Psaty BM, Alderman MH, et al: Health 

outcomes associated with calcium antagonists 

compared with other first-line antihypertensive 

therapies: A meta-analysis of randomised controlled 

trials. Lancet 356:1949, 2000. 

140. Psaty BM, Heckbert SR, Koepsell TD, et al: The risk 

of myocardial infarction associated with antihypertensive 

drug therapies. JAMA 274:620, 1995. 

141. Pahor M, Guralnik JM, Corti C, et al: Long-term 

survival and use of antihypertensive medications in 

older persons. J Am Geriatr Soc 43:1191, 1995. 

142. Furberg CD, Psaty BM: Calcium antagonists: Not 

appropriate as first-line antihypertensive agents. 


143. Epstein E: Calcium antagonists should continue 

to be used for first-line treatment of hypertension 

(commentary). Arch Intern Med 155:2150, 1995. 

144. Grossman E, Messerli FH: Calcium antagonists. 

Prog Cardiovasc Dis 47: 34, 2004. 

145. Sica DA, Douglas JG: The African American Study 

of Kidney Disease and Hypertension (AASK): New 

findings. J Clin Hypertens 3:244, 2001. 

146. Sica DA, Gehr TW: Pharmacologic treatment of 

hypertension. In Antman EM (ed): Cardiovascular 

Therapeutis, A Companion to Braunwald’s Heart 

Disease 3rd ed. Philadelphia: Saunders/Elsevier 

2007: 578. 

147. Chugh AR, Bakris GL: Treatment of hypertension 

with chronic renal insufficiency or albuminuria. In 

Izzo JL Jr., Sica DA, Black HR (eds): Hypertension 

Primer 4th ed. Dallas, American Heart Assn, 2008: 

522. 

148. Frishman WH, Weinberg P, Peled H, et al: Calcium-entry 

blockers for the treatment of severe hypertension 

and hypertensive emergencies. Am J 

Med 77(2B):35, 1984. 

149. Ellrodt AG, Ault M, Riedinger MS, et al: Efficacy of 

sublingual nifedipine in hypertensive emergencies. 

Am J Med 79(4A):19, 1985. 

150. Curran MP, Robinson DM, Keating GM: Intravenous 

nicardipine. Its use in the short-term 

treatment of hypertension and various other indications. 

Drugs 66: 1755, 2006. 

151. Vidt DG: Treatment of hypertensive urgencies 

and emergencies. In Izzo JL Jr., Sica DA, Black HR 

(eds): Hypertension Primer 4th ed. Dallas, American 

Heart Assn 2008: 489.

152. Prlesi L, Cheng-Lai A: Clevidipine: a novel ultrashort 

acting calcium antagonist. Cardiol in Rev 17: 

147, 2009. 

153. Deedwania PC, Carbajal EV: Silent myocardial 

ischemia: A clinical perspective. Arch Intern Med 

151:2373, 1991. 

154. Epstein SE, Quyyumi Aa, Bonow RO: Myocardial 

ischemia—silent or symptomatic. N Engl J Med 

318:1038, 1988. 

155. Stone PH, Gibson RS, Glasser SP, et al: Comparison 

of propranolol, diltiazem and nifedipine in the 

treatment of ambulatory ischemia in patients with 

stable angina. Differential effects on ambulatory 

ischemia, exercise performance, and anginal symptoms. 


156. Rogers WJ, Bourassa MG, Andrews TC, et al: Asymptomatic 

Cardiac Ischemia Pilot (ACIP) Study: 

Outcome at 1 year for patients with asymptomatic 

cardiac ischemia randomized to medical therapy or 

revascularization. J Am Coll Cardiol 26:594, 1995. 

157. Pratt CM, McMahon RP, Goldstein S, et al: Comparison 

of subgroups assigned to medical regimens 

used to suppress cardiac ischemia [The Asymptomatic 

Cardiac Ischemia Pilot (ACIP) Study]. Am 

J Cardiol 77:1302, 1996. 

158. Nayler WG: Cardioprotective effects of calcium 

ion antagonists in myocardial ischemia. Clin Invest 

Med 3:91, 1980. 

159. Frishman WH, Skolnick AE: Secondary prevention 

post-infarction: The role of b-adrenergic blockers, 

calcium-channel blockers and aspirin. In: Gersh BJ, 

Rahimtoola SH, eds. Acute Myocardial Infarction, 

2nd ed. New York: Chapman & Hall, 1997:766–796. 

160. Furberg CD, Psaty BM, Meyer JV: Nifedipine: 

Dose-related increase in mortality in patients with 

coronary heart disease. Circulation 92:1326, 1995. 

161. Gibson RS, Boden WE, Theroux P, et al: Diltiazem 

and reinfarction in patients with non-Q-wavemyocardial 

infarction. N Engl J Med 315:423,1986. 

162. The Multicenter Diltiazem Postinfarction Trial 

Research Group: The effect of diltiazem on mortality 

and reinfarction after myocardial infarction. N 

Engl J Med 319(7):385, 1988. 

163. The Danish Study on Verapamil in Myocardial Infarction: 

The effect of verapamil on mortality and 

major events after myocardial infarction: The Danish 

Verapamil Infarction Trial II (DAVIT II). Am J 

Cardiol 66:779, 1990. 

164. Boden WE, van Gilst WH, Scheldewaert RG, et 

al for the Incomplete Infarction Trial of European 

Research Collaborators Evaluating Prognosis post- 

Thrombolysis (INTERCEPT): Diltiazem in acute 

myocardial infarction treated with thrombolytic 

agents: A randomised placebo-controlled trial. 


Lancet 355:1751, 2000. 

165. Theroux P, Gregoire J, Chin C, et al: Intravenous 

diltiazem in acute myocardial infarction. Diltiazem 

as adjunctive therapy to activase (DATA) trial. J 


166. Sleight P: Calcium antagonists during and after 

myocardial infarction. Drugs 51:216, 1996. 

167. Gibson RS, Hansen JF, Messerli F, et al: Long-term 

effects of diltiazem and verapamil on mortality 

and cardiac events in non-Q-wave acute myocardial 

infarction without pulmonary congestion: Post 

hoc subset analysis of the Multicenter Diltiazem 

Postinfarction Trial and the Second Danish Verapamil 

Infarction Trial studies. Am J Cardiol 86:275, 

2000. 

168. Pelliccia F, Cianfrocca C, Romeo F, et al: Hypertrophic 

cardiomyopathy: Long-term effects of propranolol 

versus verapamil in preventing sudden 

death in low-risk patients. Cardiovasc Drugs Ther 

4:1515, 1990. 

169. Cohen LS, Braunwald E: Amelioration of angina 

pectoris in idiopathic hypertrophic subaortic stenosis 

with beta-adrenergic blockade. Circulation 

35:847, 1967. 

170. Rosing DR, Bonow RO, Packer M, et al: Verapamil 

therapy for the management of hypertrophic cardiomyopathy. 

In: Packer M, Frishman WH, eds. 

Calcium Channel Antagonists in Cardiovascular 

Disease. Norwalk, CT: Appleton-Century-Crofts, 

1984:313–342. 

171. Kaitenbach M, Hopf R, Kober G, et al: Treatment 

of hypertrophic obstructive cardiomyopathy with 

verapamil. Br Heart J 42:35, 1979. 

172. Rosing DR, Kent KM, Maron BJ, et al: Verapamil 

therapy—a new approach for the pharmacologic 

treatment of hypertrophic cardiomyopathy: II. Effects 

on exercise capacity and symptomatic status. 


173. Bonow RO, Rosing DR, Bacharach SL, et al: Effects 

of verapamil on left ventricular systolic function 

and diastolic filling in patients with hypertrophic 

cardiomyopathy. Circulation 64:787, 1981. 

174. Rosing DR, Cannon RO, Watson RM, et al: Comparison 

of verapamil and nifedipine effects on 

symptoms and exercise capacity in patients with 

hypertrophic cardiomyopathy. Circulation 66(Suppl 

II):II-24, 1982. 

175. Betocchi S, Piscione F, Losi M-A, et al: Effects of 

diltiazem on left ventricular systolic and diastolic 

function in hypertrophic cardiomyopathy. Am J 

Cardiol 78:451, 1996. 

176. Packer M: Calcium channel blockers in chronic 


177. Charlap S, Frishman WH: Calcium antagonists and


heart failure. Med Clin North Am 73:339, 1989. 

178. Elkayam U, Amin J, Mehra A, et al: A prospective, 

randomized, double-blind, crossover study to compare 

the efficacy and safety of chronic nifedipine 

therapy with that of isosorbide dinitrate and their 

combination in the treatment of chronic congestive 


179. Polese A, Fiorentini C, Olivari MT, Guazzi M: Clinical 

use of a calcium antagonistic agent (nifedipine) 

in acute pulmonary edema. Am J Med 66:825, 1979. 

180. Fifer MA, Colucci WS, Lorell BH, et al: Comparison 

of hemodynamic responses to nifedipine in 

heart failure: Comparison with nitroprusside. J Am 

Coll Cardiol 5:731, 1985. 

181. Packer M, Lee WH, Medina N, et al: Prognostic importance 

of the immediate hemodynamic response 

to nifedipine in patients with severe left ventricular 

dysfunction. J Am Coll Cardiol 10:1303, 1987. 

182. Cleophas TJ, van Marum R: Meta-analysis of efficacy 

and safety of second-generation dihydropyridine 

calcium channel blockers in heart failure. Am 

J Cardiol 87:487, 2001. 

183. Krombach RS, Clair MJ, Hendrick JW, et al: Amlodipine 

therapy in congestive heart failure: Hemodynamic 

and neurohormonal effects at rest and 

after treadmill exercise. Am J Cardiol 84:3L, 1999. 

184. Udelson JE, DeAbate A, Berk M, et al for the Amlodipine 

Exercise Trial Investigators: Effects of amlodipine 

on exercise tolerance, quality of life, and 

left ventricular function in patients with heart failure 

from left ventricular systolic dysfunction. Am 

Heart J 139:503, 2000. 

185. Figulla HR, Gietzen F, Zeymer U, et al: Diltiazem 

improves cardiac function and exercise capacity in 

patients with idiopathic dilated cardiomyopathy. 


186. Boden WE, Ziesche S, Carson PE, et al for the V- 

HeFT III Investigators: Rationale and design of the 

Third Vasodilator-Heart Failure Trial (V-HeFT III): 

Felodipine as adjunctive therapy to enalapril and 

loop diuretics with or without digoxin in chronic 

congestive heart failure. Am J Cardiol 77:1078,1996. 

187. Smith RF, Germanson T, Judd D, et al: Plasma norepinephrine 

and atrial natriureticpeptide in heart 

failure: Influence of felodipine in the Third Vasodilator 

Heart FailureTrial. V-HeFT III Investigators. J 

Card Fail 6:97, 2000. 

188. OConnor CM, Belkin RN, Carson PE, et al: Effect 

of amlodipine on mode of death in severe chronic 

heart failure: The PRAISE Trial. Circulation 92:676, 

1996. 

188. Packer M, O’Connor CM, Ghali JK, et al: Effect of 

amlodipine on morbidity and mortality in severe 

chronic heart failure. N Engl J Med 335:1107, 1996. 

190. Wijeysundera HC, Hansen MS, Stanton E, et al: 

Neurohormones and oxidative stress in nonischemic 

cardiomyopathy: relationship to survival and 

the effect of treatment with amlodipine. Am Heart 

J 146: 291, 2003. 

191. Kostis JB, Lacy CR, Cosgrove NM, Wilson AC: Association 

of calcium channel blocker use with the 

increased rate of myocardial infarction in patients 

with left ventricular dysfunction. Am Heart J 133: 

550, 1997. 

192. Scognamiglio R, Rahimtoola S, Fasoli G, et al: Nifedipine 

in symptomatic patients with severe aortic 

regurgitation and normal left ventricular function. 

N Engl J Med 331:689, 1994. 

193. Sotaro JF, Zaret BL, Schulman DS, et al: Usefulness 

of verapamil for congestive heart failure associated 

with abnormal left ventricular diastolic filling and 

normal left ventricular systolic performance. Am J 

Cardiol 66:981, 1990. 

194. Nishikawa N, Masuyama T, Yamamoto K, et al: 

Long-termadministration of amlodipine prevents 

decompensation to diastolic heartfailure in hypertensive 

rats. J Am Coll Cardio 38:1539, 2001. 

195. Sondergaard L, Aldershvile J, Hildebrandt P, et al: 

Vasodilatation with felodipine in chronic asymptomatic 

aortic regurgitation. Am Heart J 139:667, 

2000. 

196. Fein SA, Frishman WH: The pathophysiology and 

management of primary pulmonary hypertension. 

Cardiol Clin 5:563, 1987. 

197. Farber HW, Loscalzo J: Pulmonary arterial hypertension. 

N Engl J Med 351:1655, 2004. 

198. Rich S, Kaufman E, Levy PS: The effect of high 

doses of calcium channel blockers on survival in 

primary pulmonary hypertension. N Engl J Med 

327:76, 1992. 

199. Packer M: Vasodilator therapy for primary pulmonary 

hypertension. Limitations and hazards. Ann 

Intern Med 103:258, 1985. 

200. Neely CF, Stein R, Matot I, et al: Calcium blockage 

in pulmonary hypertension and hypoxic vasoconstriction. 

New Horizons 4:99, 1996. 

201. Allen GS, Ahn HS, Preziosi TJ, et al: Cerebral arterial 

spasm—A controlled trial of nimodipine in 

patients with subarachnoid hemorrhage. N Engl J 

Med 308:619, 1983. 

202. Bussey HI, Talbert RL: Promising uses of calciumchannel 

blocking agents. Pharmacotherapy 4:137, 

1984. 

203. Allen GS, Bahr AL: Cerebral arterial spasm: X. 

Reversal of acute and chronic spasm in dogs with 

orally administered nifedipine. Neurosurgery 4:43, 

1979. 

204. Wadworth AN, McTavish D: Nimodipine: A re-

view of its pharmacological properties, and therapeutic 

efficacy in cerebral disorders. Drugs Aging 

2:262, 1992. 

205. Feigin VL, Rinkel GJ, Algra A, et al: Calcium antagonists 

in patients with subarachnoid hemorrhage: 

A systematic review. Neurology 50:876, 1998. 

206. Gelmers HJ, Gorter K, DeWeerdt CJ, Wiezer HJA: 

A controlled trial of nimodipine in acute ischemic 

stroke. N Engl J Med 318:203, 1988. 

207. Weinberger J, Terashita D: Drug therapy of neurovascular 

disease. Heart Dis 1:163, 1999. 

208. Steen PA, Gisvold SE, Milde JH, et al: Nimodipine 

improves outcome when given after complete cerebral 

ischemia in primates. Anesthesiology 62:406, 

1985. 

209. Trust Study Group: Randomised, double-blind, 

placebo-controlled trial of nimodipine in acute 

stroke. Lancet 336:1205, 1990. 

210. The American Nimodipine Study Group: Clinical 

trial of nimodipine in acute ischemic stroke. Stroke 

23:3, 1992. 

211. Meyer JS: Calcium channel blockers in the prophylactic 

treatment of vascular headache. Ann Intern 

Med 102:395, 1985. 

212. Meyer JS, Hardenberg J: Clinical effectiveness of 

calcium entry blockers in prophylactic treatment of 

migraine and cluster headaches. Headache 23:266, 

1983. 

213. Morich FJ, Bieber F, Lewis JM, et al: Nimodipine in 

the treatment of probable Alzheimers disease. Clin 

Drug Invest 11:185, 1996. 

214. Burger SK, Saul RF, Selhorst JB, et al: Transient 

monocular blindness caused by vasospasm. N Engl 

J Med 325:870, 1991. 

215. Winterkorn JMS, Kupersmith MJ, Wirtschafter JD, 

et al: Brief report: treatment of vasospastic amaurosis 

fugax with calcium-channel blockers. N Engl J 

Med 329:396, 1993. 

216. Bartsch P, Maggiorini M, Ritter M, et al: Prevention 

of high altitude pulmonary edema by nifedipine. N 

Engl J Med 325:1284, 1991. 

217. Coffman JD: Raynaud’s phenomenon. Hypertension 

17:593, 1991. 

218. Rodeheffer RJ, Rommer JA, Wigley F, et al: Controlled 

double-blind trial of nifedipine in the treatment 

of Raynaud’s phenomenon. N Engl J Med 

308:880, 1983. 

219. Raynaud’s Treatment Study Investigators: Comparison 

of sustained-release nifedipine and temperature 

biofeedback for treatment of primary 

Raynaud phenomenon: results from a randomized 

clinical trial with 1-year follow up. Arch Intern Med 

160:1101, 2000. 

220. Ram CV: Antiatherosclerotic and vasculoprotec- 


tive actions of calcium antagonists. Am J Cardiol 

66:29I, 1990. 

221. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, et al: 

Retardation of angiographic progression of coronary 

artery disease by nifedipine. Lancet 335:1109, 

1990. 

222. Waters D, Lesperance J, Francetich M, et al: A controlled 

clinical trial to assess the effect of a calcium 

channel blocker on the progression of coronary 

atherosclerosis. Circulation 82:1940, 1990. 

223. Motro M, Shemesh J: Calcium channel blocker 

nifedipine slows down progression of coronary calcification 

in hypertensive patients compared with 

diuretics. Hypertension 37:1410, 2001. 

224. Mason RP: Mechanisms of atherosclerotic plaque 

stabilization for a lipophilic calciumantagonist amlodipine. 

Am J Cardiol 88 (Suppl): 2M, 2001. 

225. Pitt B, Byington RP, Furberg CD, et al: Effect of 

amlodipine on the progression of atherosclerosis 

and the occurrence of clinical events. Circulation 

102:1503, 2000. 

226. Mason RP: Scientific rationale for combination of 

a calcium channel antagonist and an HMG-CoA 

reductase inhibitor. A new approach to risk factor 

management. Drugs 68: 885, 2008. 

227. Schroeder JS, Gao S-Z, Alderman EL, et al: A preliminary 

study of diltiazem in the prevention of 

coronary artery disease in heart transplant recipients. 

N Engl J Med 328:164, 1993. 

228. Borhani NO, Mercuri M, Borhani PA, et al: Final 

outcome results of the multicenter isradipine 

diuretic atherosclerosis study (MIDAS). JAMA 

276:785, 1996. 

229. Einecke D: ELSA studies progression of atherosclerosis: 

Calcium antagonist arrests the process more 

than a beta blocker. MMW Fortschr Med 143:6, 

2001. 

230. Schwartz ML, Rotmensch HH, Frishman WH, 

Vlasses P: Potential applications of calcium-channel 

antagonists in the management of noncardiac 

disorders. In: Packer M, Frishman WH, eds. 

Calcium Channel Antagonists in Cardiovascular 

Disease. Norwalk, CT: Appleton-Century-Crofts, 

1984:371–382. 

231. Cristakis GT, Fremes SE, Weisel RD, et al: Diltiazem 

cardioplegia: A balance of risk and benefit. J 

Thorac Cardiovasc Surg 91:647, 1986. 

232. Seitelberger R, Zwolfer W, Huber S, et al: Nifedipine 

reduces the incidence of myocardial infarction 

and transient ischemia in patients undergoing coronary 

bypass grafting. Circulation 83:460, 1991. 

233. Piessens J, Brzostek T, Stammen F, et al: Effect of intravenous 

diltiazem on myocadial ischemia during 

percutaneous transluminal coronary angioplasty.


Am J Cardiol 64:1103, 1989. 

234. Hillegass WB, Ohman EM, Leimberger JD, et al: A 

meta-analysis of randomized trials of calcium antagonists 

to reduce restenosis after coronary angioplasty. 

Am J Cardiol 23:835, 1994. 

235. Factor SM, Minase T, Cho S, et al: Microvascular 

spasm in the cardiomyopathic Syrian hamster: A 

preventable cause of focal myocardial necrosis. Circulation 

66:342, 1982. 

236. Palmer BF, Dawidson I, Sagalowsky A, et al: Improved 

outcome of cadaveric renal transplantation 

due to calcium channel blockers. Transplantation 

52:640, 1991. 

237. Epstein M: Calcium antagonists and renal protection: 

Current status and future perspectives. Arch 

Intern Med 152:1573, 1992. 

238. Terry RW: Nifedipine therapy in angina pectoris: 

Evaluation of safety and side effects. Am Heart J 

104:681, 1982. 

239. Ellis JS, Seymour RA, Steele JG, et al: Prevalence 

of gingival overgrowth induced by calcium channel 

blockers: A community-based study. J Periodontol 

70:63, 1999. 

240. Croom KF, Wellington K: Modified-release nifedipine. 

A review of the use of modified-release 

formulations in the treatment of hypertension and 

angina pectoris. Drugs 66: 497, 2006. 

241. Padrell MD, Navarro M, Faura CC, Horga JF: Verapamil-induced 

parkinsonism. Am J Med 99:436, 

1995. 

242. Garcia Rodriguez LA, Cattaruzzi C, Grazia Troncon 

M, Agostinis L: Risk of hospitalization for upper 

gastrointestinal tract bleeding associated with 

ketorolac, other nonsteroidal anti-inflammatory 

drugs, calcium antagonists, and other antihypertensive 

drugs. Arch Intern Med 158:33, 1998. 

243. Cohen HJ, Pieper CF, Hanlon JT, et al: Calcium 

channel blockers and cancer. Am J Med 108: 210, 

2000. 

244. Lindholm LH, Anderson H, Ekbom T, et al: Relation 

between drug treatment and cancer in hypertensives 

in the Swedish Trial in Old Patients 

with Hypertension 2: A 5-year, prospective, randomised, 

controlled trial. Lancet 358:539, 2001. 

245. Sorensen HT, Olsen JH, Mellemkjaer L, et al: Cancer 

risk and mortality in users of calcium channel 

blockers. A cohort study. Cancer 89:165, 2000. 

246. Harris NS: Case 24-2006: A 40-year old woman 

with hypotension after an overdose of amlodipine. 

N Engl J Med 355: 602, 2006. 

247. Boyer EW, Shannon M: Treatment of calciumchannel 

blocker intoxication with insulin infusion 

(correspondence). N Engl J Med 344:1721, 2001. 

248. Frishman WH, Sica DA: Calcium channel blockers. 

In Frishman WH, Sonnenblick EH, Sica DA 

(eds): Cardiovascular Pharmacotherapeutics 2nd 

ed. New York: McGraw Hill: 2003, 105. 

249. Klein HO, Lang R, Weiss E, et al: The influence of 

verapamil on serum digoxin concentrations. Circulation 

65:998, 1982. 

250. Pedersen KE, Dorph-Pedersen A, Hvidt S, et al: Digoxin-verapamil 

interaction. Clin Pharmacol Ther 

30:311, 1981. 

251. Belz GG, Aust PE, Munkes R: Digoxin plasma concentrations 

and nifedipine. Lancet 1:844, 1981. 

252. Mitchell LB, Jutzy KR, Lewis SJ, et al: Intracardiac 

electrophysiologic study of intravenous diltiazem 

and combined diltiazem-digoxin in patients. Am 

Heart J 103:57, 1982. 

253. Dargie HJJ for the TIBET Study Group: Medical 

treatment of angina can favourably affect outcome 

(abstr). Eur Heart J 14(Suppl):304, 1993. 

254. Saseen JJ, Carter BL, Brown TER, et al: Comparison 

of nifedipine alone and with diltiazem or verapamil 

in hypertension. Hypertension 28:109, 1996.


The Renin-Angiotensin Axis 

Angiotensin-Converting Enzyme Inhibitors 

and Angiotensin Receptor Blockers 


Todd W. B. Gehr, MD 



on Prevention, Detection, Evaluation, and 

Treatment of High Blood Pressure. Hypertension 

42:1206, 2003. 

2 Brunner HR, Waeber B, Nussberger J: Angiotensin-converting 

enzyme inhibitors. In: Messerli F, 

ed. Cardiovascular Drug Therapy. 2nd ed. Philadelphia: 

WB Saunders, 690–711, 1996. 

3. Sica DA. Renin-angiotensin system blockade: 

Therapeutic Agents. In: Singh AJ, William GH 

(Eds). Textbook of Nephro-Endocrinology. (1st edition), 

New York, New York. Elsevier 189, 2009. 

4. Ahimastos AA, Lawler A, Reid CM, et al: Ramipril 

markedly improves walking ability in patients with 

peripheral arterial disease. Ann Intern Med 144: 

660, 2006. 

5. Cheng A, Frishman WH: Use of angiotensin-converting 

enzyme inhibitors as monotherapy and in 

combination with diuretics and calcium channel 

blockers. J Clin Pharmacol 38:477, 1998. 

6 Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-converting 

enzyme inhibitor, ramipril, 

on cardiovascular events in high-risk patients. The 

Heart Outcomes Prevention Evaluation Study Investigators. 

N Engl J Med 342:145, 2000. 

7. Fox KM, EURopean trial On reduction of cardiac 

events with perindopril in stable coronary artery 

disease investigators. Efficacy of perindopril in reduction 

of cardiovascular events among patients 

with stable coronary artery disease: randomized, 

double-blond, placebo-controlled, multicentre trial 

(the EUROPA study). Lancet 362: 782, 2003. 

8 Giatras I, Lau J, Levey SS: Effect of angiotensinconverting 

enzyme inhibitors on the progression 

of nondiabetic renal disease: A meta-analysis of 

randomized trials. Ann Intern Med 127:337, 1997. 

9. Jafar TH, Schmid CH, Landa M, et al: Angiotensin-converting 

enzyme inhibitors and progression 

of nondiabetic renal disease. A meta-analysis of 

patient-level data. Ann Intern Med 135:73, 2001. 

10. Hoogwerf BJ. Renin-angiotensin system blockade 

and cardiovascular and renal protection. Am J Cardiol 

105 (1 Suppl):30A, 2010. 

11. Garg R, Yusuf S, for the Collaborative Group on 

ACE Inhibitor Trials. Overview of randomized trials 

of angiotensin-converting enzyme inhibitors on 

mortality and morbidity in patients with heart failure. 

JAMA 273:1450, 1995. 

12. Law MR, Morris JK, Wald NJ. Use of blood pressure 

lowering drugs in the prevention of cardiovascular 

disease: meta-analysis of 147 randomised trials in 

the context of expectations from prospective epidemiological 

studies. BMJ 338: B1665, 2009. 

13. Kjeldsen SE, Julius S. Hypertension mega-trials 

with cardiovascular end points: effect of angiotensin-converting 

enzyme inhibitors and angiotensin 

receptor blockers. Am Heart J 148. 747, 2004. 

14. Toto R: Angiotensin II subtype 1-receptor blockers 

and renal function. Arch Intern Med 161:1492, 

2001. 

15. Al Khalaf MM, Thalib L, Doi SA. Cardiovascular 

outcomes in high-risk patients without heart failure 

treated with ARBs: a systematic review and 

meta-analysis. Am J Cardiovasc Drugs 9:29, 2009. 

16. JAMAli AH, Tang WH, Khot UN, Fowler MB: The 

role of angiotensin receptor blockers in the management 

of chronic heart failure. Arch Intern Med 

161:667, 2001. 

17. Johnston C, Risvanis J: Preclinical pharmacology 

of angiotensin II receptor antagonists: Update and 

outstanding issues. Am J Hypertens 10:306S, 1997. 

18. Burnier M: Angiotensin II type 1-receptor block- 



9-1


ers. Circulation 103:904, 2001. 

19. Carretero OA, Scicli AG: The kallikrein-kinin system 

as a regulator of cardiovascular and renal function. 

In: Brenner BM, Laragh JH, eds. Hypertension: 

Pathophysiology, Diagnosis, and Management. 2nd 

ed. New York: Raven Press, 1995:983–999. 

20. Juillerat L, Nussberger J, Menard J, et al: Determinants 

of angiotensin II generation during converting 

enzyme inhibition. Hypertension 16:564, 1990. 

21. Bacani C, Frishman WH: Chymase: a new pharmacologic 

target in cardiovascular disease. Cardiol in 

Rev 14: 187, 2006. 

22. Petrie MC, Padmanabhan N, McDonald JE, et al: 

Angiotensin-converting enzyme and non-ACE dependent 

angiotensin II generation in resistance arteries 

from patients with heart failure and coronary 

heart disease. J Am Coll Cardiol 37:1056, 2001. 

23. Ennezat PV, Berlowitz M, Sonnenblick EH, Le Jemtel 

TH: Therapeutic implications of escape from 

angiotensin-converting enzyme inhibition in patients 

with chronic heart failure. Curr Cardiol Rep 

2:258, 2000. 

24. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L: 

Hormones regulating cardiovascular function in 

patients with severe congestive heart failure and 

their relation to mortality. CONSENSUS Trial 

Study Group. Circulation 82:1730, 1990. 

25. Mooser V, Nussberger J, Juillerat L, et al: Reactive 

hyperreninemia is a major determinant of plasma 

angiotensin II during ACE inhibition. J Cardiovasc 

Pharmacol 15:276, 1990. 

26. Vander AJ, Geelhoed GW: Inhibition of renin secretion 

by angiotensin II. Proc Soc Exp Biol Med 

120:399, 1965. 

27. Grima M, Ingert C, Michel B, et al: Renal tissue angiotensins 

during converting enzyme inhibition in 

the spontaneously hypertensive rat. Clin Exp Hypertens 

19:671, 1997. 

28. Nussberger J, Brunner DB, Waeber A, et al: Lack 

of angiotensin I accumulation after converting enzyme 

blockade with enalapril or lisinopril in man. 

Clin Sci (Lond) 72:387, 1987. 

29. Staessen J, Fagard R, Lijnen P, et al: The hypotensive 

effect of propranolol in captopril-treated patients 

does not involve the plasma renin-angiotensinaldosterone 

system. Clin Sci (Lond) 61:441S, 1981. 

30. Hodsman GP, Isles CG, Murray GD, et al: Factors 

related to the first dose hypotensive effect of captopril: 

Prediction and treatment. Brit Med J286:832, 

1983. 

31. Case DB, Atlas SA, Laragh JH, et al: Use of first 

dose response or plasma renin activity to predict 

the long-term effect of captopril: Identification of 

triphasic pattern of blood pressure response. J Car- 

diovasc Pharmacol 2:339, 1980. 

32. Brunner HR, Waeber B, Nussberger J: Does 

pharmacological profiling of a new drug in normotensive 

volunteers provide a useful guide to 

antihypertensive therapy. Hypertension 5 (Supple 

III):101, 1983. 

33. Egan BM, Basile JN, Rehman SU, et al. Plasma 

Renin test-guided drug treatment algorithm for 

correcting patients with treated but uncontrolled 

hypertension: a randomized controlled trial. Am J 

Hypertens 22, 792, 2009. 

34. Gainer JV, Morrow JD, Loveland A, et al: Effect of 

bradykinin-receptor blockade on the response to 

angiotensin-converting enzyme inhibitor in normotensive 

and hypertensive subjects. N Engl J Med 

339:1285, 1998. 

35. Squire IB, O’Kane KP, Anderson N, Reid JL: Bradykinin 

B (2) receptor antagonism attenuates blood 

pressure response to acute angiotensin-converting 

enzyme inhibition in normal men. Hypertension 

36:132, 2000. 

36. Su JB, Barbe F, Crozatier B, et al: Increased bradykinin 

levels accompany the hemodynamic response 

to acute inhibition of angiotensin-converting enzyme 

in dogs with heart failure. J Cardiovasc Pharmacol 

34:700, 1999. 

37. Ogihara T, Maruyama A, Hata T, et al: Hormonal 

responses to long-term converting enzyme inhibition 

in hypertensive patients. Clin Pharmacol Ther 

30:328, 1981. 

38. Gavras I: Bradykinin-mediated effects of ACE inhibition. 

Kidney Int 42:1020, 1992. 

39. Mazzolai L, Maillard M, Rossat J, et al: Angiotensin 

II receptor blockade in normotensive subjects: 

A direct comparison of three AT 1 receptor antagonists. 


40. Abadir PM, Carey RM, Siragy HM: Angiotensin 

AT2-receptors directly stimulate renal nitric oxide 

in bradykinin B2-receptor null mice. Hypertension 

42:600, 2004. 

41. Rodriguez-Garcia JL, Villa E, Serrano M, et al: 

Prostacyclin: Its pathogenic role in essential hypertension 

and the class effect of ACE inhibitors 

on prostaglandin metabolism. Blood Press 8: 279, 

1999. 

42. Waeber B, Nussberger J, Brunner HR: Angiotensin-converting 

enzyme inhibitors in hypertension. 

In: Laragh JH, Brenner BM, eds. Hypertension: 

Pathophysiology, Diagnosis, and Management. 2nd 

ed. New York: Raven Press, 1995:2861–2875. 

43. Quest DW, Gopalakrishnan V, McNeill JR, Wilson 

TW: Effect of losartan on angiotensin II-mediated 

endothelin and prostanoid excretion in humans. 

Am J Hypertens 13:1288, 2000.

44. Salvetti A, Abdel-Hag B, Magagna A, et al: Indomethacin 

reduces the antihypertensive effect of 

enalapril. Clin Exp Hypertens 9:559, 1987. 

45. Wilson SL, Poulter NR. The effect of non-steroidal 

anti-inflammatory drugs and other commonly 

used non-narcotic analgesics on blood pressure 

level in adults. J Hypertens 24:1457, 2006. 

46. Nawarskas JJ, Townsend RR, Cirigliano MD, Spinler 

SA: Effect of aspirin on blood pressure in hypertensive 

patients taking enalapril or losartan. Am J 

Hypertens 12:784, 1999. 

47. Nawarskas JJ, Spinler SA: Does aspirin interfere 

with the therapeutic efficacy of angiotensin-converting 

enzyme inhibitors in hypertension or congestive 

heart failure. Pharmacotherapy 18:1041, 

1998. 

48. Guazzi MD, Campodonico J, Celeste F, et al: Antihypertensive 

efficacy of angiotensin-converting 

enzyme inhibition and aspirin counteraction. Clin 

Pharmacol Ther 63:79, 1998. 

49. Balt JC, Mathy MJ, Pfaffendorf M, van Zwieten PA: 

Inhibition of angiotensin II-induced facilitation of 

sympathetic neurotransmission in the pithed rat: A 

comparison between losartan, irbesartan, telmisartan, 

and captopril. J Hypertens 19:465, 2001. 

50. Lang CC, Stein M, He HB, et al: Angiotensin-converting 

enzyme inhibition and sympathetic activity 

in healthy subjects. Clin Pharmacol Ther 59:668, 

1996. 

51. Ranadive SA, Chen AX, Serajuddin AT: Relative 

lipophilicities and structural-pharmacological 

considerations of various angiotensin-converting 

enzyme (ACE) inhibitors. Pharm Res 9:1480, 1992. 

52. Gohlke P, Weiss S, Jansen A, et al: AT1 receptor 

antagonist telmisartan administered peripherally 

inhibits central responses to angiotensin II in conscious 

rats. J Pharmacol Exp Ther 298:62, 2001. 

53. Culman J, von Heyer C, Piepenburg B, et al: Effects 

of systemic treatment with irbesartan and losartan 

on central responses to angiotensin II in conscious, 

normotensive rats. Eur J Pharmacol 367:255, 1999. 

54. Krum H: Differentiation in the angiotensin II receptor 

1 blocker class on autonomic function. Curr 

Hypertens Rep 3 (Suppl 1):S17, 2001. 

55. Fagard R, Amery A, Reybrouck T, et al: Acute 

and chronic systemic and hemodynamic effects 

of angiotensin-converting enzyme inhibition with 

captopril in hypertensive patients. Am J Cardiol 

46:295, 1980. 

56. Yee KM, Struthers AD: Endogenous angiotensin 

II and baroreceptor dysfunction: A comparative 

study of losartan and enalapril in man. Br J Clin 

Pharmacol 46:583, 1998. 

57. Vanhoutte PM: Endothelial dysfunction and inhi- 


bition of converting enzyme. Eur Heart J 19 (Supple 

J):J7, 1998. 

58. Schiffrin EL, Park JB, Pu Q: Effect of crossing over 

hypertensive patients from a beta-blocker to an angiotensin 

receptor antagonist on resistance artery 

structure and on endothelial function. J Hypertens 

20:71, 2002. 

59. Schiffrin EL: Effects of antihypertensive drugs on 

vascular remodeling: Do they predict outcome in 

response to antihypertensive therapy. Curr Opin 

Nephrol Hypertens 10:617, 2001. 

60. Oparil S, Guthrie R, Lewin AJ, et al: An electivetitration 

study of the comparative effectiveness of 

two angiotensin II-receptor blockers, irbesartan 

and losartan. Irbesartan/Losartan Study Investigators. 

Clin Ther 20:398, 1998. 

61. Souza Dos Santos RA, Passaglio KT, Pesquero JB, et 

al: Interactions between angiotensin-(1–7), kinins, 

and angiotensin II in kidney and blood vessels. Hypertension 

38:660, 2001. 

62. Chappell MC, Allred AJ, Ferrario CM: Pathways 

of angiotensin-(1–7) metabolism in the kidney. 

Nephrol Dial Transplant 16(Suppl 1):22, 2001. 

63. Iusuf D, Henning RH, van Gilst WH, Roks AJ. Angiotensin-(1-7): 

pharmacological properties and 

pharmacotherapeutic perspectives. Eur J Pharmacol 

585:303, 2008. 

64. White CM: Pharmacologic, pharmacokinetic, and 

therapeutic differences among ACE inhibitors. 

Pharmacotherapy 18:588, 1998. 

65. Cody R: Optimizing ACE inhibitor therapy of congestive 

heart failure: Insights from pharmacodynamic 

studies. Clin Pharmacokinet 24:59, 1993. 

66. Dickstein K: Pharmacokinetics of enalapril in congestive 

heart failure. Drugs 32(Suppl 5):40, 1986. 

67. Herman AG: Differences in structure of angiotensin-converting 

enzyme inhibitors might predict 

differences in action. Am J Cardiol 70:102C, 1992. 

68. Salvetti A: Newer ACE inhibitors: A look at the future. 

Drugs 40:800, 1990. 

69. Zusman RM: Effects of converting-enzyme inhibitors 

on the renin-angiotensin-aldosterone, bradykinin, 

and arachidonic acid-prostaglandin systems: 

Correlation of chemical structure and biological 

activity. Am J Kidney Dis 10(Suppl 1):13, 1987. 

70. Chalmers D, Whitehead A, Lawson DH: Postmarketing 

surveillance of captopril for hypertension. 

Br J Clin Pharmacol 34:215, 1992. 

71. Punzi HD: Safety update: Focus on cough. Am J 

Cardiol 72:45H, 1993. 

72. Sharif MN, Evans BL, Pylypchuk GB: Cough induced 

by quinapril with resolution after changing 

to fosinopril. Ann Pharmacother 28:720, 1994. 

73. Zusman RM: Angiotensin-converting enzyme in-


hibitors: More different than alike. Am J Cardiol 

72:25H, 1993. 

74. Zusman RM, Christensen DM, Higgins J, Boucher 

CA: Effects of fosinopril on cardiac function in 

patients with hypertension. Radionuclide assessment 

of left ventricular systolic and diastolic performance. 


75. Sica DA: Angiotensin-converting enzyme inhibitors: 

Fosinopril. In: Messerli F, ed. Cardiovascular 

Drug Therapy. 2d ed. Philadelphia: WB Saunders 

1996:801–809. 

76. Brockmeier D: Tight binding influencing the future 

of pharmacokinetics. Methods Find Exp Clin 

Pharmacol 20:505–516, 1998. 

77. Reid JL: From kinetics to dynamics: Are there differences 

between ACE inhibitors. Eur Heart J 18 

(Suppl E): E14, 1997. 

78. Hoyer J, Schulte K-L, Lenz T: Clinical pharmacokinetics 

of angiotensin-converting enzyme inhibitors 

in renal failure. Clin Pharmacokinet 24:230, 1993. 

79. Dzau VJ, Bernstein K, Celermajer D, et al: The relevance 

of tissue angiotensin-converting enzyme: 

Manifestations in mechanistic and end-point data. 

Am J Cardiol 88 (Suppl 9):1L, 2001. 

79a. Kostis JB: Differences among ACE inhibitors: Am J 

Hypertens 23: 1156, 2010. 

79b. Ruzicka M, Coletta E, White R, et al: Effects of 

ACE inhibitors on cardiac angiotensin II and aldosterone 

in humans: “relevance of lipophilicity and 

affinity for ACE”. Am J Hypertens 23: 1179, 2010. 

80. Sica DA: Kinetics of angiotensin-converting enzyme 

inhibitors in renal failure. J Cardiovasc Pharmacol 

20 (Supp 10):S13, 1992. 

81. Ebihara A, Fujimura A: Metabolites of antihypertensive 

drugs. An updated review of their clinical 

pharmacokinetic and therapeutic implications. 

Clin Pharmacokinet 21:331, 1991. 

82. Kelly JG, Doyle GD, Carmody M, et al: Pharmacokinetics 

of lisinopril, enalapril and enalaprilat 

in renal failure: Effects of haemodialysis. Br J Clin 

Pharmacol 26:781, 1988. 

83. Schunkert H, Kindler J, Gassmann M, et al: Pharmacokinetics 

of ramipril in hypertensive patients 

with renal insufficiency. Eur J Clin Pharmacol 

37:249, 1989. 

84. Hui KK, Duchin KL, Kripalani KJ, et al: Pharmacokinetics 

of fosinopril in patients with various 

degrees of renal function. Clin Pharmacol Ther 

49:457, 1991. 

85. Danielson B, Querin S, LaRochelle P, et al: Pharmacokinetics 

and pharmacodynamics of trandolapril 

after repeated administration of 2 mg to patients 

with chronic renal failure and healthy control subjects. 

J Cardiovasc Pharmacol 23(Supp 4):S50, 1994. 

86. Kaiser G, Ackermann R, Sioufi A: Pharmacokinetics 

of a new angiotensin-converting enzyme 

inhibitor, benazepril hydrochloride, in special populations. 

Am Heart J 117:746, 1989. 

87. Noormohamed FH, McNabb WR, Lant AF: Pharmacokinetic 

and pharmacodynamic actions of 

enalapril in humans: Effect of probenecid pretreatment. 

J Pharmacol Exp Ther 253:362, 1990. 

88. Lin JH, Chen IW, Ulm EH, Duggan DE: Differential 

renal handling of angiotensin-converting enzyme 

inhibitors enalaprilat and lisinopril in rats. 

Drug Metab Dispos 16:392, 1998. 

89. Sica DA, Cutler RE, Parmer RJ, et al: Comparison 

of the steady-state pharmacokinetics of fosinopril, 

lisinopril, and enalapril in patients with chronic renal 

insufficiency. Clin Pharmacokinet 20:420, 1991. 

90. Greenbaum R, Zucchelli P, Caspi A, et al: Comparison 

of the pharmacokinetics of fosinoprilat with 

enalaprilat and lisinopril in patients with congestive 

heart failure and chronic renal insufficiency. Br 


91. Sica DA, Deedwania PC: Renal considerations in 

the use of angiotensin-converting enzyme inhibitors 

in the treatment of congestive heart failure. 

Cong Heart Fail 3:54, 1997. 

92. Brown NJ, Vaughn DE: Angiotensin-converting 

enzyme inhibitors. Circulation 97:1411, 1998. 

93. Fabris B, Jackson B, Kohzuki M, et al: Increased 

cardiac angiotensin-converting enzyme in rats 

with chronic heart failure. Clin Exp Pharmacol 

Physiol 17:309, 1990. 

94. Johnston CI, Fabris B, Yamada H, et al: Comparative 

studies of tissue inhibition by angiotensin-converting 

enzyme inhibitors. J Hypertens 7 

(Suppl):S11, 1989. 

95. Fabris B, Chen BZ, Pupic V, et al: Inhibition of 

angiotensin-converting enzyme (ACE) in plasma 

and tissue. J Cardiovasc Pharmacol 15(Suppl 2):S6, 

1990. 

96. Opie LH: ACE Inhibitors: Specific agents and 

pharmacokinetics. In: Opie LH, ed. Angiotensin- 

Converting Enzyme Inhibitors: Scientific Basis for 

Clinical Use. New York: Authors’ Publishing House, 

1994:171–247. 

97. Jackson EK, Garrison JC: Renin and angiotensin. 

In: Hardman JG, Limbird L, eds. Goodman & Gilman’s 

The Pharmacological Basis of Therapeutics. 

New York: McGraw-Hill, 1999:743–746. 

98. Johnston CI, Fabris B, Yoshida K: The cardiac renin-angiotensin 

system in heart failure. Am Heart J 

126:756, 1993. 

99. Fabris B, Yamada H, Cubela R, et al: Characterization 

of cardiac angiotensin-converting enzyme and 

in vivo inhibition following oral quinapril to rats.

Br J Pharmacol 100:651, 1990. 

100. Kinoshita A, Urata H, Bumpus FM, Husain A: 

Measurement of angiotensin I-converting enzyme 

inhibition in the heart. Circ Res 73: 51, 1993. 

101. Leonetti G, Cuspidi C: Choosing the right ACE inhibitor. 

A guide to selection. Drugs 49:516, 1995. 

102. Ruddy MC, Kostis JB, Frishman WH: Drugs that affect 

the renin-angiotensin system. In: Frishman W, 

Sonnenblick E, eds. Cardiovascular Pharmacotherapeutics. 


103. Briscoe TA, Dearing CJ: Clinical and economic 

effects of replacing enalapril with benazepril in 

hypertensive patients. Am J Health Syst Pharm 

53:2191, 1996. 

104. The SOLVD investigators. Effect of enalapril on 

survival in patients with reduced left ventricular 

ejection fractions and congestive heart failure. N 

Engl J Med 325:293, 1991. 

105. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The 

effect of angiotensin-converting enzyme inhibition 

on diabetic nephropathy. The Collaborative Study 

Group. N Engl J Med 329:1456, 1993. 

106. Sica DA: The HOPE Study: ACE inhibitors – are 

their benefits a class effect or do individual agents 

differ. Curr Opin Nephrol Hypertens 10:597, 2001. 

107. Jafar TH, Stark PC, Schmid CH, et al: Proteinuria 

as a modifiable risk factor for the progression of 

non-diabetic renal disease. Kidney Int 60:1131, 

2001. 

108. Wilson Tang WH, Vagelos RH, et al: Neurohormonal 

and clinical responses to high- versus lowdose 

enalapril therapy in chronic heart failure. J 


109. Packer M, Poole-Wilson PA, Armstrong PW, et al: 

Comparative effects of low and high doses of the 

angiotensin-converting enzyme inhibitor, lisinopril, 

on morbidity and mortality in chronic heart 

failure. ATLAS Study Group. Circulation 100:2312, 

1999. 

110. Massie B: Neurohormonal blockade in chronic 

heart failure. How much is enough. Can there be 

too much J Am Coll Cardiol 39:79, 2002. 

111. Tang WH, Vagelos RH, Yee YG, et al: Neurohormonal 

and clinical responses to high- versus lowdose 

enalapril therapy in chronic heart failure. J 


112. Van Veldhuisen DJ, Genth-Zotz S, Brouwer J, et al: 

High- versus low-dose ACE inhibition in chronic 

heart failure. A double-blind, placebo-controlled 

study of imidapril. J Am Coll Cardiol 32:1811, 1998. 

113. The American College of Cardiology/American 

Heart Association Task Force on Practical Guidelines 

(Committee on Evaluation and Management 

of Heart Failure) Guidelines for the evaluation and 


management of heart failure. Circulation 92:2764, 

1995. 

114. Sica DA: Pharmacology and clinical efficacy of 

angiotensin-receptor blockers. Am J Hypertens 

14:242S, 2001. 

115. Kassler-Taub K, Littlejohn T, Elliott W, et al: Comparative 

efficacy of two angiotensin II receptor antagonists, 

irbesartan and losartan, in mild to moderate 

hypertension. Am J Hypertens 11:445, 1998. 

116. Oparil S, Guthrie R, Lewin AJ, et al: An electivetitration 

study of the comparative effectiveness of 

two angiotensin II-receptor blockers, irbesartan 

and losartan. Clin Ther 20:398, 1998. 

117. Israili ZH: Clinical pharmacokinetics of angiotensin 

II (AT1) receptor blockers in hypertension. J 

Hum Hypertens 14 (Suppl 1): S73, 2000. 

177a. Azilsartan medoxomil (Edarbi)—the eighth ARB. 

The Medical Letter 43: 39, 2011. 

118. Atacand (candesartan cilexetil). Product information. 

Wilmington, DE: Astra Zeneca; 1998. 

119. Riddell JG: Bioavailability of candesartan is unaffected 

by food in healthy volunteers administered 

candesartan cilexetil. J Hum Hypertens 11 (Suppl 

2): S29, 1997. 

120. Tenero D, Martin D, Ilson B, et al: Pharmacokinetics 

of intravenously and orally administered eprosartan 

in healthy males: Absolute bioavailability and effect of 

food. Biopharm Drug Disp 19:351, 1998. 

121. Cox PJ, Bush BD, Gorycki PD, et al: The metabolic 

fate of eprosartan in healthy volunteers. Exp Toxicol 

Pathol 48(Suppl II):75, 1996. 

122. Bottorff MB, Tenero DM: Pharmacokinetics of 

eprosartan in healthy subjects, patients with hypertension, 

and special populations. Pharmacotherapy 

19:73S, 1999. 

123. Chapelsky MC, Martin DE, Tenero DM, et al: A 

dose proportionality study if eprosartan in healthy 

male volunteers. J Clin Pharmacol 38:34, 1998. 

124. Vachharajani NN, Shyu WC, Chando TJ, et al: Oral 

bioavailability and disposition characteristics of 

irbesartan, an angiotensin antagonist, in healthy 

volunteers. J Clin Pharmacol 38:702, 1998. 

125. Vachharajani NN, Shyu WC, Mantha S, et al: Lack 

of effect of food on the oral bioavailability of irbesartan 

in healthy male volunteers. J Clin Pharmacol 

38:433, 1998. 

126. Lo MW, Goldberg MR, McCrea JB, et al: Pharmacokinetics 

of losartan, an angiotensin II receptor 

antagonist, and its active metabolite, EXP3174 in 

humans. Clin Pharmacol Ther 58:641, 1995. 

127. Cozaar (losartan). Product information. West 

Point, PA: Merck & Co; 1995. 

128. Laeis P, Puchler K, Kirch W: The pharmacokinetic 

and metabolic profile of olmesartan medoxomil


limits the risk of clinically relevant drug interactions. 

J Hypertens 19 (Suppl 1): S21, 2001. 

129. Mycardis (telmisartan). Product information. 

Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 

1998. 

130. Stangier J, Schmid J, Turck D et al: Absorption, metabolism, 

and excretion of intravenously and orally 

administered [ 14 C] telmisartan in healthy volunteers. 


131. Flesch G, Muller P, Lloyd P: Absolute bioavailability 

and pharmacokinetics of valsartan, an angiotensin 

II receptor antagonist, in man. Eur J Clin 

Pharmacol 52:115, 1997. 

132. Diovan (valsartan). Product information. East Hanover, 

NJ: Novartis Pharmaceuticals; 1998. 

133. Gillis JC, Markham A: Irbesartan. A review of its 

pharmacodynamic and pharmacokinetic properties 

and therapeutic use in the management of hypertension. 

Drugs 54:885, 1997. 

134. Marino MR, Langenbacher K, Ford NF, et al: Pharmacokinetics 

and pharmacodynamics of irbesartan 

in healthy subjects. J Clin Pharmacol 38: 246, 

1998. 

135. Ludden TM: Nonlinear pharmacokinetics: Clinical 

implications. Clin Pharmacokinet 20: 429, 1991. 

136. Lo MW, Goldberg MR, McCrea JB, et al: Pharmacokinetics 

of losartan, an angiotensin II receptor 

antagonist, and its active metabolite, EXP3174 in 

humans. Clin Pharmacol Ther 58:641, 1995. 

137. Lo MW, Toh J, Emmert SE, et al: Pharmacokinetics 

of intravenous and oral losartan in patients with 

heart failure. Clin Pharmacol Ther 38:525, 1998. 

138. van Lier JJ, Heiningen PNM, Sunzel M: Absorption, 

metabolism and excretion of 14 C-candesartan 

and 14 C-candesartan cilexetil in healthy volunteers. 

J Hum Hypertens 11 (Suppl 2): S27, 1997. 

139. Criscione L, Bradley WA, Buylamayer P, et al: Valsartan: 

Preclinical and clinical profile of an antihypertensive 

angiotensin II antagonist. Cardiovasc 

Drug Rev 13:230, 1995. 

140. Bergmann K, Laeis P, Puchler K, et al: Olmesartan 

medoxomil: Influence of age, renal and hepatic 

function on the pharmacokinetics of olmesartan 

medoxomil. J Hypertens 19 (Suppl 1): S33, 2001. 

141. Christ DD: Human plasma protein binding of the 

angiotensin II receptor antagonist losartan potassium 

(DuP 753/MK 954) and its pharmacologically 

active metabolite EXP3174. J Clin Pharmacol 

35:515, 1995. 

142. Martin DE, Chapelsky MC, Ilson B, et al: Pharmacokinetics 

and protein binding of eprosartan in 

healthy volunteers and in patients with varying degrees 

of renal impairment. J Clin Pharmacol 38:129, 

1998. 

143. Colussi DM, Parisot C, Rossolino ML, et al: Protein 

binding of valsartan, a new angiotensin receptor 

antagonist. J Clin Pharmacol 37: 214, 1997. 

144. van Lier JJ, Heiningen PNM, Sunzel M: Absorption, 

metabolism and excretion of 14 C-candesartan 

and 14 C-candesartan cilexetil in healthy volunteers. 

J Hum Hypertens 11(Suppl 2):S27, 1997. 

145. Yun CH, Lee HS, Lee H, et al: Oxidation of the angiotensin 

II receptor antagonist losartan (DuP 753) 

in human liver microsomes; role of cytochrome 

P4503A (4) in formation of the active metabolite 

EXP3174. Drug Metab Dispos 23:285, 1995. 

146. Stearns RA, Chakravarty PK, Chen R, et al: Biotransformation 

of losartan to its active carboxylic 

acid metabolite in human liver microsomes. Role 

of cytochrome P 450 2C and 3A subfamily members. 


147. McCrea JB, Cribb A, Rushmore T, et al: Phenotypic 

and genotypic investigations of a healthy volunteer 

deficient in the conversion of losartan to its active 

metabolite E-3174. Clin Pharmacol Ther 65:348, 

1999. 

148. Hubner R, Hogemann AM, Sunzel M, et al: Pharmacokinetics 

of candesartan after single and multiple 

doses of candesartan cilexetil in young and 

elderly healthy volunteers. J Hum Hypertens 11 

(Suppl 2): S19, 1997. 

149. Kazierad DJ, Martin DE, Blum RA, et al: Effect of 

fluconazole on the pharmacokinetics of eprosartan 

and losartan in healthy male volunteers. Clin Pharmacol 

Ther 62:417, 1997. 

150. McCrea JB, Low MW, Furtek CI, et al: Ketoconazole 

does not effect the systemic conversion of 

losartan to E-3174. Clin Pharmacol Ther 59:A169, 

1996. 

151. Yasar U, Tybring G, Hidestrand M, et al: Role of 

CYP2C9 polymorphism in losartan oxidation. 


152. Zaidenstein R, Soback S, Gips M, et al: Effect of 

grapefruit juice on the pharmacokinetics of losartan 

and its active metabolite E3174 in healthy volunteers. 

Ther Drug Monit 23:369, 2001. 

153. Chando TJ, Everett DW, Kahle AD, et al: Biotransformation 

of irbesartan in man. Drug Metab Dispos 

26:408, 1998. 

154. Marino MR, Hammett JL, Ferreira I, et al: Effect 

of nifedipine on the steady-state pharmacokinetics 

and pharmacodynamics of irbesartan in healthy 

subjects. J Cardiovasc Pharmacol 3: 111, 1998. 

155. de Zeeuw D, Remuzzi G, Kirch W: The pharmacokinetics 

of candesartan cilexetil in patients with 

renal or hepatic impairment. J Hum Hypertens 11 

(Suppl 2):S37, 1997. 

156. Sica DA, Shaw WC, Lo MW, et al: The pharmacoki-

netics of losartan in renal insufficiency. J Hypertens 

13 (Suppl 1): S49, 1995. 

157. Sica DA, Marino MR, Hammett JL, et al: The pharmacokinetics 

of irbesartan in renal failure and 

maintenance hemodialysis. Clin Pharmacol Ther 

62: 610, 1997. 

158. Stangier J, Su CA, Brickl R, Franke H: Pharmacokinetics 

of single-dose telmisartan 120 mg given 

during and between hemodialysis in subjects 

with severe renal insufficiency: Comparison with 

healthy volunteers. J Clin Pharmacol 40: 1365, 

2000. 

159. Prasad P, Mangat S, Choi L, et al: Effect of renal 

function on the pharmacokinetics of valsartan. 

Clin Drug Invest 13:207, 1997. 

160. Kovacs SJ, Tenero DM, Martin DE, et al: Pharmacokinetics 


hemodialysis-dependent patients with end-stage 

renal disease. Pharmacotherapy 19:612, 1999. 

161. Martin DE, Chapelsky MC, Ilson B, et al: Pharmacokinetics 


healthy volunteers and in patients with varying degrees 

of renal impairment. J Clin Pharmacol 38:129, 

1998. 

162. Toto R, Shultz P, Jaij L, et al: Efficacy and tolerability 

of losartan in hypertensive patients with renal 

impairment. Hypertension 31: 684, 1998. 

163. Sharma AM, Hollander A, Koster J, et al. Efficacy 

and safety in patients with renal impairment; 

treated with Telmisartan (ESPRIT) Study Group. 

Telmisartan in patients with mild/moderate hypertension 

and chronic kidney disease. Clin Nephrol 

63: 250, 2005. 

164. Schulz EG, Bahri S, Schettler V, et al. Pharmacokinetics 

and antihypertensive effects of candesartan 

cilexetil in patients undergoing haemodialysis: an 

open-label, single-centre study. Clin Drug Investig 

29:713, 2009. 

165. Plum J, Bünten B, Németh R, Grabensee B. Effects 

of the angiotensin II antagonist valsartan on blood 

pressure, proteinuria, and renal hemodynamics in 

patients with chronic renal failure and hypertension. 

J Am Soc Nephrol 9: 2223, 1998. 

166. De Rosa ML, de Cristofaro A, Rossi M, et al: Irbesartan 

effects on renal function in patients with 

renal impairment and hypertension: a drug-withdrawal 

study. J Cardiovasc Pharmacol 38: 482, 2001. 

167. Hunsicker LG, Atkins RC, Lewis JB, et al. Impact of 

irbesartan, blood pressure control, and proteinuria 

on renal outcomes in the Irbesartan Diabetic Nephropathy 

Trial. Kidney Inter 66: S99, 2004. 

168. Sica DA, Gehr TW, Fernandez A: Risk-benefit ratio 

of angiotensin antagonists versus ACE inhibitors in 

end-stage renal disease. Drug Saf 22: 350, 2000. 


169. Brunner HR: The new angiotensin II receptor antagonist, 

irbesartan. Pharmacokinetic and pharmacodynamic 

considerations. Am J Hypertens 10: 

311S, 1997. 

170. Mazzolai L, Maillard M, Rossat J, et al: Angiotensin 

II receptor blockade in normotensive subjects. A 

direct comparison of three AT1-receptor antagonists. 


171. Hodges JC, Hamby JM, Blankey CJ: Angiotensin 

II receptor binding inhibitors. Drugs Fut 17:575, 

1992. 

172. Dickinson KE, Cohen RB, Skwish S, et al: BMS 

180560, an insurmountable inhibitor of angiotensin-II 

stimulated responses: Comparison with 

losartan and EXP-3174. Br J Pharmacol 113:179, 

1994. 

173. Liu YJ, Shankley NP, Welsh NJ, et al. Evidence 

that the apparent complexity of receptor antagonism 

by angiotensin II analogues is due to a 

reversible and syntopic action. Br J Pharmacol 106: 

233,1992. 

174. Ojima M, Inada Y, Shibouta Y, et al: Candesartan 

(CV-11974) dissociates slowly from the angiotensin 

AT1 receptor. Eur J Pharmacol 319:137, 1997. 

175. McConnaughey MM, McConnaughey JS, Ingenito 

AJ: Practical considerations of the pharmacology 

of angiotensin receptor blockers. J Clin Pharmacol 

39:547, 1998. 

176. Hansson L: The relationship between dose and 

antihypertensive effect for different AT1-receptor 

blockers. Blood Press Suppl 3:33, 2001. 

177. Maillard MP, Wurzner G, Nussberger J, et al: 

Comparative angiotensin II receptor blockade in 

healthy volunteers: The importance of dosing. Clin 


178. Hollenberg NK: Renal implications of angiotensin 

receptor blockers. Am J Hypertens 14:237S, 2001. 

179. Hodsman GP, Isles CG, Murray GD, et al: Factors 

related to first-dose hypotensive effect of captopril: 

Prediction and treatment. Br Med J 286:832, 1983. 

180. Muiesan G, Alicandri CL, Agabiti-Rosei E, et al: 

Angiotensin-converting enzyme inhibition, catecholamines, 

and hemodynamics in essential 

hypertension. Am J Cardiol 46:1420, 1980. 

181. Saragoca MA, Homsi E, Ribeiro AB, et al: Hemodynamic 

mechanism of blood pressure response to 

captopril in human malignant hypertension. Hypertension 

5 (Suppl I):53, 1983. 

182. Magrini F, Shimizu M, Roberts N, et al: Converting-enzyme 

inhibition and coronary blood flow. 


183. Yusuf S, Lonn E: Anti-ischemic effects of ACE inhibitors: 

Review of current clinical evidence and 

ongoing clinical trials. Eur Heart J 19 (Suppl J): J36,


1998. 

184. Brugts JJ, den Uil CA, Danser AH, Boersma E. The 

renin-angiotensin-aldosterone system: approaches 

to guide angiotensin-converting enzyme inhibition 

in patients with coronary artery disease. Cardiology 

112:303, 2009. 

185. Waldemar G, Ibsen H, Strandgaard S, et al: The effect 

of fosinopril sodium on cerebral blood flow in 

moderate essential hypertension. Am J Hypertens 

3:464, 1990. 

186. Sare GM, Gray LJ, Bath PM. Effect of antihypertensive 

agents on cerebral blood flow and flow velocity 

in acute ischaemic stroke: systematic review of 

controlled studies. J Hypertens 26:1058, 2008. 

187. Sica DA. Calcium channel blocker-related peripheral 

edema: can it be resolved? J Clin Hypertens 

(Greenwich) 5: 291, 2003. 

188. Morioka S, Simon G, Cohn JN: Cardiac and hormonal 

effects of enalapril in hypertension. Clin 


189. Omvik P, Lund-Johansen P: Combined captopril 

and hydrochlorothiazide therapy in severe hypertension: 

Long-term haemodynamic changes at rest 

and during exercise. J Hypertens 2:73, 1984. 

190. Hollenberg N, Raij L: Angiotensin-converting enzyme 

inhibition and renal protection. Arch Intern 

Med 153:2426, 1993. 

191. Toto RD, Mitchell HC, Lee HC, et al: Reversible 

renal insufficiency due to angiotensin-converting 

enzyme inhibitors in hypertensive nephrosclerosis. 


192. Mancia G, De Backer G, Dominiczak A, et al. ESH- 

ESC Task Force on the Management of Arterial 

Hypertension. 2007 ESH-ESC Practice Guidelines 

for the Management of Arterial Hypertension: 

ESH-ESC Task Force on the Management of Arterial 

Hypertension. J Hypertens 25:1751, 2007. 

193. Khan NA, Hemmelgarn B, Herman RJ, et al. Canadian 

Hypertension Education Program. The 2009 

Canadian Hypertension Education Program recommendations 

for the management of hypertension: 

Part 2 - therapy. Can J Cardiol 25:287, 2009. 

194. Sica DA: Old antihypertensive agents - diuretics 

and beta-blockers: Do we know how and in whom 

they reduce blood pressure Curr Hypertens Rep 

1:296, 1999. 

195. Julius S, Nesbitt SD, Egan BM, et al for the Trial 

of Preventing Hypertension (TROPHY) study investigators: 

Feasibility of treating prehypertension 

with an angiotensin-receptor blockers. N Engl J 

Med 354: 1685, 2006. 




Engl J Med 328:914, 1993. 

197. Elliott WJ: Therapeutic trials comparing angiotensin-converting 

enzyme inhibitors and angiotensin 

II receptor blockers. Curr Hypertens Rep 2:402, 

2000. 

197a. Catanzaro DF, Frishman WH: Angiotensin receptor 

blockers for management of hypertension. 

South Med J 103: 669, 2010. 

198. Caro JJ, Speckman JL, Salas M, et al: Effect of initial 

drug choice on persistence with antihypertensive 

therapy: The importance of actual practice data. 

CMAJ 160:41, 1999. 

199. Matchar DB, McCrory DC, Orlando LA, et al. 

Systematic review: comparative effectiveness of 

angiotensin-converting enzyme inhibitors and angiotensin 

II receptor blockers for treating essential 

hypertension. Ann Intern Med 148:16, 2008. 

200. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects 

of losartan on renal and cardiovascular outcomes 

in patients with type 2 diabetes and nephropathy. 

N Engl J Med 345:861, 2001. 

201. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective 

effect of the angiotensin-receptor antagonist 

irbesartan in patients with nephropathy due 

to type 2 diabetes. N Engl J Med 345:851, 2001. 

202. Halkin A, Keren G: Potential indications for angiotensin-converting 

enzyme inhibitors in atherosclerotic 

vascular disease. Am J Med 112:126, 2002. 

203. Hansson L, Lindholm L, Niskanen L, et al: Effect 

of angiotensin-converting-enzyme inhibition compared 

with conventional therapy on cardiovascular 

morbidity and mortality in hypertension: The Captopril 

Prevention Project (CAPPP) randomised 

trial. Lancet 353:611, 1999. 

204. Sica DA. Do pleiotropic effects of antihypertensive 

medications exist or is it all about the blood pressure? 

Curr Hypertens Rep 10:415, 2008. 

205. Smith RD, Franklin SS: Comparison of effects of 

enalapril plus hydrochlorothiazide versus standard 

triple therapy on renal function in renovascular hypertension. 

Am J Med 79 (Suppl 3C):14, 1985. 

206. Maillard JO, Descombes E, Fellay G, Regamey C: 

Repeated transient anuria following losartan administration 

in a patient with a solitary kidney. Renal 

Fail 23:143, 2001. 

207. Flack JM, Saunders E, Gradman A, et al: Antihypertensive 

efficacy and safety of losartan alone and 

in combination with hydrochlorothiazide in adult 

African Americans with mild-to-moderate hypertension. 

Clin Ther 23:1193, 2001. 

208. Weidmann P, De Myttenaere-Bursztein S, Maxwell 

MH: Effect of aging on plasma renin and aldosterone 

in normal man. Kidney Int 8:325, 1975. 

209. Gradman AH. Role of angiotensin II type 1 recep-

tor antagonists in the treatment of hypertension in 

patients aged > or = 65 years. Drugs Aging 26:751, 

2009. 

210. Sehgal AR. Overlap between whites and blacks in 

response to antihypertensive drugs. Hypertension 

43: 566, 2004. 

211. Weir MR, Gray JM, Paster R, et al: Differing mechanisms 

of action of angiotensin-converting enzyme 

inhibition in black and white hypertensive patients. 


212. Agodoa LY, Appel L, Bakris GL, et al: Effect of 

ramipril vs amlodipine on renal outcomes in hypertensive 

nephrosclerosis: A randomized controlled 

trial. JAMA 285:2719, 2001. 

213. Whitworth JA; World Health Organization, International 

Society of Hypertension Writing Group. 

2003 World Health Organization (WHO)/International 

Society of Hypertension (ISH) statement on 

management of hypertension. J Hypertens 21:1983, 

2003. 

214. Zannad F: Trandolapril: how does it differ from 

other angiotensin-converting enzyme Inhibitors. 

Drugs 46 (Suppl 2):172, 1993. 

215. Omboni S, Fogari R, Palatini P, et al: Reproducibility 

and clinical value of the trough-to-peak ratio 

of the antihypertensive effect. Evidence from the 

Sample Study. Hypertension 32:424, 1998. 

216. Izzo JL, Sica DA: Antihypertensive drugs: pharmacologic 

principles and dosing effects. In: Izzo JL, 

Sica DA, Black HR, eds. Hypertension Primer. 4th 

ed. Philadelphia Lippincott, Williams & Wilkins, 

2008:432–435. 

217. Gradman AH, Lewin A, Bowling BT, et al: Comparative 

effects of candesartan cilexetil and losartan in 

patients with systemic hypertension. Candesartan 

Versus Losartan Efficacy Comparison (CANDLE) 

Study Group. Heart Dis 1:52, 1999. 

218. Mancia G, Dell’Oro R, Turri C, Grassi G: Comparison 

of angiotensin II receptor blockers: impact of 

missed doses of candesartan cilexetil and losartan 

in systemic hypertension. Am J Cardiol 84:28S, 

1999. 

219. Oparil S, Williams D, Chrysant SG, et al: Comparative 

efficacy of olmesartan, losartan, valsartan, and 

irbesartan in the control of essential hypertension. 

J Clin Hypertens 3:283, 2001. 

220. Vidt DG, White WB, Ripley E, et al: A forced titration 

study of antihypertensive efficacy of candesartan 

cilexetil in comparison to losartan: CLAIM 

Study II. J Hum Hypertens 15:475, 2001. 

221. Meredith PA: Clinical comparative trials of angiotensin 

II type 1 (AT1)-receptor blockers. Blood 

Press Suppl 3:11, 2001. 

222. Oparil S: Are there meaningful differences in blood 


pressure control with current antihypertensive 

agents. Am J Hypertens 15:14S, 2002. 

223. Conlin PR, Spence JD, Williams B, et al: Angiotensin 

II antagonists for hypertension: Are there differences 

in efficacy. Am J Hypertens 13:418, 2000. 

224. Fogari R, Mugellini A, Zoppi A, et al: A doubleblind 

crossover study of the antihyper-tensive efficacy 

of angiotensin II-receptor antagonists and 

their activation of the renin-angiotensin system. 

Curr Ther Res Clin Exp 61:669, 2000. 

225. Hansson L: The relationship between dose and 

antihypertensive effect for different AT1-receptor 

blockers. Blood Press Suppl 3:33, 2001. 

226. Veteran’s Administration Cooperative Study Group 

on Antihypertensive Agents. Low-dose captopril 

for the treatment of mild to moderate hypertension. 

Hypertension 5 (Suppl III): 139, 1983. 

227. Neutel JM, Black HR, Weber MA: Combination 

therapy with diuretics: An evolution of understanding. 

Am J Med 101:61S, 1996. 

228. Sica DA: Rationale for fixed-dose combinations in 

the treatment of hypertension: The cycle repeats. 

Drugs 62:443, 2002. 

229. Veteran Administration Cooperative Study Group 

on Antihypertensive Agents. Racial differences in 

response to low-dose captopril are abolished by the 

addition of hydrochloro-thiazide. Br J Clin Pharmacol 

14:97S, 1982. 

230. Hansson L: Beta blockers with ACE inhibitors - a 

logical combination. J Hum Hypertens 3:97, 1989. 

231. Belz GG, Essig J, Erb K, et al: Pharmacokinetic and 

pharmacodynamic interactions between the ACE 

inhibitor cilazapril and beta-adrenoreceptor antagonist 

propranolol in healthy subjects and in hypertensive 

patients. Br J Clin Pharmacol 27 (Suppl 

2): 317S, 1989. 

232. Black HR, Sollins JS, Garofalo JL: The addition of 

doxazosin to the therapeutic regimen of hypertensive 

patients inadequately controlled with other 

antihypertensive medications: A randomized, placebo-controlled 

study. Am J Hypertens 13:468–474, 

2000. 

233. Frampton JE, Scott LJ. Amlodipine/valsartan single-pill 

combination: a review of its use in the management 

of hypertension. Am J Cardiovasc Drugs 

9:309, 2009. 

234. Frishman WH, Ram CV, McMahon FG, et al., for 

the Benazepril/Amlodipine Study Group. Comparison 

of amlodipine and benazepril monotherapy 

to amlodipine plus benazepril in patients with systemic 

hypertension: A randomized, double-blind, 

placebo-controlled, parallel-group study. J Clin 

Pharmacol 35:1060, 1995. 

235. DeQuattro V, Lee D: Fixed-dose combination ther-


apy with trandolapril and verapamil SR is effective 

in primary hypertension. Am J Hypertens 10 (Suppl 

2): 138S, 1997. 

235a. Kostis JB: Antihypertensive therapy with CCB/ 

ARB combination in older individuals: focus on 

amlodipine/valsartan combination. Am J Therap 

17: 188, 2010. 

236. Calhoun DA, Lacourcière Y, Chiang YT, Glazer 

RD. Triple antihypertensive therapy with amlodipine, 

valsartan, and hydrochlorothiazide: a randomized 

clinical trial. Hypertension 54: 32, 2009. 

237. Fogari R, Malamani G, Corradi L, et al. Effect of 

valsartan or olmesartan addition to amlodipine 

on ankle edema in hypertensive patients. Adv Ther 

27:48, 2010. 

237a. Bakris GL, Sarafidis PA, Weir MR, et al for the AC- 

COMPLISH Trial Investigators: Renal outcomes 

with different fixed-dose combination therapies 

in patients with hypertension at high risk for cardiovascular 

events (ACCOMPLISH): a prespecified 

secondary analysis of a randomized controlled 

trial. Lancet 375: 1173, 2010. 

238. Sica DA. Combination ACE inhibitor and angiotensin 

receptor blocker therapy - future considerations. 

J Clin Hypertens (Greenwich) 9:78, 2007. 

239. Doulton TW, He FJ, MacGregor GA. Systematic review 

of combined angiotensin-converting enzyme 

inhibition and angiotensin receptor blockade in 


240. Taylor AA: Is there a place for combining angiotensin-converting 

enzyme inhibitors and angiotensin-receptor 

antagonists in the treatment of 

hypertension, renal disease or congestive heart failure. 

Curr Opin Nephrol Hypertens 10:643, 2001. 

241. ONTARGET Investigators, Yusuf S, Teo KK, et al. 

Telmisartan, ramipril, or both in patients at high 

risk for vascular events. N Engl J Med 358:1547, 

2008. 

242. Mann JF, Schmieder RE, McQueen M, et al. Renal 

outcomes with telmisartan, ramipril, or both, 

in people at high vascular risk (the ONTARGET 

study): a multicentre, randomised, double-blind, 


243. Bevan EG, Pringle SD, Walker PC, et al: Comparison 

of captopril, hydralazine and nifedipine as 

third drug in hypertensive patients. J Hum Hypertens 

7:83, 1993. 

244. Dufloux JJ, Prasquier R, Chatellier G, et al: Effects 

of captopril and minoxidil on left ventricular hypertrophy 

in resistant hypertensive patients: A 

6-month double-blind comparison. J Am Coll Cardiol 

16:137, 1990. 

245. Kazerani H, Hajimoradi B, Amini A, et al. Clinical 

efficacy of sublingual captopril in the treatment 

of hypertensive urgency. Singapore Med J 50:400, 

2009. 

246. Hirschl MM, Binder M, Bur A, et al: Impact of the 

renin-angiotensin-aldosterone system on blood 

pressure response to intravenous enalaprilat in patients 

with hypertensive crises. J Hum Hypertens 

11:177, 1997. 

247. Sica DA: Dosage considerations with perindopril 

for hypertension. Am J Cardiol88 (Suppl 1):13, 

2001. 

248. Schlaich MP, Schmieder RE: Left ventricular hypertrophy 

and its regression: Pathophysiology and 

therapeutic approach. Am J Hypertens 11:1394, 

1998. 

249. Prisant LM. Management of hypertension in patients 

with cardiac disease: use of renin-angiotensin 

blocking agents. Am J Med 121 (8 Suppl): S8, 

2008. 

250. Grandi AM, Laurita E, Solbiati F, et al. Angiotensin-converting 

enzyme inhibitors influence left 

ventricular mass and function independently of the 

antihypertensive effect. J Cardiovasc Pharmacol 48: 

207, 2006. 

251. Fagard RH, Celis H, Thijs L, Wouters S. Regression 

of left ventricular mass by antihypertensive treatment: 

a meta-analysis of randomized comparative 

studies. Hypertension 54:1084, 2009. 

252. Verdecchia P, Sleight P, Mancia G, et al. ON- 

TARGET/TRANSCEND Investigators. Effects of 

telmisartan, ramipril, and their combination on left 

ventricular hypertrophy in individuals at high vascular 

risk in the Ongoing Telmisartan Alone and 

in Combination With Ramipril Global End Point 

Trial and the Telmisartan Randomized Assessment 

Study in ACE Intolerant Subjects With Cardiovascular 

Disease. Circulation 120:1380, 2009. 

253. Os I, Franco V, Kjeldsen SE, et al: Effects of losartan 

in women with hypertension and left ventricular 

hypertrophy. Results from the Losartan 

Intervention for Endpoint Reduction in Hypertension 

Study. Hypertension 51: 1103, 2008. 

254. Koren MJ, Devereux RB, Casale PN, et al: Relation 

of left ventricular mass and geometry to morbidity 

and mortality in uncomplicated essential hypertension. 


255. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular 

morbidity and mortality in the Losartan 

Intervention for Endpoint reduction in hypertension 

study (LIFE): A randomised trial against atenolol. 

Lancet 359: 995, 2002. 

256. Longobardi G, Corbi G, Cacciatore F, et al: Effect of 

losartan in treatment of exercise-induced myocardial 

ischemia. Am J Cardiol 100; 1517, 2007. 

257. Daly P, Mettauer B, Rouleau JL, et al: Lack of reflex

increase in myocardial sympathetic tone after captopril: 

Potential antianginal mechanism. Circulation 

71:317, 1985. 

258. Chrysant SG: Vascular remodeling: The role of angiotensin-converting 

enzyme inhibitors. Am Heart 

J 135:S21, 1998. 

259. Schiffrin EL, Park JB, Pu Q: Effect of crossing over 

hypertensive patients from a beta-blocker to an angiotensin 

receptor antagonist on resistance artery 

structure and on endothelial function. J Hypertens 

20:71, 2002. 

260. Frei A, Muller-Brand J: Cerebral blood flow and 

antihypertensive treatment with enalapril. J Hypertens 

4:365, 1986. 

261. Roberts DH, Tsao Y, McLoughlin GA, et al: Placebo-controlled 

comparison of captopril, atenolol, labetalol, 

and pindolol in hypertension complicated 

by intermittent claudication. Lancet 2:650, 1987. 

262. Ostergren J, Sleight P, Dagenais G, et al. Impact 

of ramipril in patients with evidence of clinical or 

subclinical peripheral arterial disease. Eur Heart J 

25:17, 2004. 

263. Preston RA: Renoprotective effects of antihypertensive 

drugs. Am J Hypertens 12:19S, 1999. 

264. Wright JT Jr, Bakris G, Greene T, et al. Effect of 

blood pressure lowering and antihypertensive drug 

class on progression of hypertensive kidney disease: 

results from the AASK trial. JAMA 288: 2421, 

2002. 

265. Malini P, Stochi E, Ambrosioni E, et al: Long-term 

antihypertensive, metabolic and cellular effects of 

enalapril. J Hypertens 2 (Suppl 2): 101, 1984. 

266. Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr. 

Angiotensin-converting enzyme inhibitors or angiotensin 

receptor blockers for prevention of type 

2 diabetes: a meta-analysis of randomized clinical 

trials. J Am Coll Cardiol 46: 821, 2005. 

267. Scheen AJ. Renin-angiotensin system inhibition 

prevents type 2 diabetes mellitus. Part 1. A metaanalysis 

of randomised clinical trials. Diabetes 

Metab 30: 487, 2004. 

268. The DREAM Trial Investigators. Effect of ramipril 

on the incidence of diabetes. N Engl J Med 355:1551, 

2006. 

269. The NAVIGATOR Study Group. Effect of Valsartan 

on the Incidence of Diabetes and Cardiovascular 

Events. N Engl J Med Mar 16, 2010. [Epub ahead of 

print] 

270. Sacco RL: Reducing the risk of stroke in diabetes: 

What have we learned that is new Diabetes Obes 

Metab 4 (Suppl 1):27, 2002. 

271. Bosch J, Yusuf S, Pogue J, et al: Use of ramipril in 

preventing stroke: Double blind randomised trial. 

BMJ 324:699, 2002. 


272. Leenen FH, Nwachuku CE, Black HR, et al. Clinical 

events in high-risk hypertensive patients randomly 

assigned to calcium channel blocker versus 

angiotensin-converting enzyme inhibitor in the 

antihypertensive and lipid-lowering treatment to 

prevent heart attack trial. Hypertension 48:374, 

2006. 

273. Beckett NS, Peters R, Fletcher AE et al; HYVET 

Study Group. Treatment of hypertension in patients 

80 years of age or older. N Engl J Med 358:1887, 

2008. 

274. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. 

Prevention of cardiovascular events 

with an antihypertensive regimen of amlodipine 

adding perindopril as required versus atenolol adding 

bendroflumethiazide as required, in the Anglo-Scandinavian 

Cardiac Outcomes Trial-Blood 

Pressure Lowering ARM (ASCOT-BPLA): a multicentre 

randomised controlled trial. Lancet 366:895, 

2005. 

275. Jamerson K, Weber MA, Bakris GL, et al. Benazepril 

plus amlodipine or hydrochloro-thiazide for 

hypertension in high-risk patients. N Engl J Med 

359: 2417, 2008. 

276. Randomised trial of a perindopril-based bloodpressure-lowering 

regimen among 6,105 individuals 

with previous stroke or transient ischaemic 

attack. Lancet 358:1033, 2001. 

277. Lithell H, Hansson L, Skoog I, et al; SCOPE Study 

Group. The Study on Cognition and Prognosis in 

the Elderly (SCOPE); principal results of a randomized, 

double-blind intervention trial. J Hypertens 

21:875, 2003. 

278. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in 

hypertensive patients at high cardiovascular risk 

treated with regimens based on valsartan or amlodipine: 

the VALUE randomised trial. Lancet. 363: 

2022, 2004. 

279. Yusuf S, Teo K, Anderson C et al. Telmisartan Randomised 

Assessment Study in ACE-Intolerant Subjects 

With Cardiovascular Disease (TRANSCEND) 

Investigators. Effects of the angiotensin-receptor 

blocker telmisartan on cardiovascular events in 

high-risk patients intolerant to angiotensin-converting 

enzyme inhibitors: a randomised controlled 

trial. Lancet 372:1174, 2008. 

280. Schrader J, Lüders S, Kulschewski A, et al. The AC- 

CESS Study: evaluation of Acute Candesartan Cilexetil 

Therapy in Stroke Survivors. Stroke 34: 1699, 

2003. 

281. Schrader J, Lüders S, Kulschewski A, et al. Morbidity 

and Mortality After Stroke, Eprosartan compared 

with nitrendipine for secondary prevention: 

principal results of a prospective randomized con-


trolled study (MOSES). Stroke 36:1218, 2005. 

282. Yusuf S, Diener HC, Sacco RL, et al; PRoFESS 

Study Group. Telmisartan to prevent recurrent 

strokes and cardiac events. N Engl J Med 359:1225, 

2008. 

283. Lu GC, Cheng JW, Zhu KM, et al. A systematic review 

of angiotensin receptor blockers in preventing 

stroke. Stroke 40:3876, 2009. 

284. Reboldi G, Angeli F, Cavallini C, et al. Comparison 

between angiotensin-converting enzyme inhibitors 

and angiotensin receptor blockers on the risk of 

myocardial infarction, stroke and death: a metaanalysis. 

J Hypertens 26: 1282, 2008. 

285. Parving HH, Lehnert H, Brochner-Mortensen J, et 

al: The effect of irbesartan on the development of 

diabetic nephropathy in patients with type 2 diabetes. 

N Engl J Med 345:870, 2001. 

286. Keane WF: Proteinuria: Its clinical importance and 

role in progressive renal disease. Am J Kidney Dis 

35 (Suppl 1):S97, 2000. 

287. Levey AS, Coresh J, Balk E, et al. National Kidney 

Foundation practice guidelines for chronic kidney 

disease: evaluation, classification, and stratification. 


288. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The 

effect of angiotensin-converting-enzyme inhibition 

on diabetic nephropathy: The Collaborative 

Study Group. N Engl J Med 329:1456, 1993. 

289. Ravid M, Lang R, Rachmani R, et al: Long-term 

renoprotective effect of angiotensin-converting enzyme 

inhibition in non-insulin dependent diabetes 

mellitus. A 7-year follow-up study. Arch Intern Med 

156:286, 1996. 

290. Viberti G, Mogensen CE, Groop LC, Pauls JF: Effect 

of captopril on progression to clinical proteinuria 

in patients with insulin-dependent diabetes 

mellitus and microalbuminuria: European Microalbuminuria 

Captopril Study Group. JAMA 

271:275, 1994. 

291. Maschio G, Alberti D, Janin G, et al: Effect of the 

angiotensin-converting enzyme inhibitor benazepril 

on the progression of chronic renal insufficiency. 

N Engl J Med 334:939, 1996. 

292. Uhle BU, Whitworth JA, Shahinfar S, et al: Angiotensin-converting 

enzyme inhibition in nondiabetic 

progressive renal insufficiency: A controlled 

double-blind trial. Am J Kidney Dis 27:489, 1996. 

293. The Gisen Group: Randomized placebo-controlled 

trial of effect of ramipril on decline in glomerular 

filtration rate and risk of terminal renal failure 

in proteinuric, non-diabetic nephropathy. Lancet 

349:1857, 1997. 

294. Giatras I, Lau J, Levey As, et al., for the Angiotensin-Converting 

Enzyme Inhibition and Pro- 

gressive Renal Disease Study Group. Effect of 

angiotensin-converting enzyme inhibitors on the 

progression of nondiabetic renal disease: A metaanalysis 

of randomized trials. Ann Intern Med 

127:337, 1997. 

295. Ruggenenti P, Perna A, Gherardi G, et al: Chronic 

proteinuric nephropathies: Outcomes and response 

to treatment in a prospective cohort of 352 

patients with different patterns of renal injury. Am 

J Kidney Dis 35:1155, 2000. 

296. Ahmad J, Siddiqui MA, Ahmad H: Effective postponement 

of diabetic nephropathy with enalapril 

in normotensive type 2 diabetic patients with microalbuminuria. 

Diabetes Care 20:1576, 1997. 

297. Ravid M, Savin H, Jutrin I, et al: Long-term stabilizing 

effect of angiotensin-converting enzyme inhibition 

on plasma creatinine and on proteinuria in 

normotensive type II diabetic patients. Ann Intern 

Med 118:577, 1993. 

298. Mathiesen ER, Hommel R, Giese J, Parving H: Efficacy 

of captopril in postponing nephropathy in 

normotensive insulin dependent diabetic patients 

with microalbuminuria. BMJ 303:81, 1991. 

299. The EUCLID Study Group. Randomized placebo-controlled 

trial of lisinopril in normotensive 

patients with insulin-dependent diabetes and normoalbuminuria 

and microalbuminuria. Lancet 

349:1787, 1997. 

300. Sano T, Kawamura T, Matsumae H, et al: Effects 

of long-term enalapril treatment on persistent microalbuminuria 

in well-controlled hypertensive 

and normotensive NIDDM patients. Diabetes Care 

17:420, 1994. 

301. Ravid M, Brosh D, Levi Z, et al: Use of enalapril 

to attenuate decline in renal function in normotensive, 

normoalbuminuric patients with type 2 diabetes 

mellitus. Ann Intern Med 128: 982–988, 1998. 

302. Hou FF, Zhang X, Zhan GH, et al: Efficacy and 

safety of benazepril for advanced chronic renal insufficiency. 

N Engl J Med 354: 131, 2006. 

303. Lebovitz s, Wiegmann TB, Cnaan A, et al: Renal 

protective effect of enalapril in hypertensive NI- 

DDM: Role of baseline albuminuria. Kidney Int 45 

(Suppl):S150, 1994. 

304. Fogari R, Zoppi A, Corradi L, et al: Long-term effects 

of ramipril and nitrendipine on albuminuria 

in hypertensive patients with type II diabetes and 

impaired renal function. J Hum Hypertens 13:47, 

1999. 

305. Nielsen FS, Rossing P, Gall MA, et al: Long-term 

effect of lisinopril and atenolol on kidney function 

in hypertensive NIDDM subjects with diabetic nephropathy. 

Diabetes 46:1182, 1997. 

306. Bakris GL, Copley JB, Vicknair N, et al: Calcium

channel blockers versus other antihypertensive 

therapies on progression of NIDDM associated nephropathy. 

Kidney Int 50:1641, 1996. 

307. UK Prospective Diabetes Study Group. Tight blood 

pressure control and risk of macrovascular and microvascular 

complications in type 2 diabetes: 

UKPDS 38. UK Prospective Diabetes Study Group. 

BMJ 317:703–713, 1998. 

308. Estacio RO, Jeffers BW, Gifford N, Schrier RW: 

Effect of blood pressure control on diabetic microvascular 

complications in patients with hypertension 

and type 2 diabetes. Diabetes Care 23(Suppl 

2):B54, 2000. 

309. Mann JF, Gerstein HC, Pogue J, et al: Renal insufficiency 

as a predictor of cardiovascular outcomes 

and the impact of ramipril: The HOPE randomized 


310. Bakris G, Burgess E, Weir M, et al. Telmisartan is 

more effective than losartan in reducing proteinuria 

in patients with diabetic nephropathy. Kidney 

Int 74:364, 2008. 

311. Burgess E, Muirhead N, Rene de Cotret P, and 

SMART (Supra Maximal Atacand Renal Trial) 

Investigators. Supramaximal dose of candesartan 

in proteinuric renal disease. J Am Soc Nephrol 

20:893, 2009. 

312. Viberti G, Wheeldon NM; MicroAlbuminuria Reduction 

With VALsartan (MARVAL) Study Investigators. 

Microalbuminuria reduction with valsartan 

in patients with type 2 diabetes mellitus: a blood 

pressure-independent effect. Circulation 106: 672, 

2002. 

313. Makino H, Haneda M, Babazono T, et al. Microalbuminuria 

reduction with telmisartan in normotensive 

and hypertensive Japanese patients with 

type 2 diabetes: a post-hoc analysis of The Incipient 

to Overt: Angiotensin II Blocker, Telmisartan, Investigation 

on Type 2 Diabetic Nephropathy (IN- 

NOVATION) study. Hypertens Res 31: 657, 2008. 

314. Menne J, Farsang C, Deák L, et al. Valsartan in 

combination with lisinopril versus the respective 

high dose monotherapies in hypertensive patients 

with microalbuminuria: the VALERIA trial. J Hypertens 

26:1860, 2008. 

315. Hermida RC, Calvo C, Ayala DE, López JE. Decrease 

in urinary albumin excretion associated 

with the normalization of nocturnal blood pressure 

in hypertensive subjects. Hypertension 46:960, 

2005. 

316. Zatz R, Dunn BR, Meyer TW, et al: Prevention of 

diabetic glomerulopathy by pharmacological amelioration 

of glomerular capillary hypertension. J 

Clin Invest 77:1925, 1986. 

317. Bakris GL, Weir MR: Angiotensin-converting en- 


zyme inhibitor-associated elevations in serum creatinine: 

Is this a cause for concern Arch Intern Med 

160:685, 2000. 

318. Apperloo AJ, de Zeeuw D, de Jong PE: A shortterm 

antihypertensive-treatment induced drop in 

glomerular filtration rate predicts long-term stability 

of renal function. Kidney Int 51:793, 1997. 

319. Abbate M, Zoja C, Remuzzi G. How does proteinuria 

cause progressive renal damage? J Am Soc 

Nephrol 17: 2974,2006. 

320. Gagliardini E, Benigni A. Therapeutic potential of 

TGF-beta inhibition in chronic renal failure. Expert 

Opin Biol Ther 7:293, 2007. 

321. Osei SY, Price DA, Laffel LMB, et al: Effect of angiotensin 

II antagonist eprosartan on hyperglycemiainduced 

activation of intrarenal renin-angiotensin 

system in healthy humans. Hypertension 36:122, 

2000. 

322. Buter H, Hemmelder MH, Navis G, et al. The 

blunting of the antiproteinuric efficacy of ACE 

inhibition by high sodium intake can be restored 

by hydrochlorothiazide. Nephrol Dial Transplant 

13:1682, 1998. 

323. Gansevoort RT, de Zeeuw D, de Jong PE: Additive 

antiproteinuric effect of ACE inhibition and a low 

protein diet in human renal disease. Nephrol Dial 

Transplant 10:497, 1995. 

324. Chauveau P, Combe C, Rigalleau V, et al. Restricted 

protein diet is associated with decrease in proteinuria: 

consequences on the progression of renal failure. 

J Ren Nutr 17:250, 2007. 

325. Rigat B, Hubert C, Alhenc-Gelas F, et al: An insertion-deletion 

polymorphism in the angiotensin 

I converting enzyme gene accounting for half 

the variance of serum enzyme levels. J Clin Invest 

86:1343, 1990. 

326. Ueda S, Elliott, Morton JJ, et al. Enhanced pressor 

response to angiotensin I in normotensive men 

with the deletion genotype (DD) for angiotensinconverting 

enzyme. Hypertension 25:1266, 1995. 

327. Cambien F, Poirier O, Lecerf L, et al: Deletion polymorphism 

in the gene for angiotensin-converting 

enzyme is a potent risk factor for myocardial infarction. 

Nature 359: 641, 1992. 

328. van Essen GG, Rensma PL, de Zeeuw D, et al: Association 

between angiotensin-converting enzyme 

gene polymorphism and failure of renoprotective 

therapy. Lancet 347:94, 1996. 

329. Parving HH, Jacobsen P, Tarnow L, et al: Effect of 

deletion polymorphism of angiotensin-converting 

enzyme gene on progression of diabetic nephropathy 

during inhibition of angiotensin-converting 

enzyme. Observational follow-up study. BMJ 

313:591, 1996.


330. Nonoguchi H, Nakayama Y, Shiigai T, et al. Lowresponders 

to angiotensin II receptor blockers and 

genetic polymorphism in angiotensin-converting 

enzyme. Clin Nephrol 68:209, 2007. 

331. Jessup M, Abraham WT, Casey DE, et al. 2009 

focused update: ACCF/AHA Guidelines for the 

Diagnosis and Management of Heart Failure in 

Adults: a report of the American College of Cardiology 

Foundation/American Heart Association 

Task Force on Practice Guidelines: developed 

in collaboration with the International Society 

for Heart and Lung Transplantation. Circulation 

119:1977, 2009. 

332. Howlett JG, McKelvie RS, Arnold JM, et al. Canadian 

Cardiovascular Society Consensus Conference 

Guidelines on heart failure, update 2009: 

diagnosis and management of right-sided heart 

failure, myocarditis, device therapy and recent important 

clinical trials. Can J Cardiol 25:85, 2009. 

333. Remme WJ: Effect of ACE inhibition on neurohormones. 

Eur Heart J 19 (Suppl J): J16, 1998. 

334. Flather MD, Yusuf S, Kober L, et al: Long-term 

ACE-inhibitor therapy in patients with heart failure 

or left-ventricular dysfunction: A systematic 

overview of data from individual patients. ACE-Inhibitor 

Myocardial Infarction Collaborative Group. 

Lancet 355:1575, 2000. 

335. Fonarow GC, Yancy CW, Albert NM, et al. Heart 

failure care in the outpatient cardiology practice 

setting: findings from IMPROVE HF. Circ Heart 

Fail 1:98, 2008. 

336. Philbin EF, Andreou C, Rocco TA, et al: Patterns 

of angiotensin-converting enzyme inhibitor use in 

congestive heart failure in two community hospitals. 

Am J Cardiol 77:832, 1996. 

337. Bungard TJ, McAlister FA, Johnson JA, Tsuyuki 

RT: Underutilization of ACE inhibitors in patients 

with congestive heart failure. Drugs 61:2021, 2001. 

338. Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox 

CS: Renal considerations in angiotensin-converting 

enzyme inhibitor therapy: A statement for 

healthcare professionals from the Council on the 

Kidney in Cardiovascular Disease and the Council 

for High Blood Pressure Research of the American 

Heart Association. Circulation 104:1985, 2001. 

339. Domanski MJ, Exner DV, Borkowf CB, et al: Effect 

of angiotensin-converting enzyme inhibition on 

sudden cardiac death following acute myocardial 

infarction. A meta-analysis of randomized clinical 

trials. J Am Coll Cardiol 33:598, 1999. 

340. Megarry M, Sapsford R, Hall AS, et al: Do ACE 

inhibitors provide protection for the heart in the 

clinical setting of acute myocardial infarction. 

Drugs 54 (Suppl 5):48, 1997. 

341. Perez MI, Musini VM, Wright JM. Effect of early 

treatment with anti-hypertensive drugs on short 

and long-term mortality in patients with an acute 

cardiovascular event. Cochrane Database Syst Rev 

(4):CD006743, 2009. 

342. Indications for ACE inhibitors in the early treatment 

of acute myocardial infarction: Systematic 

review of individual data from 100,000 patients in 

randomised trials. Circulation 97:2202, 1998. 

343. Naccarella F, Naccarelli GV, Maranga SS, et al: Do 

ACE inhibitors or angiotensin II antagonists reduce 

total mortality and arrhythmic mortality? 

A critical review of controlled clinical trials. Curr 

Opin Cardiol 17:6, 2002. 

344. Dickstein K, Kjekshus J, OPTIMAAL Steering 

Committee of the OPTIMAAL Study Group. Effects 

of losartan and captopril on mortality and 

morbidity in high-risk patients after acute myocardial 

infarction: The OPTIMAAL randomised trial. 

Lancet 360:752, 2002. 

345. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Trial 

Investigators. Valsartan, captopril, or both in myocardial 

infarction complicated by heart failure, left 

ventricular dysfunction, or both. N Engl J Med 

349:1893, 2003. 

346. Pitt B, Segal R, Martinez FA, et al: Randomised trial 

of losartan versus captopril in patients over 65 with 

heart failure (Evaluation of Losartan in the Elderly 

Study, ELITE). Lancet 349: 747–752, 1997. 

347. Pitt B, Poole-Wilson PA, Segal R, et al: Effect of 

losartan compared with captopril on mortality 

in patients with symptomatic heart failure: Randomised 

trial - the Losartan Heart Failure Survival 

Study ELITE II. Lancet 355:1582, 2000. 

348. Cohn JN, Tognoni G: A randomized trial of the 

angiotensin-receptor blocker valsartan in chronic 

heart failure. N Engl J Med 345:1667, 2001. 

349. McMurray JJV, Ostergren J, Swedberg K et al. Effects 

of candesartan in patients with chronic heart 

failure and reduced left ventricular systolic function 

taking angiotensin-converting-enzyme inhibitors: 

the CHARM-Added Trial. Lancet 362,767, 

2003. 

350. Granger CB, McMurray JJV, Yusuf S et al. Effects 

of candesartan in patients with chronic heart failure 

and reduced left ventricular systolic function 

intolerant to angiotensin-converting-enzyme inhibitors: 

The CHARM-Alternative Trial. Lancet 

362,772, 2003. 

351. Yusuf S, Pfeffer MA, Swedberg K et al. Effects of 

candesartan in patients with chronic heart failure 

and preserved left ventricular systolic function: The 

CHARM-Preserved Trial. Lancet 362,777, 2003. 

352. Massie BM, Carson PE, McMurray JJ, et al. Irbe-

sartan in patients with heart failure and preserved 

ejection fraction. N Engl J Med 359:2456, 2008. 

353. Shah RV, Desai AS, Givertz MM. The effect of renin-angiotensin 

system inhibitors on mortality and 

heart failure hospitalization in patients with heart 

failure and preserved ejection fraction: a systematic 

review and meta-analysis. J Card Fail 16:260, 2010. 

353a. Zile MR, Gaasch WH, Anand IS, et al: Mode of 

death in patients with heart failure and a preserved 

ejection fraction: results from the Irbesartan in 

Heart Failure with Preserved Ejection Fraction 

Study (I-Preserve) trial. Circulation 121: 1393, 

2010. 

354. Mochizuki S, Dahlöf B, Shimizu M, et al. Valsartan 

in a Japanese population with hypertension and 

other cardiovascular disease (Jikei Heart Study): a 

randomised, open-label, blinded endpoint morbidity-mortality 

study. Lancet 369:1431, 2007. 

355. Baker WL, Coleman CI, Kluger J, et al. Systematic 

review: comparative effectiveness of angiotensinconverting 

enzyme inhibitors or angiotensin IIreceptor 

blockers for ischemic heart disease. Ann 

Intern Med 151:861, 2009. 

356. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, 

Weaver WD: Angiotensin converting enzyme inhibitors 

in coronary artery disease and preserved 

left ventricular systolic function. A systematic review 

and meta-analysis of randomized controlled 

trials. J Am Coll Cardiol 47: 1576, 2006. 

357. Danchin N, Cucherat M, Thuillez C, et al: Angiotensin 

converting enzyme inhibitors in patients 

with coronary artery disease and absence of heart 

failure or left ventricular systolic dysfunction. An 

overview of long-term randomized controlled trials. 


358. Dagenais GR, Pogue J, Fox K, et al: Angiotensin 

converting enzyme inhibitors in stable vascular 

disease without left ventricular systolic dysfunction 

or heart failure: a combined analysis of three trials. 

Lancet 368: 581, 2006. 

359. Solomon SD, Janardhanan R, Verma A, et al: for 

the Valsartan in Diastolic Dysfunction (VALIDD) 

investigators: Effect of angiotensin receptor blockade 

and antihypertensive drugs on diastolic function 

in patients with hypertension and diastolic 

dysfunction: a randomised trial. Lancet 369: 2079, 

2007. 

359a. Werner C, Pöss J, Böhm M: Optimal antagonism of 

the renin-angiotensin-aldosterone system. Drugs 

70: 1215, 2010. 

360. Fine EJ. Diuretic renography and angiotensin converting 

enzyme inhibitor renography. Radiol Clin 

North Am 39:979, 2001. 

361. Wu VC, Chang HW, Liu KL, et al. Primary aldo- 


steronism: diagnostic accuracy of the losartan and 

captopril tests. Am J Hypertens 22:821, 2009. 

362. Rossi GP, Belfiore A, Bernini G, et al. Comparison 

of the captopril and the saline infusion test for excluding 

aldosterone-producing adenoma. Hypertension 

50: 424, 2007. 

363. Plata R, Cornejo A, Arratia C, et al: Angiotensinconverting 

enzyme inhibition therapy in altitude 

polycythaemia: A prospective randomised trial. 

Lancet 359:663, 2002. 

364. Esposito R, Giammarino A, De Blasio A, et al. 

Ramipril in post-renal transplant erythrocytosis. J 

Nephrol 20: 57, 2007. 

365. Zhu X, Chen J, Han F, et al. Efficacy and safety of 

losartan in treatment of hyperuricemia and posttransplantation 

erythrocytosis: results of a prospective, 

open, randomized, case-control study. 

Transplant Proc 41:3736, 2009. 

366. Ohtani K, Egashira K, Ihara Y, et al: Angiotensin 

II type 1 receptor blockade attenuates in-stent restenosis 

by inhibiting inflammation and progenitor 

cells. Hypertension 48: 664, 2006. 

367. Peters S. Comparison of efficacy of low- (80 mg/ 

day) and high- (160-320 mg/day) dose valsartan in 

the prevention of in-stent restenosis after implantation 

of bare-metal stents in type B2/C coronary 

artery lesions. Am J Cardiovasc Drugs 8:83, 2008. 

368. Gillis AM: Angiotensin receptor blockers for prevention 

of atrial fibrillation – a matter of timing or 

target? N Engl J Med 360: 1669, 2009. 

369. Ehrlich JR, Hohnloser SH, Nattel R: Role of angiotensin 

system and effects of its inhibition in atrial 

fibrillation: clinical and experimental evidence. Eur 

Heart J 27: 512, 2006. 

370. Casaclang-Verzosa G, Gersh BJ, Tsang TS: Structural 

and functional remodeling of the left atrium: 

clinical and therapeutic implications for atrial fibrillation. 

J Am Coll Cardiol 51: 1, 2008. 

371. Iravanian S, Dudley SC Jr. The renin angiotensin 

aldosterone system (RAAS) and cardiac arrhythmias. 

Heart Rhythm 5 Suppl: S12, 2008. 

372. Jibrini MB, Molnar J, Arora RR: Prevention of atrial 

fibrillation by way of abrogation of the renin angiotensin 

system: a systematic review and metaanalysis. 

Am J Therap 15: 36, 2008. 

373. Anand K, Mooss AN, Hee TT, Mohiuddin SM: Meta-analysis: 

inhibition of renin-angiotensin system 

prevents new onset atrial fibrillation. Am Heart J 

152: 217, 2006. 

374. Belluzzi F, Sernesi L, Preti P, et al: Prevention of 

recurrent lone atrial fibrillation by the angiotensin 

II converting enzyme inhibitor ramipril in normotensive 

patients. J Am Coll Cardiol 53: 24, 2009. 

375. Garg S, Narula J, Marelli C, Cesario D: Role of an-


giotensin receptor blockers in the prevention and 

treatment of arrhythmias. Am J Cardiol 97: 921, 

2006. 

376. Chrysant SG, Chrysant GS: The pleiotropic effects 

of angiotensin receptor blockers. J Clin Hypertens 

8: 261, 2006. 

376a. Schneider MP, Hua TA, Böhm M, et al: Prevention 

of atrial fibrillation by renin-angiotensin system inhibition. 


377. Salehian O, Healey J, Stambler B, et al on behalf of 

the HOPE Investigators: Impact of ramipril on the 

incidence of atrial fibrillation: results of the Heart 

Outcomes Prevention Evaluation study. Am Heart 

J 154: 448, 2007. 

378. GISSI-AF Investigators: Valsartan for prevention of 

recurrent atrial fibrillation. N Engl J Med 360: 1606, 

2009. 

379. Chaturvedi N, Porta M, Klein R, et al for the DI- 

RECT Programme study group: Effect of candesartan 

on prevention (DIRECT-Prevent 1) and 

progression (DIRECT-Protect 1) of retinopathy in 

type 1 diabetes: randomised, placebo-controlled 

trials. Lancet 372: 1394, 2008. 

380. Sjølie AK, Klein R, Porta M, et al for the DIRECT 

Programme study group: Effect of candesartan on 

progression and regression of retinopathy in type 2 

diabetes (DIRECT-Protect 2): a randomised, placebo-controlled 

trial. Lancet 372: 1385, 2008. 

380a. The Navigator Study Group: Effect of valsartan 

on the incidence of diabetes and cardiovascular 

events. N Engl J Med 362: 1477, 2010. 

381. Habashi JP, Judge DP, Holm TM, et al: Losartan, 

an AT1 antagonist prevents aortic aneurysm in a 

mouse model of Marfan syndrome. Science 312: 

117, 2006. 

382. Hackam DG, Thiruchelvam D, Redelmeier DA: 

Angiotensin converting enzyme inhibitors and 

aortic rupture: a population-based case-control 

study. Lancet 368: 659, 2006. 

383. The SOLVD investigators: Effect of enalapril on 

survival in patients with reduced left ventricular 

ejection fractions and congestive heart failure. N 

Engl J Med 325:293, 1991. 

384. Bastiaens MT, Zwan NV, Verschueren GL, et al: 

Three cases of pemphigus vegetans: Induction by 

enalapril - association with internal malignancy. 

Int J Dermatol 33:168, 1994. 

385. Larbre JP, Nicolas JF, Collet P, et al: Kaposi’s sarcoma 

in a patient with rheumatoid arthritis possible 

responsibility of captopril in the development 

of lesions. J Rheumatol 18:476, 1991. 

386. Vogt B, Frey FJ: Inhibition of angiogenesis in Kaposi’s 

sarcoma by captopril. Lancet 349:1148, 1997. 

387. Meier CR, Derby LE, Jick SS, Jick H: Angioten- 

sin-converting enzyme inhibitors, calcium channel 

blockers, and breast cancer. Arch Intern Med 

160:349, 2000. 

388. Stahl M, Bulpitt CJ, Palmer AJ, et al: Calcium channel 

blockers, ACE inhibitors, and the risk of cancer 

in hypertensive patients: A report from the Department 

of Health Hypertension Care Computing 

Project (DHCCP). J Hum Hypertens 14:299, 2000. 

389. Pahor M, Guralnik JM, Salive ME, et al: Do calcium 

channel blockers increase the risk of cancer? 


390. Lever AF, Hole DJ, Gillis CR, et al: Do inhibitors of 

angiotensin-I-converting enzyme protect against 

risk of cancer? Lancet 352:179, 1998. 

391. Sorensen HT, Mellemkjaer L, et al: Angiotensinconverting 

enzyme inhibitors and the risk of cancer: 

A population-based cohort study in Denmark. 

Cancer 92:2462, 2001. 

392. Friis S, Felmeden DC, Lip GY: Antihypertensive 

therapy and cancer risk. Drug Saf 24:727–739, 

2001. 

393. Rosenthal T, Gavras I. Angiotensin inhibition and 

malignancies: a review. J Hum Hypertens 23:623, 

2009. 

393a. Sipahi I, Debanne SM, Rowland DY, et al: Angiotensin 

receptor blockade and risk of cancer: metaanalysis 

of randomised controlled trials. Lancet 

Oncol 11: 627, 2010. 

394. Textor SC: Renal failure related to angiotensinconverting 

enzyme inhibitors. Semin Nephrol 

17:67, 1997. 

395. Textor SC, Bravo EL, Fouad FM, Tarazi RC: Hyperkalemia 

in azotemic patients during angiotensinconverting 

enzyme inhibition and aldosterone 

reduction with captopril. Am J Med 73:719, 1982. 

396. Garcia NH, Baigorria ST, Juncos LI: Hyperkalemia, 

renal failure, and converting-enzyme inhibition: 

An overrated connection. Hypertension 38:639, 

2001. 

397. Bakris GL, Siomos M, Richardson D, et al: ACE inhibition 

or angiotensin receptor blockade: impact 

on potassium in renal failure. VAL-K Study Group. 

Kidney Int 58:2084, 2000. 

398. Griffing GT, Sindler BH, Aurecchia SA, Melby JC: 

Reversal of diuretic-induced secondary hyperaldosteronism 

and hypokalemia by enalapril (MK-421): 

A new angiotensin-converting enzyme inhibitor. 

Metabolism 32:711, 1983. 

399. Israili ZH, Hall WD: Cough and angioneurotic 

associated with angiotensin-converting enzyme 

inhibitor therapy: A review of the literature and 

pathophysiology. Ann Intern Med 117:234, 1992. 

400. Chalmers D, Dombey SL, Lawson DH: Post-marketing 

surveillance of captopril (for hypertension):

A preliminary report. Br J Clin Pharmacol 24:343, 

1987. 

401 Bensenor IM, Lotufo PA: Headache, hypertension, 

and irbesartan therapy. Arch Intern Med 161:775– 

776, 2001. 

402. Etminan M, Levine MA, Tomlinson G, Rochon 

PA: Efficacy of angiotensin II receptor antagonists 

in preventing headache: A systematic overview and 

meta-analysis. Am J Med 112:642, 2002. 

403. Weber MA, Messerli FH: Angiotensin converting 

enzyme inhibitors and angioedema. Estimating the 

risk. Hypertension 51: 1465, 2008. 

404. Herkner H, Temmel AF, Mullner M, et al: Different 

patterns of angioedema in patients with and 

without angiotensin-converting enzyme inhibitor 

therapy. Wien Klin Wochenschr 113:167, 2001. 

405. Vleeming W, van Amsterdam JG, Stricker BH, et 

al: ACE inhibitor-induced angioedema. Drug Saf 

18:171, 1998. 

406. Brown NJ, Snowden M, Griffin MR: Recurrent angiotensin-converting 

enzyme inhibitor-associated 

angioedema. JAMA 278:232, 1997. 

407. Dobbels P, Van Overbeke L, Vanbeckevoort D, 

Hiele M. Acute abdomen due to intestinal angioedema 

induced by ACE inhibitors: not so rare? 

Acta Gastroenterol Belg 72:455, 2009. 

408. Haymore BR, Yoon J, Mikita CP, et al. Risk of angioedema 

with angiotensin receptor blockers in 

patients with prior angioedema associated with 

angiotensin-converting enzyme inhibitors: a metaanalysis. 

Ann Allergy Asthma Immunol 101:495, 

2008. 

409. Warner KK, Visconti JA, Tschampel MM: Angiotensin 

II receptor blockers in patients with ACE 

inhibitor-induced angioedema. Ann Pharmacother 

34:526, 2000. 

410. Sica DA, Black HR. Current concepts of pharmacotherapy 

in hypertension: ACE inhibitor-related 

angioedema: can angiotensin-receptor blockers be 

safely used? J Clin Hypertens (Greenwich) 4:375, 

2002. 

411. Cohen DL, Townsend RR: Can an angiotensin receptor 

blocker be used in a patient in whom angioedema 

developed with an angiotensin converting 

enzyme inhibitor? J Clin Hypertens 10: 949, 2008. 

412. Quan A. Fetopathy associated with exposure to angiotensin 

converting enzyme inhibitors and angiotensin 

receptor antagonists. Early Hum Dev 82:23, 

2006. 

413. Lambot MA, Vermeylen D, Noel JC: Angiotensin-II-receptor 

inhibitors in pregnancy. Lancet 

357:1619, 2001. 


414. Burrows RF, Burrows EA: Assessing the teratogenic 

potential of angiotensin-converting enzyme 

inhibitors in pregnancy. Aust N Z J Obstet Gynaecol 

38:306, 1998. 

415. Cooper WO, Hernandez-Diaz S, Arbogast PG, et 

al. Major congenital malformations after first-trimester 

exposure to ACE inhibitors. N Engl J Med 

354:2443, 2006. 

416. Magee LA: Treating hypertension in women of 

childbearing age and during pregnancy. Drug Saf 

24:457, 2001. 

417. Martin U, Foreman MA, Travis JC, et al. Use of 

ACE inhibitors and ARBs in hypertensive women 

of childbearing age. J Clin Pharm Ther 33:507, 

2008. 

418. Shannon ME, Malecha SE, Cha AJ: Angiotensinconverting 

enzyme inhibitors and angiotensin II 

receptor blockers and lactation: an update. J Hum 

Lact 16:152, 2000. 

419. Zwanzger P, Marcuse A, Boerner RJ, et al: Lithium 

intoxication after administration of AT1 blockers. J 

Clin Psychiatry 62:208, 2001. 

420. Juurlink DN, Mamdani MM, Kopp A, et al. Druginduced 

lithium toxicity in the elderly: a population-based 

study. J Am Geriatr Soc 52:794, 2004. 

421. Indermitte J, Burkolter S, Drewe J, et al. Risk factors 

associated with a high velocity of the development 

of hyperkalaemia in hospitalised patients. Drug Saf 

30:71, 2007. 

422. Conlin PR, Moore TJ, Swartz SL, et al: Effect of 

indomethacin on blood pressure lowering by captopril 

and losartan in hypertensive patients. Hypertension 

36:461, 2000. 

423. Fricker AF, Nussberger J, Meilenbrock S, et al: Effect 

of indomethacin on the renal response to angiotensin 

II receptor blockade in healthy subjects. 

Kidney Int 54: 2089, 1998. 

424. Pavlicević I, Kuzmanić M, Rumboldt M, Rumboldt 

Z. Interaction between antihypertensives and 

NSAIDs in primary care: a controlled trial. Can J 

Clin Pharmacol 15:e372, 2008. 

425. Adhiyaman V, Asghar M, Oke A, et al: Nephrotoxicity 

in the elderly due to co-prescription of 

angiotensin-converting enzyme inhibitors and 

nonsteroidal anti-inflammatory drugs. J R Soc Med 

94:512, 2001. 

426. Samanta A, Burden AC: Fever, myalgia, and arthralgia 

in a patient on captopril and allopurinol. 

Lancet 1:679,1984.


The Renin-Angiotensin Axis 

Direct Renin Inhibition 



1. Chobanian AV, Bakris GL, Black HR, et al.: The 

Seventh Report of the Joint National Committee on 

Prevention, Detection, Evaluation, and Treatment 

of High Blood Pressure: the JNC 7 report. JAMA. 

289:2560, 2003. 

2. Yusuf S, Sleight P, Pogue J, et al.: Effects of an angiotensin-converting-enzyme 

inhibitor, ramipril, 

on cardiovascular events in high-risk patients. The 

Heart Outcomes Prevention Evaluation Study Investigators. 

N Engl J Med. 342: 145, 2000. 

3. Staessen J, Lijnen P, Fagard R, et al.: Rise in plasma 

concentration of aldosterone during long-term 

angiotensin II suppression. J Endocrinol. 91:457, 

1981. 

4. MacFadyen RJ, Lee AF, Morton JJ, et al.: How often 

are angiotensin II and aldosterone concentrations 

raised during chronic ACE inhibitor treatment in 

cardiac failure? Heart 82:57, 1999. 

5. Müller DN, Luft FD: Direct renin inhibition with 

aliskiren in hypertension and target organ damage. 

Clin J Am Soc Nephrol 1: 221, 2006. 

6. Bacani C, Frishman WH: Chymase: a new pharmacologic 

target in cardiovascular disease. Cardiol in 

Rev 14: 187, 2006. 

7. Urata H, Healy B, Stewart RW, et al: Angiotensin 

II-forming pathways in normal and failing human 

hearts. Circ Res 66:883, 1990. 

8. Okunishi H, Oka Y, Shiota N, et al: Marked speciesdifference 

in the vascular angiotensin II-forming 

pathways: humans versus rodents. Jpn J Pharmacol 

62:207, 1993. 

9. Hollenberg NK. Pharmacologic interruption of the 

renin-angiotensin system and the kidney: differential 

responses to angiotensin-converting enzyme 

and renin inhibition. J Am Soc Nephrol 10 Suppl 

11:S239, 1999. 

9a. Fisher NDL, Danser J, Nussberger J, et al: Renal 

and hormonal responses to direct renin inhibition 

with aliskiren in healthy humans. Circulation 117: 

3199, 2008. 

10. Allan DR, Hui KY, Coletti C, et al.: Renin vs. angiotensin-converting 

enzyme inhibition in the rat: 

consequences for plasma and renal tissue angiotensin. 

J Pharmacol Exp Ther 283: 661, 1997. 

11. Dzau VJ, Burt DW, Pratt RE: Molecular biology of 

the renin-angiotensin system. Am J Physiol. 255(4 

Pt 2):F563, 1988. 

12. Beierwaltes WH: Prorenin and renin. In Izzo JL Jr, 

Sica DA, Black HR (eds): Hypertension Primer 4th 

ed. Dallas: American Heart Assn 2008: 44. 

13. Kurtz A, Wagner C: Regulation of renin secretion 

by angiotensin II-AT1 receptors. J Am Soc Nephrol 

10 Suppl 11:S162, 1999. 

14. Pratt RE, Ouellette AJ, Dzau VJ: Biosynthesis of renin: 

multiplicity of active and intermediate forms. 

Proc Natl Acad Sci USA 80(22):6809, 1983. 

15. Galen FX, Devaux C, Houot AM, et al.: Renin biosynthesis 

by human tumoral juxtaglomerular cells. 

Evidences for a renin precursor. J Clin Invest. 73: 

1144, 1984. 

16. Corvol P, Chauveau D, Jeunemaitre X, et al.: Human 

renin inhibitor peptides. Hypertension 16:1, 

1990. 

17. Dhanaraj V, Dealwis CG, Frazao C, et al.: X-ray 

analyses of peptide-inhibitor complexes define the 

structural basis of specificity for human and mouse 

renins. Nature 357:466, 1992. 

18. Oliver JA: Receptor-mediated actions of renin and 

prorenin. Kidney Intl 69: 13, 2006. 

19. Sealey JE, Catanzaro DF, Lavin TN, et al: Specific 

prorenin/renin binding (ProBP). Identification 

and characterization of a novel membrane site. Am 



10-1


J Hypertens 9: 491, 1996. 

19a. Reudelhuber TL: Prorenin, renin, and their receptor. 

Moving targets. Hypertension 55: 1071, 2010. 

20. Clauser E, Gaillard I, Wei L, et al.: Regulation of angiotensinogen 

gene. Am J Hypertens. 2(5 Pt 1):403, 

1989. 

21. Tewksbury DA, Dart RA, Travis J: The amino terminal 

amino acid sequence of human angiotensinogen. 

Biochem Biophys Res Commun. 99:1311, 

1981. 

22. Kageyama R, Ohkubo H, Nakanishi S: Primary 

structure of human preangiotensinogen deduced 

from the cloned cDNA sequence. Biochemistry 

23:3603, 1984. 

23. Brand M, Lamande N, Sigmund CD, et al.: Angiotensinogen 

modulates renal vasculature growth. 


24. Hilgers KF, Veelken R, Muller DN, et al.: Renin uptake 

by the endothelium mediates vascular angiotensin 

formation. Hypertension 38:243, 2001. 

25. Turner AJ, Hooper NM: The angiotensin-converting 

enzyme gene family: genomics and pharmacology. 

Trends Pharmacol Sci 23:177, 2002. 

26. Erdos EG, Deddish PA, Marcic BM: Potentiation of 

bradykinin actions by ACE inhibitors. Trends Endocrinol 

Metab 10:223, 1999. 

27. Frishman WH, Shanik MH, Lin C: Specific inhibitors 

of renin in cardiac therapy. In Frishman WH, 

Sonnenblick EH, Sica DA (eds): Cardiovascular 

Pharmacotherapeutics 2nd ed. New York: McGraw 

Hill 2003; 589. 

28. Deodhar SD, Haas E, Goldblatt H: Production of 

antirenin to homologous renin and its effect of experimental 

renal hypertension. J Exp Med 119:425, 

1964. 

29. Helmer OM: Studies on renin antibodies. Circulation 

17(4, Part 2):648, 1958. 

30. Dzau VJ, Kopelman RI, Barger AC, et al.: Reninspecific 

antibody for study of cardiovascular homeostasis. 

Science 207:1091, 1980. 

31. Wood JM, Baum HP, Bews JP, et al: Effects of 

chronic administration of a monoclonal antibody 

against human renin in the marmoset. Clin Exp 

Hypertens 9:1467, 1987. 

32. Wood JM, Heusser C, Gulati N, et al: Monoclonal 

antibodies against human renin. Blood pressure effects 

in the marmoset. Hypertension 8:600, 1986. 

33. Evin G, Devin J, Castro B, et al.: Synthesis of peptides 

related to the prosegment of mouse submaxillary 

gland renin precursor: an approach to renin 

inhibitors. Proc Natl Acad Sci USA 81:48, 1984. 

34. Cumin F, Evin G, Fehrentz JA, et al.: Inhibition of 

human renin by synthetic peptides derived from its 

prosegment. J Biol Chem 260:9154, 1985. 

35. Aoyagi T, Kunimoto S, Morishima H, et al.: Effect 

of pepstatin on acid proteases. J Antibiot (Tokyo) 

24:687, 1971. 

36. Gross F, Lazar J, Orth H. Inhibition of the reninangiotensinogen 

reaction by pepstatin. Science 

175:656, 1972. 

37. Miller RP, Poper CH, Wilson CW, et al.: Renin inhibition 

by pepstatin. Biochem Pharmacol 21:2941, 

1972. 

38. Boger J, Lohr NS, Ulm EH, et al: Novel renin inhibitors 

containing the amino acid statine. Nature 

303:81, 1983. 

39. Guegan R, Diaz J, Cazaubon C, et al: Pepstatin 

analogues as novel renin inhibitors. J Med Chem 

29:1152, 1986. 

40. Rich DH, Bernatowicz MS, Agarwal NS, et al.: 

Inhibition of aspartic proteases by pepstatin and 

3-methylstatine derivatives of pepstatin. Evidence 

for collected-substrate enzyme inhibition. Biochemistry 

24:3165, 1985. 

41. Kokubu T, Ueda E, Fujimoto S, et al.: Peptide inhibitors 

of the renin-angiotensin system. Nature 

217:456, 1968. 

42. Poulsen K, Burton J, Haber E: Competitive inhibitors 

of renin. Biochemistry 12:135, 1976. 

43. Burton J, Cody RJ Jr, Herd JA, et al: Specific inhibition 

of renin by an angiotensinogen analog: studies 

in sodium depletion and renin-dependent hypertension. 

Proc Natl Acad Sci USA 77:5476, 1980. 

44. Zusman RM, Burton J, Christensen D, et al.: Hemodynamic 

effects of a competitive renin inhibitory 

peptide in humans: evidence for multiple 

mechanisms of action. Trans Assoc Am Physicians 

96:365, 1983. 

45. Szelke M, Leckie B, Hallett A, et al.: Potent new inhibitors 

of human renin. Nature 299:555, 1982. 

46. Kokubu T, Hiwada K, Nagae A, et al.: Statine-containing 

dipeptide and tripeptide inhibitors of human 

renin. Hypertension 8(6 Pt 2):II1, 1986. 

47. Kokubu T, Hiwada K, Murakami E, et al.: In vitro 

inhibition of human renin by statine-containing 

tripeptide renin inhibitor (ES-1005). J Cardiovasc 

Pharmacol 10 Suppl 7:S88,1987. 

48. Bock MG, DiPardo RM, Evans BE, et al.: Renin inhibitors. 

Statine-containing tetrapeptides with varied 

hydrophobic carboxy termini. J Med Chem 30: 

1853, 1987. 

49. Iizuka K, Kamijo T, Kubota T, et al.: New human 

renin inhibitors containing an unnatural amino 

acid, norstatine. J Med Chem 31:701, 1988. 

50. Toda N, Miyazaki M, Etoh Y, et al.: Human renin 

inhibiting dipeptide. Eur J Pharmacol. 129:393, 

1986. 

51. Thaisrivongs S, Pals DT, Kati WM, et al.: Difluoros-

tatine- and difluorostatone-containing peptides as 

potent and specific renin inhibitors. J Med Chem 

28: 1553, 1985. 

52. Thaisrivongs S, Pals DT, Kati WM, et al.: Design 

and synthesis of potent and specific renin inhibitors 

containing difluorostatine, difluorostatone, 

and related analogues. J Med Chem 29:2080, 1986. 

53. Boger J, Payne LS, Perlow DS, et al.: Renin inhibitors. 

Syntheses of subnanomolar, competitive, transition-state 

analogue inhibitors containing a novel 

analogue of statine. J Med Chem 28:1779, 1985. 

54. Dellaria JF, Maki RG, Bopp BA, et al.: Optimization 

and in vivo evaluations of a series of small, potent, 

and specific renin inhibitors containing a novel 

Leu-Val replacement. J Med Chem 30:2137, 1987. 

55. Hui KY, Holtzman EJ, Quinones MA, et al.: Design 

of rat renin inhibitory peptides. J Med Chem 

31:1679, 1988. 

56. Hiwada K, Kokubu T, Murakami E, et al.: A highly 

potent and long-acting oral inhibitor of human renin. 

Hypertension 11(6 Pt 2):708, 1988. 

57. Luly JR, BaMaung N, Soderquist J, et al.: Renin 

inhibitors. Dipeptide analogues of angiotensinogen 

utilizing a dihydroxyethylene transition-state 

mimic at the scissile bond to impart greater inhibitory 

potency. J Med Chem 31: 2264, 1988. 

58. Kleinert HD, Luly JR, Marcotte PA, et al.: Renin 

inhibitors. Improvements in the stability and biological 

activity of small peptides containing novel 

Leu-Val replacements. FEBS Lett. 230:38, 1988. 

59. Kempf DJ, de Lara E, Stein HH, et al: Renin inhibitors 

based on novel dipeptide analogues. Incorporation 

of the dehydrohydroxyethylene isostere at 

the scissile bond. J Med Chem 30:1978, 1987. 

60. Allen MC, Fuhrer W, Tuck B, et al: Renin inhibitors. 

Synthesis of transition-state analogue inhibitors 

containing phosphorus acid derivatives at the 

scissile bond. J Med Chem 32:1652, 1989. 

61. Evin G, Devin J, Castro B, et al: Synthesis of peptides 

related to the prosegment of mouse submaxillary 

gland renin precursor: an approach to renin 

inhibitors. Proc Natl Acad Sci USA 81:48, 1984. 

62. Sawyer TK, Pals DT, Mao B, et al.: Design, structure-activity, 

and molecular modeling studies of 

potent renin inhibitory peptides having N-terminal 

Nin-For-Trp (Ftr): angiotensinogen congeners 

modified by P1-P1’ Phe-Phe, Sta, Leu psi[CH(OH) 

CH2]Val or leu psi[CH2NH]Val substitutions. J 

Med Chem 31:18, 1988. 

63. Haber E, Hui KY, Carlson WD, et al.: Renin inhibitors: 

a search for principles of design. J Cardiovasc 

Pharmacol 10 Suppl 7:S54, 1987. 

64. Bock MG, DiPardo RM, Evans BE, et al.: Renin 

inhibitors containing hydrophilic groups. Tetra- 


peptides with enhanced aqueous solubility and 

nanomolar potency. J Med Chem 31:1918, 1988. 

65. Glassman HN, Kleinert HD, Boger RS, et al.: Clinical 

pharmacology of enalkiren, a novel, dipeptide 

renin inhibitor. J Cardiovasc Pharmacol 16 Suppl 

4:S76, 1990. 

66. Paruszewski R, Jaworski P, Winiecka I, et al.: New 

renin inhibitors with pseudodipeptidic units in 

P(1)-P(1’) and P(2’)-P(3’) positions. Chem Pharm 

Bull (Tokyo 50:850, 2002. 

67. de Gasparo M, Cumin F, Nussberger J, et al.: Pharmacological 

investigations of a new renin inhibitor 

in normal sodium-unrestricted volunteers. Br J 

Clin Pharmacol 27:587,1989. 

68. Boyd SA, Fung AK, Baker WR, et al.: C-terminal 

modifications of nonpeptide renin inhibitors: improved 

oral bioavailability via modification of 

physicochemical properties. J Med Chem 35:1735, 

1992. 

69. Wood JM, Maibaum J, Rahuel J, et al.: Structurebased 

design of aliskiren, a novel orally effective 

renin inhibitor. Biochem Biophys Res Commun. 

308:698, 2003. 

70. Rahuel J, Rasetti V, Maibaum J, et al. Structurebased 

drug design: the discovery of novel non peptide 

orally active inhibitors of human renin. Chem 

Biol 7: 493, 2000. 

71. Nussberger J, Wuerzner G, Jensen C, Brunner HR. 

Angiotensin II suppression in humans by the orally 

active renin inhibitor aliskiren (SPP100): comparison 

with enalapril. Hypertension 39:E1, 2003. 

72. Azizi M, Webb R, Nussberger J, Hollenberg NK. 

Renin inhibition with aliskiren: where are we now 

and where are we going? J Hypertens 24: 243, 2006. 

73. Vaidyanathan S, Warren V, Yeh C, et al: Pharmacokinetics, 

safety and tolerability of the oral renin 

inhibitor aliskiren in patients with hepatic impairment. 

J Clin Pharmacol 47: 192, 2007. 

74. Zhao C, Vaidyanathan S, Yeh CM, et al: Aliskiren 

exhibits similar pharmacokinetics in healthy volunteers 

and patients with type 2 diabetes mellitus. 


75. Gradman AH, Schmieder RE, Lins RL, et al. 

Aliskiren, a novel orally effective renin inhibitor, 

provides dose-dependent antihypertensive efficacy 

and placebo-like tolerability in hypertensive patients. 

Circulation 111:1012, 2005. 

76. Sica D, Gradman A, Lederballe I, Meyers M, et 

al. Aliskiren, an oral renin inhibitor, provides 

long-term antihypertensive efficacy and safety in 

patients with hypertension. Eur Heart J 27 (Supplement): 

P797, 2006. 

77. Feldman DL, Persohn E, Schutz H, et al. Renal localization 

of the renin inhibitor aliskiren (abst). J


Clin Hypertens 8 (Supplement A): A80, 2006. 

78. Herron J, Mitchell J, Oh B, et al. The novel renin 

inhibitor aliskiren is not associated with rebound 

effects on blood pressure or plasma renin activity 

following treatment withdrawal (abst). J Clin Hypertens 

8 (Supplement A): A86, 2006. 

79. Wood JM, Schnell CR, Cumin F, et al: Aliskiren, a 

novel, orally effective renin inhibitor, lowers blood 

pressure in marmosets and spontaneously hypertensive 

rats. J Hypertens 23:417, 2005. 

80. Westermann D, Riad A, Lettau O, et al: Renin inhibition 

improves cardiac function and remodeling 

after myocardial infarction independent of blood 

pressure. Hypertension 52: 1068, 2008. 

81. Verma S, Gupta MK: Aliskiren improves nitric oxide 

bioavailability and limits athero-sclerosis. Hypertension 

52: 467, 2008. 

82. Nussberger J, Aubert JF, Bouzourene K, et al: Renin 

inhibition by aliskiren prevents atherosclerosis 

progression. Comparison with irbesartan, atenolol, 

and amlodipine. Hypertension 51: 1306, 2008. 

83. Perlini S, Salinaro F, Fonte ML: Direct renin inhibition. 

Another weapon to modulate the renin 

angiotensin system in postinfarction remodeling? 

Hypertension 52: 1019, 2008. 

84. Feldman DL, Jin L, Xuan H, et al: Effects of aliskiren 

on blood pressure, albuminuria and (pro)renin 

receptor expression in diabetic TG(mRen-2)27 

rats. Hypertension 52: 130, 2008. 

85. Carey RM: Antihypertensive and renoprotective 

mechanisms of renin inhibition in diabetic rats. 


86. Sepehrdad R, Frishman WH, Stier CT Jr., Sica 

DA: Direct inhibition of renin as a cardio-vascular 

pharmacotherapy. Focus on aliskiren. Cardiol in 

Rev 15: 242, 2007. 

87. Frampton JE, Curran MP: Aliskiren. A review of its 

use in the management of hypertension. Drugs 67: 

1767, 2007. 

88. Gradman AH, Schmieder RE, Lins RL, et al: 

Aliskiren, a novel orally effective renin inhibitor, 

provides dose-dependent antihypertensive efficacy 

and placebo-like tolerability in hypertensive patients. 

Circulation 111:1012, 2005. 

89. Stanton A, Jensen C, Nussberger J, et al: Blood 

pressure lowering in essential hypertension with 

an oral renin inhibitor, aliskiren. Hypertension 42: 

1137, 2003. 

90. Pool JL, Schmieder RE, Azizi M, et al: Aliskiren, 

an orally effective renin inhibitor, provides antihypertensive 

efficacy alone and in combination with 

valsartan. Am J Hypertens 20: 11, 2007. 

91. Strasser R, Puig JG, Farsang C, et al: The oral renin 

inhibitor aliskiren has comparable safety and effi- 

cacy to lisinopril in patients with severe hypertension 

(abst). J Hypertens 24 (Suppl 6): 99, 2006. 

92. Sica D, Gradman A, Lederballe O, et al: Aliskiren, 

a novel renin inhibitor, is well tolerated and has 

sustained BP-lowering effects alone and in combination 

with HCTZ during long-term (52 weeks) 

treatment of hypertension. Presented at the 15th 

World Congress of Cardiology, Barcelona, Spain, 

September 2-6, 2006, p 797. 

93. Azizi M, Menard J, Bissery A, et al: Pharmacologic 

demonstration of the synergistic effects of a combination 

of the renin inhibitor aliskiren and the AT1 

receptor antagonist valsartan on the angiotensin 

II-renin feedback interruption. J Am Soc Nephrol 

15:3126, 2004. 

94. Oparil S, Yarows SA, Patel S, et al: Efficacy and 

safety of combined use of aliskiren and valsartan in 

patients with hypertension: a randomised, doubleblind 

trial. Lancet 370: 221, 2007. 

95. Uresin Y, Taylor A, Kilo C, et al: Aliskiren, a novel 

renin inhibitor, has greater BP lowering than 

ramipril and additional BP lowering when combined 

with ramipril in patients with diabetes and 

hypertension. Presented at the 16th Scientific 

Meeting of the European Society of Hypertension, 

Madrid, Spain, June 12-15, 2006. 

96. Villamil A, Chrysant SG, Calhoun D, et al: Renin 

inhibition with aliskiren provides additive antihypertensive 

efficacy when used in combination with 

hydrochlorothiazide. J Hypertens 25: 217, 2007. 

97. Jordan J, Engeli S, Boye SW, et al: Direct renin inhibition 

with aliskiren in obese patients with arterial 

hypertension. Hypertension 49: 1047, 2007. 

98. Schmieder RE, Philipp T, Guerediaga J, et al: Longterm 

antihypertensive efficacy and safety of the 

oral direct renin inhibition aliskiren. A 12 month 

randomized, double-blind comparator trial with 

hydrochlorothiazide. Circulation 119: 417, 2009. 

99. Drummond W, Munger MA, Essop MF, et al: Antihypertensive 

efficacy of the oral direct renin inhibitor 

aliskiren as add-on therapy in patients not 

responding to amlodipine monotherapy. J Clin Hypertens 

9: 742, 2007. 

100. Parving HH, Persson F, Lewis JB, et al for the 

AVOID study investigators: Aliskiren combined 

with losartan in type 2 diabetes and nephropathy. 

N Engl J Med 358: 2433, 2008. 

101. Ingelfinger JR: Aliskiren and dual therapy in type 2 

diabetes mellitus. N Engl J Med 358: 2503, 2008. 

101a. Persson F, Lewis JB, Lewis EJ, et al: Impact of baseline 

renal function on the efficacy and safety of 

aliskiren added to losartan in patients with type 2 

diabetes and nephropathy. Diabetes Care 33: 2304, 

2010.

102. Solomon SD, Appelbaum E, Manning WJ, et al for 

the ALLAY trial investigators: Effect of the direct 

renin inhibitor aliskiren, the angiotensin receptor 

blocker losartan, or both on left ventricular mass 

in patients with hypertension and left ventricular 

hypertrophy. Circulation 119: 530, 2009. 

103. Nussberger J, Wuerzner G, Jensen C, et al: Angiotensin 

II suppression in humans by the orally active 

renin inhibitor Aliskiren (SPP100): comparison 

with enalapril. Hypertension. 39: E1, 2002. 

104. Weir MR, Bush C, Anderson DR, et al: Antihypertensive 

efficacy, safety, and tolerability of the oral 

direct renin inhibitor aliskiren in patients with hypertension: 

a pooled analysis. J Am Soc Hypertens 

1: 264: 2007. 

104a. White WB, Bresalier R, Kaplan AP, et al: Safety and 

tolerability of the direct renin inhibitor aliskiren: a 

pooled analysis of clinical experience in more than 

12,000 patients with hypertension. J Clin Hypertens 

12: 765, 2010. 

104b. Duggan ST, Chwieduk CM, Curran MP: Aliskiren. 

A review of its use as mono-therapy and as combination 

therapy in the management of hypertension. 

Drugs 70: 2011, 2010. 

105. Aliskiren (Tekturna) for hypertension. The Medical 

Letter 49: 29, 2007. 

106. Ayalasomayajula S, Yeh CM, Vaidyanathan S, et 

al: Effects of aliskiren, a direct renin inhibitor, on 

cardiac repolarization and conduction in healthy 

subjects. J Clin Pharmacol 48: 799, 2008. 

107. Dieterle W, Corynen S, Mann J: Effect of the oral 

renin inhibitor aliskiren on the pharmacokinetics 

and pharmacodynamics of a single dose of warfarin 

in healthy subjects. Br J Clin Pharmacol 58:433, 

2004. 

108. Dieterle W, Corynen S, Vaidyanathan S, et al: Pharmacokinetic 

interactions of the oral renin inhibitor 

aliskiren with lovastatin, atenolol, celecoxib and cimetidine. 

Int J Clin Pharmacol Ther 43:527, 2005. 

109. Vaidyanathan S, Reynolds C, Yeh C-M, et al: Pharmacokinetics, 

safety, and tolerability of the novel 

oral direct renin inhibitor aliskiren in elderly 

healthy subjects. J Clin Pharmacol 47: 453, 2007. 

110. Aliskiren/hydrochlorothiazide (Tekturna HCT) for 

hypertension. The Medical Ltr 50: 65, 2008. 


111. Baldwin CM, Plosker GL: Aliskiren/hydrochlorothiazide 

combination in mild to moderate hypertension. 

Drugs 69: 833, 2009. 

112. Aliskiren/valsartan (Valturna) for hypertension. 

The Medical Ltr 51: 94, 2009. 

113. Staessen JA, Li Y, Richart T: Oral renin inhibitors. 

Lancet 368: 1449, 2006. 

114. Bergset J, Storozynsky E, Bisognano JD : Renin inhibition 

for hypertension : selecting the right role 

for a new class of drug. Am J Therap 17: 182, 2010. 

115. McMurray JJV, Pitt B, Latini R, et al for the ALOFT 

investigators : Effects of the oral direct renin inhibitor 

aliskiren in patients with symptomatic heart 

failure. Circ Heart Fail 1: 17, 2008. 

116. Cleland JGF, Coletta AP, Buga L, et al: Clinical trials 

update from the American College of Cardiology 

meeting 2010: DOSE, ASPIRE, CONNECT, 

STICH, STOP AF, CABANA, RACE II, EVEREST 

II, ACCORD AND NAVIGATOR. Eur J Heart Fail 

12: 623, 2010. 

117. Novartis six months efficacy and safety of aliskiren 

therapy on top of standard therapy, on morbidity 

and mortality in patients with acute decompensated 

heart failure (ASTRONAUT). Clinicaltrials.gov 

NCT00894387. US National Institutes of Health. 

Available from URL: http://clinicaltrials.gov (accessed 

Aug 23 2010) 

118. Krum H, Massie B, Abraham WT, et al on behalf 

of the ATMOSPHERE Investigators: Direct renin 

inhibition in addition to or as an alternative to angiotensin 

converting enzyme inhibition in patients 

with chronic systolic heart failure: rationale and design 

of the Aliskiren Trial to Minimize OutcomeS 

in Patients with Heart failuRE (ATMOSPHERE) 

study. Eur J Heart Fail 13: 107, 2011. 

119. Scirica BM, Morrow DA, Bode C, et al: Patients 

with acute coronary syndromes and elevated levels 

of natriuretic peptides: results of the AVANT- 

GARDE-TIMI 43 trial. Eur Heart J 31: 1993, 2010. 

120. Parving HH, Brenner BM, McMurray JJ, et al: 

Aliskiren trial in type 2 diabetes using cardio-renal 

endpoints (ALTITUDE): rationale and study design. 

Nephrol Dial Transplant 24: 1663, 2009.


Diuretic Therapy 

in Cardiovascular Disease 


Todd W. B. Gehr, MD 


1. Dustan H, Rocella EJ, Garrison H: Controlling hypertension. 

A research success story. Arch Intern 

Med 156:1926, 1996. 


on Prevention, Detection, Evaluation, and 

Treatment of High Blood Pressure. Hypertension 

42:1206, 2003. 

3. Szady AD, Hill JA: Diuretics in heart failure. A critical 

appraisal of efficacy and toler-ability. Drugs 69: 

2461, 2009. 

4. Reddy P, Mooradian AD: Diuretics: an update on 

the pharmacology and clinical uses. Am J Therap 

16: 74, 2009. 

5. Brater DC: Diuretic therapy. N Engl J Med 339:387, 

1998. 

6. Ichikawa I, Kon V: Role of peritubular capillary 

forces in the renal action of carbonic anhydrase inhibitor. 

Kidney Int 30:828, 1986. 

7. Eveloff J, Warnock DG: Renal carbonic anhydrase. 

In: Dirks JH, Sutton RA, eds. Diuretics: Physiology, 

Pharmacology and Clinical Use. Philadelphia: WB 

Saunders, 1986:49–65. 

8. Cogan MG, Maddox DA, Warnock DG, et al: Effect 

of acetazolamide on bicarbonate reabsorption 

in the proximal tubule of the rat. Am J Physiol 

237:F447, 1979. 

9. Mirza N, Marson AG, Pirmohamed M. Effect of 

topiramate on acid-base balance: extent, mechanism 

and effects. Br J Clin Pharmacol 68: 655, 2009. 

10. Hassan ZU, Kruer JJ, Fuhrman TM. Electrolyte 

changes during craniotomy caused by administration 

of hypertonic mannitol. J Clin Anesth 19:307, 

2007. 

11. Weaver A, Sica DA: Mannitol-induced acute renal 

failure. Nephron 45:233, 1987. 

12. O’Grady SM, Palfrey HC, Field M: Characteristics 

and function of Na-K-2Cl cotransport in epithelial 

tissues. Am J Physiol 252:C177, 1987. 

13. Radtke HW, Rumrich G, Kinne-Saffran E, Ulrich 

KJ: Dual action of acetazolamide and furosemide 

on proximal volume absorption in the rat kidney. 

Kidney Int 1:100, 1972. 

14. Duarte CG, Chomety F, Giebisch G: Effect of 

amiloride, ouabain, and furosemide on distal tubular 

function in the rat. Am J Physiol 221:632, 1971. 

15. Jung KY, Endou H: Furosemide acts on short loop 

of descending thin limb, but not on long loop. J 

Pharmacol Exp Ther 253:1184, 1990. 

16. Wilson DR, Honrath U, Sonnenberg H: Furosemide 

action on collecting ducts: Effect of prostaglandin 

synthesis inhibition. Am J Physiol 244:F666, 1983. 

17. White MG, van Gelder J, Eastes G: The effect of 

loop diuretics on the excretion of Na + , Ca 2+ , Mg 2+ , 

and Cl – . J Clin Pharmacol 21:610, 1981. 

18. Ryan MP, Devane J, Ryan MG, Counihan TB: Effects 

of diuretics on the renal handling of magnesium. 

Drugs 28(Suppl 1):167, 1984. 

19. Steele TH, Oppenheimer S: Factors affecting urate 

excretion following diuretic administration in 

man. Am J Med 47:564, 1969. 

20. Gerber JG: Role of prostaglandins in the hemodynamic 

and tubular effects of furosemide. Fed Proc 

42:1707, 1983. 

21. Wall GC, Bigner D, Craig S. Ethacrynic acid and 

the sulfa-sensitive patient. Arch Intern Med 163: 

116, 2003. 

22. Loon NR, Wilcox CS, Unwin RJ: Mechanism of 

impaired natriuretic response to furosemide during 

prolonged therapy. Kidney Int 36: 682, 1989. 

23. Benet LZ: Pharmacokinetics/pharmacodynamics 

of furosemide in man: A review. J Pharmacokinet 



11-1


Biopharm 7:1, 1979. 

24. Murray MD, Haag KM, Black PK, et al: Variable furosemide 

absorption and poor predictability of response 

in elderly patients. Pharmacotherapy 17:98, 

1997. 

25. Bowman RH: Renal secretion of [ 35 S]furosemide 

and depression by albumin binding. Am J Physiol 

229:93, 1975. 

26. Takamura N, Maruyama T, Otagiri M: Effects of 

uremic toxins and fatty acids on serum protein 

binding of furosemide: Possible mechanism of the 

binding defect in uremia. Clin Chem 43:2274, 1997. 

27. Chennavasin P, Seiwell R, Brater DC, et al: Pharmacodynamic 

analysis of the furosemide-probenecid 

interaction in man. Kidney Int 16:187, 1979. 

28. Brater DC, Day B, Burdette A, et al: Bumetanide 

and furosemide in heart failure. Kidney Int 26:183, 

1984. 

29. Wilcox CS, Mitch WE, Kelly RA, et al: Response of 

the kidney to furosemide. I. Effects of salt intake 

and renal compensation. J Lab Clin Med 102:450, 

1983. 

30. Chennavasin P, Seiwell R, Brater DC: Pharmacokinetic-dynamic 

analysis of the indomethacin-furosemide 

interaction in man. J Pharmacol Exp Ther 

215:77, 1980. 

31. Agarwal R, Gorski JC, Sundblad K, Brater DC: Urinary 

protein binding does not affect response to 

furosemide in patients with nephrotic syndrome. J 

Am Soc Nephrol 11:1100, 2000. 

32. Knoben JE, Anderson PO, eds. Diuretics. In: Clinical 

Drug Data. 6th ed. IL: Drug Intelligence Publications; 

1988:611–616. 

33. Voelker JR, Brown-Cartwright D, Anderson S, et 

al: Comparison of loop diuretics in patients with 

chronic renal insufficiency: Mechanism of difference 

in response. Kidney Int 32:572, 1987. 

34. Marcantonio LA, Auld WH, Murdoch WR, et al: 

The pharmacokinetics and pharmacodynamics of 

the diuretic bumetanide in hepatic and renal disease. 

Br J Clin Pharmacol 15:245, 1983. 

35. Rudy DW, Gehr TW, Matzke GR, et al: The pharmacodynamics 

of IV and oral torsemide in patients 

with chronic renal insufficiency. Clin Pharmacol 

Ther 56:39, 1994. 

36. Schwartz S, Brater C, Pound D, et al: Bioavailability, 

pharmacokinetics, and pharmacodynamics of 

torsemide in patients with cirrhosis. Clin Pharmacol 

Ther 54:90, 1993. 

37. Vargo DL, Kramer WG, Black PK, et al: Bioavailability, 

pharmacokinetics, and pharmacodynamics of 

torsemide and furosemide in patients with congestive 

heart failure. Clin Pharmacol Ther 57:601, 1995. 

38. Murray MD, Deer MM, Ferguson JA, et al: Open- 

label randomized trial of torsemide compared with 

furosemide therapy for patients with heart failure. 

Am J Med 111:513, 2001. 

39. Ellison DH, Velazquez H, Wright FS: Thiazide-sensitive 

sodium chloride cotransport in early distal 

tubule. Am J Physiol 253:F546, 1987. 

40. Beyer KH: Chlorothiazide. Br J Clin Pharmacol 

13:15, 1982. 

41. Wilson DR, Honrath U, Sonnenberg H: Thiazide 

diuretic effect on medullary collecting duct function 

in the rat. Kidney Int 23:711, 1983. 

42. Seldin DW, Eknoyan G, Suki WN, et al: Localization 

of diuretic action from the pattern of water 

and electrolyte excretion. Ann N Y Acad Sci 

139:328, 1966. 

43. Giles TD, Sander GE, Roffidal LE, et al: Comparative 

effects of nitrendipine and hydrochlorothiazide 

on calciotropic hormones and bone density in 

hypertensive patients. Am J Hypertens 5:875, 1992. 

44. Weinman EJ, Eknoyan G, Suki WN: The influence 

of the extracellular fluid volume on the tubular reabsorption 

of uric acid. J Clin Invest 55:283, 1975. 

45. Leary WP, Reyes AJ: Diuretic-induced magnesium 

losses. Drugs 28(Suppl 1):182, 1984. 

46. Welling PG: Pharmacokinetics of the thiazide diuretics. 

Biopharm Drug Dispos 7:501, 1986. 

47. Beermann B, Groschinsky-Grind M: Clinical pharmacokinetics 

of diuretics. Clin Pharmacokinet 

5:221, 1980. 

48. Knauf H, Mutschler E: Diuretic effectiveness of 

hydrochlorothiazide and furosemide alone and in 

combination in chronic renal failure. J Cardiovasc 

Pharmacol 26:394, 1995. 

49. Stern A: Metolazone, a diuretic agent. Am Heart J 

91:262, 1976. 

50. Suki WN, Dawoud F, Eknoyan G, et al: Effects of 

metolazone on renal function in normal man. J 


51. Craswell PW, Ezzat E, Kopstein J, et al: Use of 

metolazone, a new diuretic, in patients with renal 

disease. Nephron 12:63, 1973. 

52. Sica DA. Metolazone and its role in edema management. 

Congest Heart Fail 9:100-105, 2003. 

53. Wingo CS: Potassium secretion by the cortical collecting 

tubule: Effect of CI gradients and ouabain. 

Am J Physiol 256:F306, 1989. 

54. Krishna GG, Shulman MD, Narins RG. Clinical use 

of the potassium sparing diuretics. Semin Nephrol 

8:354, 1988. 

55. McInnes GT: Relative potency of amiloride and 

spironolactone in healthy man. Clin Pharmacol 

Ther 31:472, 1982. 

56. Rahn KH. Clinical pharmacology of diuretics. Clin 

Exp Hypertens 5:157, 1983.

57. Andriulli A, Arrigoni A, Gindro T, et al: Canrenone 

and androgen receptor-active materials in 

plasma of cirrhotic patients during long-term Kcanrenoate 

or spironolactone therapy. Digestion 

44:155, 1989. 

58. Ménard J. The 45-year story of the development of 

an anti-aldosterone more specific than spironolactone. 

Mol Cell Endocrinol 217:45, 2004. 

59. Krum H, Nolly H, Workman D, He W, et al. Efficacy 

of eplerenone added to renin-angiotensin 

blockade in hypertensive patients. Hypertension 40: 

117, 2002. 

60. Weinberger MH, Roniker B, Krause SL, Weiss RJ. 

Eplerenone, a selective aldosterone blocker, in 

mild-to-moderate hypertension. Am J Hypertens 

15:709, 2002. 

61. Epstein M, Williams GH, Weinberger M, et al. Selective 

aldosterone blockade with eplerenone reduces 

albuminuria in patients with type 2 diabetes. 

Clin J Am Soc Nephrol 1:940, 2006. 

62. Pitt B, Remme W, Zannad F, Neaton J, et al. Eplerenone 

Post-Acute Myocardial Infarction Heart 

Failure Efficacy and Survival Study Investigators. 

Eplerenone, a selective aldosterone blocker, in patients 

with left ventricular dysfunction after myocardial 

infarction. N Engl J Med 348:1309, 2003. 

63. Teiwes J, Toto RD: Epithelial sodium channel inhibition 

in cardiovascular disease. A potential role 

for amiloride. Am J Hypertens 20: 109, 2007. 

64. Kremer D, Boddy K, Brown JJ, et al. Amiloride in 

the treatment of primary hyperaldosteronism and 

essential hypertension. Clin Endocrinol (Oxford) 

7:151, 1977. 

65. Mutschler E, Gilfrich HJ, Knauf H, et al: Pharmacokinetics 

of triamterene. Clin Exp Hypertens 

5:249, 1983. 

66. Villeneuve JP, Rocheleau F, Raymond G: Triamterene 

kinetics and dynamics in cirrhosis. Clin 


67. Knauf H, Mohrke W, Mutschler E: Delayed elimination 

of triamterene and its active metabolite in 

chronic renal failure. Eur J Clin Pharmacol 24:453, 

1983. 

68. Sica DA, Gehr TW: Triamterene and the kidney. 

Nephron 51:454, 1989. 

69. Kelly RA, Wilcox CS, Mitch WE, et al: Response of 

the kidney to furosemide. II. Effect of captopril on 

sodium balance. Kidney Int 24:233, 1983. 

70. Wilcox CS, Guzman NJ, Mitch WE, et al: Na + and 

BP homeostasis in man during furosemide: Effects 

of prazosin and captopril. Kidney Int 31:135, 1987. 

71. Wilcox CS, Loon NR, Ameer B, et al: Renal and 

hemodynamic responses to bumetanide in hypertension: 

effects of nitrendipine. Kidney Int 36:719, 


1989. 

72. Almeshari K, Ahlstom NG, Capraro FE, et al: A 

volume-independent component to post-diuretic 

sodium retention in man. J Am Soc Nephrol 3:1878, 

1993. 

73. Frohlich JC, Hollifield JW, Dormois JC, et al: Suppression 

of plasma renin activity by indomethacin 

in man. Circ Res 39:447, 1976. 

74. Ellison DH, Velazquez H, Wright FS: Adaptation 

of the distal convoluted tubule of the rat. Structural 

and functional effects of dietary salt intake 

and chronic diuretic infusion. J Clin Invest 83:113, 

1989. 

75. Kim J, Welch WJ, Cannon JK, et al: Immunocytochemical 

response of type A and type B intercalated 

cells to increased sodium chloride delivery. Am 

J Physiol 262:F288, 1992. 

76. Stanton BA, Kaissling B: Adaptation of distal tubule 

and collecting duct to increase Na + delivery. 

II. Na + and K + transport. Am J Physiol 255:F1269, 

1988. 

77. Loon NR, Wilcox CS, Unwin RJ: Mechanism of 

impaired natriuretic response to furosemide during 

prolonged therapy. Kidney Int 36:682, 1989. 

78. Idiopathic edema: Role of diuretic abuse. Kidney 

Int 19:881, 1981. 

79. Imbs JL, Schmidt M, Velly J, et al: Comparison of 

the effect of two groups of diuretics on renin secretion 

in the anesthetized dog. Clin Sci Mol Med 

52:171, 1977. 

80. Wilson TW, Loadholt CB, Privitera PJ, et al: Furosemide 

increases urine 6-keto-prostaglandin F 1α . 

Relation to natriuresis, vasodilation, and renin release. 


81. Kraus PA, Lipman J, Becker PJ: Acute preload effects 

of furosemide. Chest 98:124, 1990. 

82. Ciabattoni G, Pugliese F, Cinotti GA, et al: Characterization 

of furosemide-induced activation of 

the renal prostaglandin system. Eur J Pharmacol 

60:181, 1979. 

83. Dikshit K, Vyden JK, Forrester JS, et al: Renal and 

extrarenal hemodynamic effects of furosemide in 

congestive heart failure after acute myocardial infarction. 

N Engl J Med 288:1087, 1973. 

84. Favre L, Glasson P, Riondel A, et al: Interaction 

of diuretics and non-steroidal anti-inflammatory 

drugs in man. Clin Sci (Colch) 64:407, 1983. 

85. Tiggeler RG, Koene RA, Wijdeveld PG: Inhibition 

of frusemide-induced natriuresis by indomethacin 

in patients with nephrotic syndrome. Clin Sci Mol 

Med 52:149, 1977. 

86. Kirchner KA, Brandon S, Mueller RA, et al: Mechanism 

of attenuated hydro-chlorothiazide response 

during indomethacin administration. Kidney Int


31:1097, 1987. 

87. Cutler JA, Sorlie PD, Wolz M, et al. Trends in hypertension 

prevalence, awareness, treatment, and 

control rates in United States adults between 1988- 

1994 and 1999-2004. Hypertension 52:818, 2008. 

88. Conen D, Bamberg F. Noninvasive 24-h ambulatory 

blood pressure and cardiovascular disease: a 

systematic review and meta-analysis. J Hypertens. 

26:1290, 2008. 

89. Moser M. From JNC I to JNC 7—what have we 

learned? Prog Cardiovasc Dis 48: 303, 2006. 

89a. Ernst ME, Moser M: Use of diuretics in patients 

with hypertension: N Engl J Med 361: 2153, 2009. 

90. Roos JC, Boer P, Koomans HA, et al: Haemodynamic 

and hormonal changes during acute and 

chronic diuretic treatment in essential hypertension. 

Eur J Clin Pharmacol 19:107, 1981. 

91. Van Brummelen P, Man in’t Veld Al, Schalekamp 

MADH: Hemodynamic changes during long-term 

thiazide treatment of essential hypertension in 

responders and non-responders. Clin Pharmacol 

Ther 27:328, 1980. 

92. Tarazi RC, Dustan HP, Frohlich ED: Long-term 

thiazide therapy in essential hypertension. Circulation 

41:709, 1970. 

93. Conway J, Lauwers P: Hemodynamic and hypotensive 

effects of long-term therapy with chlorothiazide. 


94. Uzu T, Kimura G: Diuretics shift circadian rhythm 

of blood pressure from nondipper to dipper in essential 

hypertension. Circulation 100:1635, 1999. 

95. Shah S, Khatri I, Freis ED: Mechanism of antihypertensive 

effect of thiazide diuretics. Am Heart J 

95:611, 1978. 

96. Sica DA. Current concepts of pharmacotherapy 

in hypertension: thiazide-type diuretics: ongoing 

considerations on mechanism of action. J Clin Hypertens 

(Greenwich) 6:661, 2004. 

97. Bennett WM, McDonald WJ, Kuehnel E, et al: 

Do diuretics have antihypertensive properties independent 

of natriuresis? Clin Pharmacol Ther 

22:499, 1977. 

98. Sica DA, Gehr TW. Diuretic use in stage 5 chronic 

kidney disease and end-stage renal disease. Curr 

Opin Nephrol Hypertens 12:483, 2003. 

99. Sica DA. Thiazide and loop diuretics. In Izzo JL Jr., 

Sica DA, Black HR: Hypertension Primer 4th ed. 

Dallas: American Heart Assn, 2008: 439. 

100. Epstein M: Aldosterone blockers and potassiumsparing 

diuretics. In Izzo JL Jr., Sica DA, Black 

HR: Hypertension Primer 4th ed. Dallas: American 

Heart Assn, 2008: 443. 

101. Nelson MR, Reid CM, Krum H, et al. Short-term 

predictors of maintenance of normotension af- 

ter withdrawal of antihypertensive drugs in the 

second Australian National Blood Pressure Study 

(ANBP2). Am J Hypertens 16:39, 2003. 

102. Levinson PD, Khatri IM, Freis ED. Persistence of 

normal BP after withdrawal of drug treatment in 

mild hypertension. Arch Intern Med 142:2265, 

1982. 

103. Holland OB, Gomez-Sanchez CE, Kuhnert LV, et 

al: Antihypertensive comparison of furosemide 

with hydrochlorothiazide for black patients. Arch 

Intern Med 139:1015, 1979. 

104. Sica DA, Gehr TWB: Diuretic combination in refractory 

edema states: Pharmacokinetic and pharmacodynamic 

relationships. Clin Pharmacokinet 

30:229, 1996. 

105. Roca-Cusachs A, Aracil-Vilar J, Calvo-Gómez C, et 

al. Clinical effects of torasemide Prolonged release 

in mild-to-moderate hypertension: a randomized 

noninferiority trial versus torasemide immediate 

release. Cardiovasc Ther 26:91, 2008. 

106. Collins R, Peto R, MacMahon S, et al: Blood pressure, 

stroke, and coronary heart disease. Part 2: 

Short-term reductions in blood pressure: Overview 

of randomised drug trials in their epidemiological 

context. Lancet 335:827, 1990. 

107. MacMahon S, Rodgers A: The effects of antihypertensive 

treatment on vascular disease: reappraisal of 

the evidence in 1994. J Vasc Med Biol 4:265, 1993. 

108. Collins R, MacMahon S: Blood pressure, antihypertensive 

drug treatment and the risks of stroke 

and of coronary heart disease. Br Med Bull 50:272, 

1994. 

109. Gueyffier F, Boutitie F, Boissel JP, et al: Effect of 

antihypertensive drug treatment on cardiovascular 

outcomes in women and men: A meta-analysis 

of individual patient data from randomised controlled 

trials. Ann Intern Med 126:761, 1997. 

110. Psaty B, Smith N, Siscovick D, et al: Health outcomes 

associated with antihypertensive therapies 

used as first-line agents: A systematic review and 

meta-analysis. JAMA 277:739, 1997. 

111. Veterans Administration Cooperative Study Group 

on Antihypertensive Agents: Effects of treatment 

on morbidity in hypertension. II. Results in patients 

with diastolic blood pressure averaging 90 

through 114 mm Hg. JAMA 213:1143, 1970. 

112. Hypertension Detection and Follow Up Program 

Cooperation Group. Five-year findings of the Hypertension 

Detection and follow up program. I. 

Reduction in mortality of patients with high blood 


242:2562, 1979. 

113. Management Committee: The Australian therapeutic 

trial in mild hypertension. Lancet I:1261,

1980. 



patients with isolated systolic hypertension. Final 

results of the Systolic Hypertension in the Elderly 

Program (SHEP). JAMA 265:3255, 1991. 



with Hypertension (STOP-Hypertension). 

Lancet 338:1281, 1991. 

116. Wright JM, Lee CH, Chambers GK: Systematic 

review of antihypertensive therapies: Does the evidence 

assist in choosing a first-line drug? CMAJ 

161:25, 1999. 

117. Amery A, Birkenhager W, Brixko R, et al: Mortality 

and morbidity results from the European Working 

Party on High Blood Pressure in the Elderly Trial. 

Lancet 1:1349, 1985. 

118. MRC Working Party: Medical Research Council 

trial of treatment of hypertension in older adults: 

Principal results. BMJ 304:405, 1992. 

119. Wilhelmsen L, Berglund G, Elmfeld D, et al: Beta-blockers 

versus diuretics in hypertensive men: 

Main results from the HAPPHY trial. J Hypertens 

5:561, 1987. 

120. Blood Pressure Lowering Treatment Trialists Collaboration. 

Effects of ACE inhibitors, calcium 

antagonists, and other blood-pressure-lowering 

drugs: Results of prospectively designed overviews 

of randomised trials. Lancet 355:1955, 2000. 

121. Messerli FH, Grossman E, Goldbourt U: Are β 

blockers efficacious as first-line therapy for hypertension 

in the elderly? A systematic review. JAMA 

279:1902, 1998. 

122. Wiysonge CS, Bradley H, Mayosi BM, et al. Betablockers 

for hypertension. Cochrane Database Syst 

Rev 24;(1):CD002003, 2007. 

123. Frishman WH, Saunders E, Messerli F: Beta-adrenergic 

blocking drugs. J Clin Hypertens in press. 

124. Hansson L, Lindholm LH, Niskanen L, et al: Effect 

of angiotensin-converting-enzyme inhibition compared 

with conventional therapy on cardiovascular 

morbidity and mortality in hypertension: The Captopril 

Prevention Project (CAPPP) randomised 

trial. Lancet 353:611, 1999. 

125. Hansson L, Lindholm LH, Ekbom T, et al: Randomised 

trial of old and new antihypertensive 

drugs in elderly patients: Cardiovascular mortality 

and morbidity the Swedish Trial in Old Patients 

with Hypertension-2 study. Lancet 354:1751, 1999. 

126. UK Prospective Diabetes Study Group. Efficacy of 

atenolol and captopril in reducing risk of macrovascular 

and microvascular complications in type 

2 diabetes: UKPDS 39. BMJ 317:713, 1998. 


127. Brown MJ, Palmer CR, Castaigne A, et al: Morbidity 

and mortality in patients randomised to doubleblind 

treatment with a long-acting calcium-channel 

blocker or diuretic in the International Nifedipine 

GITS study: Intervention as a Goal in Hypertension 

Treatment (INSIGHT). Lancet 356:366, 2000. 

128. Hansson L, Hedner T, Lund-Johansen P, et al: 

Randomised trial of effects of calcium antagonists 

compared with diuretics and β-blockers on cardiovascular 

morbidity and mortality in hypertension: 

The Nordic Diltiazem (NORDIL) study. Lancet 

356:359, 2000. 

129. Turnbull F, Woodward M, Neal B, et al. Do men 

and women respond differently to blood pressurelowering 

treatment? Results of prospectively designed 

overviews of randomized trials. Eur Heart J 

29:2669,2008. 

130. Turnbull F, Neal B, Ninomiya T, et al. Effects of different 

regimens to lower blood pressure on major 

cardiovascular events in older and younger adults: 

meta-analysis of randomised trials. BMJ 336:1121, 

2008. 

131. ALLHAT Collaborative Research Group: Major 

cardiovascular events in hypertensive patients 

randomized to doxazosin vs chlorthalidone: The 

antihypertensive and lipid-lowering treatment 

to prevent heart attack trial (ALLHAT). JAMA 

283:1967, 2000. 

132. ALLHAT Officers and Coordinators for the ALL- 

HAT Collaborative Research Group. The Antihypertensive 

and Lipid-Lowering Treatment to 

Prevent Heart Attack Trial. Major outcomes in 

high-risk hypertensive patients randomized to angiotensin-converting 

enzyme inhibitor or calcium 

channel blocker vs diuretic: The Antihypertensive 

and Lipid-Lowering Treatment to Prevent Heart 

Attack Trial (ALLHAT). JAMA 288: 2981, 2002. 

133. Wright JT Jr., Probstfield JL, Cushman WC, et al for 

the ALLHAT Collaborative Research Group: ALL- 

HAT findings revisited in the context of subsequent 

analyses, other trials, and meta-analyses. Arch Intern 

Med 169: 832, 2009. 



and the effects of antihypertensive drug 

therapy. Curr Probl Cardiol 13:371, 1988. 

135. Levy D, Garrison RJ, Savage DD, et al: Prognostic 

implications of echocardiographically determined 

left ventricular mass in the Framingham Heart 

Study. N Engl J Med 322:156, 1990. 

136. Moser M, Hebert PR: Prevention of disease progression, 

left ventricular hypertrophy and congestive 

heart failure in hypertension treatment trials. J 

Am Coll Cardiol 27:1214, 1996.


137. Moser M, Setaro JF: Antihypertensive drug therapy 

and regression of left ventricular hypertrophy: 

A review with a focus on diuretics. Eur Heart J 

12:1034, 1991. 

138. Dahlof B, Pennert K, Hansson L: Reversal of left 

ventricular hypertrophy in hypertensive patients. 

A meta-analysis of 109 treatment studies. Am J Hypertens 

5:95, 1992. 

139. Schmieder RE, Martus P, Klingbeil A: Reversal of 

left ventricular hypertrophy in essential hypertension. 

JAMA 275:1507, 1996. 

140. Fagard RH, Celis H, Thijs L, Wouters S. Regression 

of left ventricular mass by antihypertensive treatment: 

a meta-analysis of randomized comparative 

studies. Hypertension 2009;54:1084-1091. 

141. Neaton JD, Grimm RH Jr, Prineas, et al: Treatment 

of mild hypertension study (TOMHS): Final results. 

JAMA 270:713, 1993. 

142. Gosse P, Sheridan DJ, Zannad F, et al: Regression 

of left ventricular hypertrophy in hypertensive 

patients treated with indapamide SR 1.5 mg versus 

enalapril 20 mg: The LIVE study. J Hypertens 

18:1465, 2000. 

143. Mancia G. Blood pressure reduction and cardiovascular 

outcomes: past, present and future. Am J 

Cardiol 100 (Suppl):3J, 2007. 




Engl J Med 328:914, 1993. 

145. Coope J, Warrender TS: Randomized trial of treatment 

of hypertension in elderly in primary care. Br 

Med J 293:1145, 1986. 

146. Hampton JR: Comparative efficacy of diuretics: 

Benefit versus risk: Results of clinical trials. Eur 

Heart J 13 (Suppl G):85, 1992. 

147. Manolis A, Doumas M. Sexual dysfunction: the 

‘prima ballerina’ of hypertension-related qualityof-life 

complications. J Hypertens 26: 2074, 2008. 

148. The IPPPSH Collaborative Group: Cardiovascular 

risk and risk factors in a randomised trial of treatment 

based on the beta blocker oxprenolol: The International 

Prospective Primary Prevention Study 

in Hypertension (IPPPSH). J Hypertens 3:379, 

1985. 

149. Wilhelmsen L, Berglund G, Elmfeld D, et al: Beta 

blockers vs diuretics in hypertensive men: main results 

from the HAPPHY trial. J Hypertens 5: 561, 

1987. 

150. Pahor M, Shorr RI, Somes GW, et al: Diureticbased 

treatment and cardiovascular events in patients 

with mild renal dysfunction enrolled in the 

Systolic Hypertension in the Elderly Program. Arch 

Intern Med 158:1340, 1998. 

151. Frishman WH: Systemic hypertension in the elderly. 

In Aronow WS, Fleg JL, Rich MW (ed): Cardiovascular 

Disease in the Elderly 4th ed. New York: 

Informa 2008:137. 

151a. ACCF/AHA/NHLBI Expert Consensus Document 

on Hypertension in the Elderly. A report of the 

American College of Cardiology Foundation Task 

Force on Expert Consensus Documents. J Am Coll 

Cardiol_2011 in press. 

151b. Fleg JL, Aronow WS, Frishman WH: Cardiovascular 

drug therapy in the elderly: benefits and challenges. 

Nat Rev Cardiol October 26, 2010 (epub). 

152. Douglas JG, Bakris GL, Epstein M, et al. Management 

of high blood pressure in African Americans: 

a consensus statement of the Hypertension in African 

Americans Working Group of the International 

Society on Hypertension in Blacks. Arch Intern 

Med 163:525, 2003. 

153. Frohlich ED, Messerli FH, Dunn FG, et al: Greater 

renal vascular involvement in the black patient 

with essential hypertension: A comparison of systemic 

and renal hemodynamics in black and white 

patients. Miner Electrolyte Metab 10:173, 1984. 

154. INTERSALT Cooperative Research Group: IN- 

TERSALT: An international study of electrolyte excretion 

and blood pressure. Results of 24 h urinary 

sodium and potassium excretion. BMJ 297:319, 

1988. 

155. Chrysant SG, Danisa K, Kem DC, et al: Racial differences 

in pressure, volume and renin interrelationships 

in essential hypertension. Hypertension 

1:136, 1979. 

156. Wilson DK, Sica DA, Miller SB: Effects of potassium 

on blood pressure in salt-sensitive and saltresistant 

black adolescents. Hypertension 34:181, 

1999. 

157. Whelton PK, He J, Cutler JA, et al: Effects of oral 

potassium on blood pressure. Meta-analysis of randomized 

controlled clinical trials. JAMA 277:1624, 

1997. 

158. Freis ED: Age and antihypertensive medication 

(hydrochlorothiazide, bendroflumethiazide, nadolol 

and captopril). Am J Cardiol 61:117, 1988. 

159. Veterans Administration Cooperative Study Group 

on Antihypertensive Drugs: Comparison of propranolol 

and hydrochlorothiazide for the initial 

treatment of hypertension. I. Results of short term 

titration with emphasis on racial differences in response. 

JAMA 248:1996, 1982. 

160. Moser M, Lunn J: Responses to captopril and hydrochlorothiazide 

in black patients with hypertension. 

Clin Pharmacol Ther 32:307, 1982. 

161. Sica DA: Fixed-dose combination therapy. Is it rational? 

Drugs 48:16, 1994.

162. Wright JT Jr, Dunn JK, Cutler JA, et al. ALLHAT 

Collaborative Research Group. Outcomes in hypertensive 

black and nonblack patients treated 

with chlorthalidone, amlodipine, and lisinopril. 

JAMA 293:1595, 2005. 

163. Flack JM, Saunders E, Gradman A, et al: Antihypertensive 

efficacy and safety of losartan alone and 

in combination with hydrochlorothiazide in adult 

African Americans with mild to moderate hypertension. 

Clin Ther 23:1193, 2001. 

164. Walker WG, Neaton JD, Cutler JA, et al: Renal 

function change in hypertensive members of the 

Multiple Risk Factor Intervention Trial: Racial and 

treatment effects. JAMA 268:3085, 1992. 

165. Rahman M, Pressel S, Davis BR, et al. Renal outcomes 

in high-risk hypertensive patients treated 

with an angiotensin-converting enzyme inhibitor 

or a calcium channel blocker vs a diuretic: a report 

from the Antihypertensive and Lipid-Lowering 

Treatment to Prevent Heart Attack Trial (ALL- 

HAT). Arch Intern Med 165:936, 2005. 

166. Sica DA: Rationale for fixed-dose combinations in 

the treatment of hypertension: the cycle repeats. 

Drugs 62:443, 2002. 

167. Neldam S, Edwards C, Telmisartan/Hydrochlorothiazide 

Investigators: Results of increasing doses 

of hydrochlorothiazide in combination with an 

angiotensin receptor blocker in patients with uncontrolled 

hypertension. J Clin Hypertens 10: 612, 

2008. 

168. Hansson L, Zanchetti A, Carruthers SG, et al: Effect 

of intensive blood-pressure lowering and low-dose 

aspirin in patients with hypertension: Principal 

results of the Hypertension Optimal Treatment 

(HOT) randomised trial. Lancet 351:1755, 1998. 

169. Frishman WH, Bryzinski BS, Coulson LR, et al: A 

multifactorial trial design to assess combination 

therapy in hypertension: Treatment with bisoprolol 

and hydrochlorothiazide. Arch Intern Med 

154:1461, 1994. 

170. Moser M: Why are physicians not prescribing diuretics 

more frequently in the management of hypertension? 

JAMA 270:1813, 1998. 

171. Vasan RS, Larson MG, Benjamin EJ, et al: Congestive 

heart failure in subjects with normal versus reduced 

left ventricular ejection fraction: Prevalence 

and mortality in a population-based cohort. J Am 

Coll Cardiol 33:1948, 1999. 

172. Gradman AH, Alfayoumi F. From left ventricular 

hypertrophy to congestive heart failure: management 

of hypertensive heart disease. Prog Cardiovasc 

Dis 48:326, 2006. 

173. Colucci WS: Molecular and cellular mechanisms of 

myocardial failure. Am J Cardiol 80:15L, 1997. 


174. LeJemtel TH, Sonnenblick EH, Frishman WH: 

Diagnosis and management of heart failure. In: 

Fuster V, Alexander RW, O’Rourke RA, eds. Hurst’s 

The Heart. 10th ed. New York: McGraw-Hill, 

2001:687–724. 

175. Givertz MM, Colucci WS: New targets for heartfailure 

therapy: Endothelin, inflammatory cytokines, 

and oxidative stress. Lancet 352 (Suppl 

1):S134, 1998. 

176. Francis GS, Benedict C, Johnstone DE, et al: Comparison 

of neuroendocrine activation in patients 

with left ventricular dysfunction with and without 

congestive heart failure: A substudy of the Studies 

Of Left Ventricular Dysfunction (SOLVD). Circulation 

82:1724, 1990. 

177. Bank AJ, Lee PC, Kubo SH: Endothelial dysfunction 

in patients with heart failure: Relationship to 

disease severity. J Card Fail 6:29, 2000. 

178. Katz SD, Khan T, Zeballos GA, et al: Decreased 

activity of the L-arginine-nitric oxide metabolic 

pathway in patients with congestive heart failure. 


179. Sam F, Colucci WS: Role of endothelin-1 in myocardial 

failure. Proc Assoc Am Physicians 111:417, 

1999. 

180. Moraes DL, Colucci WS, Givertz MM: Secondary 

pulmonary hypertension in heart failure: The role 

of the endothelium in pathophysiology and management. 

Circulation 102:1718, 2000. 

181. Ichikawa I, Yoshioka T, Fogo A, Kon V: Role of 

angiotensin II in altered glomerular hemodynamics 

in congestive heart failure. Kidney Int Suppl 

30:S123, 1990. 

182. Eiskjaer H, Bagger JP, Danielsen J, et al: Mechanisms 

of sodium retention in heart failure: Relation 

to the renin-angiotensin-aldosterone system. Am J 

Physiol 260:F883, 1991. 

183. Böhm M. Angiotensin receptor blockers versus 

angiotensin-converting enzyme inhibitors: where 

do we stand now? Am J Cardiol 100:38J, 2007. 

184. Cody RJ, Haas GJ, Binkley PF, et al: Plasma endothelin 

correlates with the extent of pulmonary 

hypertension in patients with chronic congestive 


185. Chatterjee K. Neurohumoral activation in congestive 

heart failure and role of vasopressin. Am J Cardiol 

95:8, 2007. 

186. Goldsmith SR: Vasopressin as vasopressor. Am J 

Med 82:1213, 1987. 

187. Creager MA, Faxon DP, Cutler SS, et al. Contribution 

of vasopressin to vasoconstriction in patients 

with congestive heart failure: comparison with the 

renin-angiotensin system and the sympathetic nervous 

system. J Am Coll Cardiol 7: 758. 1986.


188. Chatterjee K. Hyponatremia in heart failure. J Intensive 

Care Med 24:347, 2009. 

189. Barton M, Yanagisawa M. Endothelin: 20 years 

from discovery to therapy. Can J Physiol Pharmacol 

86:485, 2008. 

190. Dontas ID, Xanthos T, Dontas I, et al. Impact of nesiritide 

on renal function and mortality in patients 

suffering from heart failure. Cardiovasc Drugs Ther 

23: 221, 2009. 

191. Francis GS, Siegel RM, Goldsmith SR, et al: Acute 

vasoconstrictor response to intravenous furosemide 

in patients with chronic congestive heart 

failure. Activation of the neurohumoral axis. Ann 

Intern Med 103:1, 1985. 

192. Wilson JR, Reichek N, Dunkman WB, Goldberg S: 

Effect of diuresis on the performance of the failing 

left ventricle in man. Am J Med 70:234, 1981. 

193. Bauer U, Haerer W, Fehske KJ, et al: Hemodynamic 

effects of piretanide and methyldigoxine in congestive 

heart failure: Long-term results of a placebocontrolled 

randomized double blind study. In: 

Puschett J, Greenberg A, eds. Diuretics III: Chemistry, 

Pharmacology, and Clinical Applications. New 

York: Elsevier 1990:316. 

194. Vasko MR, Cartwright DB, Knochel JP, et al: Furosemide 

absorption altered in decompensated congestive 

heart failure. Ann Intern Med 102:314, 1985. 

195. Brater DC, Seiwell R, Anderson S, et al: Absorption 

and disposition of furosemide in congestive heart 

failure. Kidney Int 22:171, 1982. 

196. Wilcox CS. New insights into diuretic use in patients 

with chronic renal disease. J Am Soc Nephrol 

13:798, 2002. 

197. Cook JA, Smith DE, Cornish LA, et al: Kinetics, 

dynamics, and bioavailability of bumetanide in 

healthy subjects and patients with congestive heart 

failure. Clin Pharmacol Ther 44:487, 1988. 

198. Brater DC, Day B, Burdette A, et al: Bumetanide 

and furosemide in heart failure. Kidney Int 26:183, 

1984. 

199. Dzau VJ, Colucci WS, Williams GH, et al.: Sustained 

effectiveness of converting-enzyme inhibition 

in patients with severe congestive heart failure. 

N Engl J Med 302:1373, 1980. 

200. McLay JS, McMurray JJ, Bridges AB, et al: Acute effects 

of captopril on the renal actions of furosemide 

in patients with chronic heart failure. Am Heart J 

26:879, 1993. 

201. De Pasquale CG, Dunne JS, Minson RB, Arnolda 

LF. Hypotension is associated with diuretic resistance 

in severe chronic heart failure, independent 

of renal function. Eur J Heart Fail 7: 888, 2005. 

202. Kramer BK, Schweda F, Riegger GAJ: Diuretic 

treatment and diuretic resistance in heart failure. 

Am J Med 106:90, 1999. 

203. Brater DC, Anderson S, Baird B, et al: Effects of 

ibuprofen, naproxen, and sulindac on prostaglandins 

in men. Kidney Int 27:66, 1985. 

204. Marangoni E, Oddone A, Surian M, et al: Effect 

of high-dose furosemide in refractory congestive 

heart failure. Angiology 41:862, 1990. 

205. Gerlag PG, van Meijel JJ: High-dose furosemide in 

the treatment of refractory congestive heart failure. 


206. Eshaghian S, Horwich TB, Fonarow GC: Relation 

of loop diuretic dose to mortality in advanced heart 

failure. Am J Cardiol 97: 1759, 2006. 

207. Guglin M: Reappraisal of the role of diuretics in 

heart failure. Cardiol in Rev 17: 56, 2009. 

207a. Allen LA, Turer AT, DeWald T, et al: Continuous 

versus bolus dosing of furosemide for patients hospitalized 

for heart failure. Am J Cardiol 105: 1794, 

2010. 

208. Rudy DW, Voelker JR, Greene PK, et al: Loop diuretics 

for chronic renal insufficiency: A continuous 

infusion is more efficacious than bolus therapy. 


209. Lahav M, Regev A, Ra’anani P, et al: Intermittent 

administration of furosemide vs. continuous infusion 

preceded by a loading dose for congestive 

heart failure. Chest 102:725, 1992. 

210. Howard PA: Aggressive diuresis for severe heart 

failure in the elderly. Chest 119:807, 2001. 

210a. Jentzer JC, DeWald TA, Hernandez AF: Combination 

of loop diuretics with thiazide-type diuretics 

in heart failure. J Am Coll Cardiol 56: 1527, 2010. 

211. Brater DC, Presley RH, Anderson SA: Mechanisms 

of the synergistic combination of metolazone and 

bumetanide. J Pharmacol Exp Ther 233:70, 1985. 

212. Epstein M, Lepp BA, Hoffman DS, et al: Potentiation 

of furosemide by metolazone in refractory 

edema. Curr Ther Res 21:656, 1977. 

213. Channer KS, Richardson M, Crook R, et al: Thiazides 

with loop diuretics for severe congestive heart 

failure. Lancet 335:922, 1990. 

214. Kiyingi A, Field MJ, Pawsey CC, et al: Metolazone 

in treatment of severe refractory congestive heart 

failure. Lancet 335:29, 1990. 

215. Channer KS, McLean KA, Lawson-Matthew P, et 

al: Combination diuretic treatment in severe heart 

failure: A randomised controlled trial. Br Heart J 

71:146, 1994. 

216. Van Viet AA, Danker AJM, NAFTA JJ, Overheat 

FW: Spironolactone in congestive heart failure refractory 

to high-dose loop diuretic and low-dose 

angiotensin converting enzyme inhibitor. Am J 

Cardiol 71:21A, 1993. 

217. Farquharson CAJ, Struthers AD: Spironolactone

increases nitric oxide bioactivity, improves endothelial 

vasodilator dysfunction and suppresses 

vascular angiotensin I/angiotensin II conversion 

in patients with chronic heart failure. Circulation 

101:594, 2000. 

218. Weber KT: Aldosterone in congestive heart failure. 

N Engl J Med 345:1689, 2001. 

219. Rocha R, Williams GH: Rationale for the use of 

aldosterone antagonists in congestive heart failure. 

Drugs 62:723, 2002. 

220. Bauersachs J, Heck M, Fraccarollo D, et al: Addition 

of spironolactone to angiotensin-converting 

enzyme inhibition in heart failure improves endothelial 

vasomotor dysfunction. J Am Coll Card 

39:351, 2002. 

220a. Maron BA, Leopold JA: Aldosterone receptor antagonists. 

Effective but often forgotten. Circulation 

121: 934, 2010. 

221. Pitt B, Zannad F, Rime WJ et al: The effect of spironolactone 

on morbidity and mortality in patients 

with severe heart failure. N Engl J Med 341:709, 

1999. 

221a. Zannad F, McMurray JJ, Drexler H, et al: Rationale 

and design of the Eplerenone in Mild Patients Hospitalization 

and Survival Study in Heart Failure 

(EMPHASIS-HF). Eur J Heart Fail 12: 617, 2010. 

222. Keating GM, Plosker GL: Eplerenone. A review of 

its use in left ventricular systolic dysfunction and 

heart failure after acute myocardial infarction. 

Drugs 64: 2689, 2004. 

222a. Zannad F, McMurray JJV, Krum H, et al: Eplerenone 

in patients with systolic heart failure and 

mild symptoms. N Engl J Med November 14, 2010 

(epub). 

222b. Armstrong PW: Aldosterone antagonists – last 

man standing? N Engl J Med November 14, 2010 

(epub). 

223. Jorde UP, Vittorio T, Katz SD, et al: Elevated plasma 

aldosterone levels despite complete inhibition 

of the vascular angiotensin-converting enzyme in 

chronic heart failure, Circulation 106:1055, 2002. 

224. Ayus JC: Diuretic-induced hyponatremia (editorial). 


225. Ashraf N, Locksley R, Arieff AI: Thiazide-induced 

hyponatremia associated with death or neurologic 

damage in outpatients. Am J Med 70:1163, 1981. 

226. Mann SJ. The silent epidemic of thiazide-induced 

hyponatremia. J Clin Hypertens (Greenwich)10:477, 

2008. 

227. Szatalowicz VL, Miller PD, Lacher JW, et al: Comparative 

effect of diuretics on renal water excretion 

in hyponatraemic oedematous disorders. Clin Sci 

(Colch) 62:235, 1982. 

228. Sonnenblick M, Friedlander Y, Rosin AJ: Diuretic- 


induced severe hyponatremia. Review and analysis 

of 129 reported patients. Chest 103:601, 1993. 

229. Sterns RH: “Slow” correction of hyponatremia: A 

break with tradition? Kidney 23:1, 1991. 

230. Berl T: Treating hyponatremia: What is all the controversy 

about? [see comments]. Ann Intern Med 

113:417, 1990. 

231. Morgan DB, Davidson C: Hypokalemia and diuretics: 

An analysis of publications. Br Med J 280:905, 

1980. 

232. Khuri RN, Strieder WN, Giebisch G: Effects of flow 

rate and potassium intake on distal tubular potassium 

transfer. Am J Physiol 228:1249, 1975. 

233. Velazquez H, Wright FS: Control by drugs of renal 

potassium handling. Ann Rev Pharmacol Toxicol 

26:293, 1986. 

234. Stanton BA, Giebisch G: Effects of pH on potassium 

transport by renal distal tubule. Am J Physiol 

242:F544, 1982. 

235. Wilcox CS: Diuretics and potassium. In: Hoffman 

JF, Giebisch G, eds. Current Topics in Membranes 

and Transport. Orlando, FL: Academic Press, 

1987:250–331. 

236. Freis ED, Papademetriou V: How dangerous are diuretics? 

Drugs 30:469, 1985. 

237. Holland OB, Nixon JV, Kuhnert L: Diureticinduced 

ventricular ectopic activity. Am J Med 

70:762, 1981. 

238. MacMahon S, Collins G, Rautaharju P, et al: Electrocardiographic 

left ventricular hypertrophy and 

effects of antihypertensive drug therapy in hypertensive 

patients in the Multiple Risk Factor Intervention 

Trial. Am J Cardiol 63:202, 1989. 

239. Mann JF, Yi QL, Sleight P, Dagenais GR, et al. Serum 

potassium, cardiovascular risk, and effects of 

an ACE inhibitor: results of the HOPE study. Clin 

Nephrol 63:181, 2005. 

240. Madias J, Madias N, Gavras H: Nonarrhythmogenicity 

of diuretic-induced hypokalemia: Its 

evidence in patients with uncomplicated essential 

hypertension. Arch Intern Med 144:2171, 1984. 

241. Papademetriou V, Fletcher R, Khatri IM, et al: 

Diuretic-induced hypokalemia in uncomplicated 

systemic hypertension. Effect of plasma potassium 

correction in cardiac arrhythmias. Am J Cardiol 

52:1017, 1983. 

242. Medical Research Council, Working Party on Mild 

to Moderate Hypertension: Ventricular extrasystole 

during thiazide treatment: Substudy of MRC 

Mild Hypertension Trial. Br Med J 287:1249, 1983. 

243. Kafka H, Langevin L, Armstrong P: Serum magnesium 

and potassium in acute myocardial infarction: 

Influences on ventricular arrhythmia. Arch 

Intern Med 147:465, 1987.


244. Packer M: Potential role of potassium as a determinant 

of morbidity and mortality in patients with 

systemic hypertension and congestive heart failure. 

Am J Cardiol 65:45E, 1990. 

245. Dargie HJ, Cleland J, Leckie B, et al: Relation of arrhythmias 

and electrolyte abnormalities to survival 

in patients with severe chronic heart failure. Circulation 

75(Suppl IV):IV98, 1987. 

246. Franse LV, Pahor M, DiBari M, et al: Hypokalemia 

associated with diuretic use and cardiovascular 

events in the Systolic Hypertension in the Elderly 

Program. Hypertension 35:1025, 2000. 

247. Siscovick DS, Raghunathan TE, Psaty BM, et al: 

Diuretic therapy and the risk of primary cardiac 

arrest. N Engl J Med 330:1852, 1994. 

248. Cooper HW, Dries DL, Davis CE, et al: Diuretics 

and risk of arrhythmic death in patients with 

left ventricular dysfunction. Circulation 100:1311, 

1999. 

249. Seigel D, Hulley SB, Black DM, et al: Diuretics, 

serum and intracellular electrolyte levels, and ventricular 

arrhythmias in hypertensive men. JAMA 

267:1083, 1992. 

250. Knochel JP, Schlein EM: On the mechanism of 

rhabdomyolysis in potassium depletion. J Clin Invest 

51:1750, 1972. 

251. Relman AS, Schwartz WB: The nephropathy of potassium 

depletion: A clinical and pathological entity. 

N Engl J Med 255:195, 1956. 

252. Sica DA, Gehr TW, Yancy C. Hyperkalemia, congestive 

heart failure, and aldosterone receptor antagonism. 

Congest Heart Fail 9: 224, 2003. 

253. Quamme GA: Effect of furosemide on calcium 

and magnesium transport in the rat nephron. Am J 

Physiol 241:F340, 1981. 

254. Kroenke K, Wood DR, Hanley JF: The value of 

serum magnesium determination in hypertensive 

patients receiving diuretics. Arch Intern Med 

147:1553, 1987. 

255. Petri M, Cumber P, Grimes L, et al: The metabolic 

effects of thiazide therapy in the elderly: A population 

study. Age Aging 15:151, 1986. 

256. Dyckner T, Wester PO: Effects of magnesium infusions 

in diuretic induced hyponatraemia. Lancet 

1:585, 1981. 

257. Whang R, Oei TO, Aikawa JK, et al: Predictors of 

clinical hypomagnesemia. Hypokalemia, hypophosphatemia, 

hyponatremia, and hypocalcemia. 

Arch Intern Med 144:1984. 

258. Wester PO, Dyckner T: Intracellular electrolytes 

in cardiac failure. Acta Med Scand 707(Suppl): 33, 

1986. 

259. Eichhorn EJ, Tandon PK, DiBianco R, et al: Clinical 

and prognostic significance of serum magne- 

sium concentration in patients with severe chronic 

congestive heart failure: The PROMISE study. J Am 


260. Cannon PJ, Heineman HO, Albert MS, et al: “Contraction” 

alkalosis after diuresis of edematous patients 

with ethacrynic acid. Ann Intern Med 62:979, 

1965. 

261. Loon NR, Wilcox CS, Nelson R, Mounts M: Metabolic 

alkalosis impairs the response to bumetanide. 

Kidney Int 33:200A, 1988. 

262. O’Connell JE, Colledge NR. Type IV renal tubular 

acidosis and spironolactone therapy in the elderly. 

Postgrad Med J 69:887, 1993. 

263. Report of Medical Research Council Working 

Party on Mild to Moderate Hypertension. Adverse 

reactions to bendrofluazide and propranolol for 

the treatment of mild hypertension. Lancet 2:539, 

1981. 

264. Furman BL: Impairment of glucose intolerance 

produced by diuretics and other drugs. Pharmacol 

Ther 12:613, 1981. 

265. Dornhorst A, Powell SH, Pensky J: Aggravation by 

propranolol of hyperglycaemic effect of hydrochlorothiazide 

in type II diabetics without alteration of 

insulin secretion. Lancet 1:123, 1985. 

266. Palmer BF, Naderi ASA: Metabolic complications 

associated with use of thiazide diuretics. J Am Soc 

Hypertens 1: 381, 2007. 

267. Zillich AJ, Garg J, Basu S, et al: Thiazide diuretics, 

potassium, and the development of diabetes. A 

quantitative review. Hypertension 48: 219, 2006. 

268. Carter BL, Einhorn PT, Brands M, et al. Thiazideinduced 

dysglycemia: call for research from a 

working group from the national heart, lung, and 

blood institute. Hypertension 52:30, 2008. 

269. Cooper-DeHoff RM, Wen S, Beitelshees AL, et al. 

Impact of abdominal obesity on incidence of adversemetabolic 

effects associated with antihypertensive 

medications. Hypertension 55:61, 2010. 

270. Sowers JR, Bakris GL: Antihypertensive therapy 

and the risk of type 2 diabetes mellitus. N Engl J 

Med 342:969, 2000. 

271. Jeunemaitre X, Charru A, Chatellier G, et al: Longterm 

metabolic effects of spironolactone and thiazides 

combined with potassium-sparing agents for 

treatment of essential hypertension. Am J Cardiol 

62:1072, 1988. 

272. Cooper-DeHoff RM, Pacanowski MA, Pepine CJ. 

Cardiovascular therapies and associated glucose 

homeostasis: implications across the dysglycemia 

continuum. J Am Coll Cardiol 53 (5 Suppl):S28, 

2009. 

273. Ruppert M, Overlack A, Kolloch R, et al: Neurohormonal 

and metabolic effects of severe and mod-

erate salt restriction in non-obese normotensive 

adults. J Hypertens 11:743, 1993. 

274. Mantel-Teeuwisse AK, Kloosterman JM, Maitlandvan 

der Zee AH, et al: Drug-Induced lipid changes: 

A review of the unintended effects of some commonly 

used drugs on serum lipid levels. Drug Saf 

24:443, 2001. 

275. Lakshman MR, Reda DJ, Materson BJ, et al: Diuretics 

and β blockers do not have adverse effects 

at 1 year on plasma lipid and lipoprotein profiles in 

men with hypertension. Arch Intern Med 159:551, 

1999. 

276. Kasiske BL, Ma JZ, Kalil RS, et al. Effects of antihypertensive 

therapy on serum lipids. Ann Intern 

Med 122::133, 1995. 

277. Hypertension Detection and Follow-Up Program 

Cooperation Group. 1979. Five-year findings of the 

hypertension detection and follow-up program. I. 

Reduction in mortality of patients with high blood 


277:157, 1997. 

278. Ljunghall S, Backman U, Danielson BG, et al: Effects 

of bendroflumethiazide on urate metabolism 

during treatment of patients with renal stones. J 

Urol 127:1207, 1982. 

279. Sica DA, Schoolwerth A. Renal handing of organic 

anions and cations and renal excretion of uric acid. 

In:Brenner B, Rector F, eds. The Kidney 7th ed. 

Philadelphia: WB Saunders; 2004:637–662. 

280. Weinman EJ, Eknoyan G, Suki WN. The influence 

of the extracellular fluid volume on the tubular reabsorption 

of uric acid. J Clin Invest 55:283, 1975. 

281. Franse LV, Pahor M, Di Bari M, et al. Serum uric 

acid, diuretic treatment and risk of cardiovascular 


Program (SHEP). J Hypertens 18:1149, 2000. 

282. Young JL Jr, Boswell RB, Nies AS. Severe allopurinol 

hypersensitivity. Association with thiazides and 

prior renal compromise. Arch Intern Med 134: 553, 

1974. 

283. Shahinfar RL, Simpson RL, Carides AD, et al. Safety 

of losartan in hypertensive patients with thiazideinduced 

hyperuricemia. Kidney Int 56:1879, 1999. 

284. Lim LS, Fink HA, Kuskowski MA, et al for the Osteoporotic 

Fractures in Men (MrOS) Study Group: 

Loop diuretic use and increased rates of hip bone 

loss in older men. Arch Intern Med 168: 735, 2008. 

285. Chang SW, Fine R, Siegel D, et al: The impact of 

diuretic therapy on reported sexual function [see 

comments]. Arch Intern Med 151:2402, 1991. 

286. Bansal S. Sexual dysfunction in hypertensive men. 

A critical review of the literature. Hypertension 

12:1, 1988. 

287. Grimm RH Jr, Grandits GA, Prineas RJ, et al. Long- 


term effects on sexual function of five antihypertensive 

drugs and nutritional hygienic treatment in 

hypertensive men and women. Treatment of Mild 

Hypertension Study (TOMHS). Hypertension 29:8, 

1997. 

288. Wassertheil-Smoller S, Blaufox MD, Oberman A, 

et al. Effect of antihypertensives on sexual function 

and quality of life: the TAIM study. Ann Intern Med 

114:613, 1991. 

289. Kloner RA, Brown M, Prisant LM, et al. Effect of 

sildenafil in patients with erectile dysfunction 

taking antihypertensive therapy. Sildenafil Study 

Group. Am J Hypertens 14:70, 2001. 

290. Jeunemaitre X, Chatellier G, Kreft-Jais C, et al. Efficacy 

and tolerance of spironolactone in essential 

hypertension. Am J Cardiol 60: 820, 1987. 

291. Spironolactone and endocrine dysfunction. Ann 

Intern Med 85:630, 1976. 

292. Williams GH, Burgess E, Kolloch RE, et al. Efficacy 

of eplerenone versus enalapril as monotherapy in 

systemic hypertension. Am J Cardiol 93:990, 2004. 

293. Rybak LP: Ototoxicity of loop diuretics. Otolaryngology 

Clin 26:829, 1993. 

294. Rybak LP: Pathophysiology of furosemide ototoxicity. 

J Otolaryngol 11:127, 1982. 

295. Tuzel IH: Comparison of adverse reactions to bumetanide 

and furosemide. J Clin Pharmacol 21:615, 

1981. 

296. Reineck HJ: Diuretic use in renal failure. In: Eknoyan 

G, Martinez-Maldonado M, eds. The Physiological 

Basis of Diuretic Therapy in Clinical Medicine. 

Orlando, FL: Grune & Stratton, 1986:298. 

297. Heidland A, Wigand ME: The effect of furosemide 

at high doses on auditory sensitivity in patients 

with uremia. Klin Wochenschr 48:1052, 1970. 

298. Fries D, Pozet N, Dubois N, et al: The use of large 

doses of frusemide in acute renal failure. Postgrad 

Med J 47:(Suppl):18, 1971. 

299. Beermann B, Dalen E, Lindstrom B, Rosen A: On 

the fate of furosemide in man. Eur J Clin Pharmacol 

9:51, 1975. 

300. Brown CG, Ogg CS, Cameron JS, Bewick M: Highdose 

furosemide in acute reversible intrinsic renal 

failure. Scot Med J 19(Suppl):35, 1974. 

301. Addo HA, Ferguson J, Frain Bell W: Thiazide-induced 

photosensitivity: A study of 33 subjects. Br J 

Dermatol 116:749, 1987. 

302. Diffey BL, Langtry J: Phototoxic potential of thiazide 

diuretics in normal subjects. Arch Dermatol 

125:1355, 1989. 

303. Frommer JP, Wesson DE, Eknoyan G: Side effects 

and complications of diuretic therapy. In: Eknoyan 

G, Martinez-Maldonado M, eds. The Physiological 

Basis of Diuretic Therapy in Clinical Medicine. Or-


lando, FL: Grune & Stratton, 1986:293–309. 

304. Schwarz A, Krause PH, Kunzendorf U, et al: The 

outcome of acute interstitial nephritis: Risk factors 

for the transition from acute to chronic interstitial 

nephritis. Clin Nephrol 54:179, 2000. 

305. Magil AB, Ballon HS, Cameron EC, Rae A: Acute 

interstitial nephritis associated with thiazide diuretics. 

Clinical and pathologic observations in 

three cases. Am J Med 69:939, 1980. 

306. Grossman E, Messerli FH, Goldbourt U: Does diuretic 

therapy increase the risk of renal cell carcinoma? 

Am J Cardiol 83:1090, 1999. 

307. Tenenbaum A, Grossman E, Fisman EZ, et al: 

Long-term diuretic therapy in patients with coronary 

disease: Increased colon cancer-related mortality 

over a 5-year follow up. J Hum Hypertens 

15:373, 2001. 

308. Grossman E, Messerli FH, Goldbourt U. Carcinogenicity 

of cardiovascular drugs. Curr Hypertens 

Rep 1: 212, 1999. 

309. Corrao G, Scotti L, Bagnardi V, Sega R. Hypertension, 

antihypertensive therapy and renal-cell cancer: 

a meta-analysis. Curr Drug Saf 2:125, 2007. 

310. Lawson DH, Macadam RF, Singh MH, et al: Effect 

of furosemide on antibiotic-induced renal damage 

in rats. J Infect Dis 126:593, 1972. 

311. Shapiro S, Slone D, Lewis GP, et al: The epidemiology 

of digoxin toxicity. A study in three Boston 

hospitals. J Chronic Dis 22:361, 1969. 

312. Petersen V, Hvidt S, Thomsen K, et al: Effect of prolonged 

thiazide treatment on renal lithium clearance. 

Br Med J 3:143, 1974. 

313. Boer WH, Loomans HA, Dorhout Mees EJ: Effects 

of thiazides with and without carbonic-anhydrase 

inhibiting activity on free water and lithium clearance. 

In: Puschett J, Greenberg A, eds. Diuretics 

III: Chemistry, Pharmacology, and Clinical 

Applications. New York: Elsevier Science Publishing, 

1990:31–33. 

314. Shirley DG, Walter SJ, Sampson B: A micropuncture 

study of renal lithium reabsorption: Effects of 

amiloride and furosemide. Am J Physiol 263:F1128, 

1992. 

315. Bridgman JF, Rosen SM, Thorp JM: Complications 

during clofibrate treatment of nephrotic-syndrome 

hyperlipoproteinaemia. Lancet 2:506, 1972. 

316. Weinberg MS, Quigg RJ, Salant DJ, Bernard DB: 

Anuric renal failure precipitated by indomethacin 

and triamterene. Nephron 40:216, 1985. 

317. Packer M, Lee WH, Kessler P, et al: Identification of 

hyponatremia as a risk factor for the development 

of functional renal insufficiency during converting 

enzyme inhibition in severe chronic heart failure. J 


318. Packer M Lee WH, Medina, et al: Functional renal 

insufficiency during long-term therapy with captopril 

and enalapril in severe chronic heart failure. 


319. Schlondorff D: Renal prostaglandin synthesis: Sites 

of production and specific actions of prostaglandins. 

Am J Med 81:1, 1985. 

320. Sica DA: Dosage considerations with perindopril 

for systemic hypertension. Am J Cardiol 88(Suppl 

7):13i, 2001.


Magnesium, Potassium, and Calcium 

as Cardiovascular Disease Therapies 



1. Saris NE, Mervaala E, Karppanen H, et al: Magnesium: 

An update on physiological, clinical, and 

analytical aspects. Clin Chim Acta 294: 1, 2000. 

2. Reinhart RA: Magnesium metabolism: A review 

with special reference to the relationship between 

intracellular content and serum levels. Arch Intern 

Med 148:2415, 1988. 

3. Wacker WE, Parisi AF: Magnesium metabolism. N 

Engl J Med 278:658, 1968. 

4. Altura BM, Altura BT: Role of magnesium in the 

pathogenesis of hypertension updated: relationship 

to its actions on cardiac, vascular smooth 

muscle, and endothelial cells. In: Laragh JN, 

Brenner BM, eds. Hypertension: Pathophysiology, 

Diagnosis and Management. New York: Raven 

Press, 1995:1213. 

5. Reinhart RA: Clinical correlates of the molecular 

and cellular actions of magnesium on the cardiovascular 

system. Am Heart J 121:1513, 1991. 

6. Fox C, Ramsoomair D, Carter C: Magnesium: Its 

proven and potential clinical significance. South 

Med J 94:1195, 2001. 

7. Mroczek WJ, Lee WR, Davidov ME: Effect of magnesium 

sulfate on cardiovascular hemodynamics. 

Angiology 28:720, 1977. 

8. Laurant P, Touyz RM: Physiological and pathophysiological 

role of magnesium in the cardiovascular 

system: Implications in hypertension. J 

Hypertens 18: 1177, 2000. 

9. Iseri LT, French JH: Magnesium: nature’s physiologic 

calcium blocker. Am Heart J 108:188, 1984. 

10. Vigorito C, Giordano A, Ferraro P, et al: Hemodynamic 

effects of magnesium sulfate on the normal 

human heart. Am J Cardiol 67:1435, 1991. 

11. Turlapaty PD, Altura BM: Magnesium deficiency 

produces spasms of coronary arteries: Relationship 

to etiology of sudden death ischemic heart disease. 

Science 208:198, 1980. 

12. Arsenian MA: Magnesium and cardiovascular disease. 


13. Satake K, Lee JD, Shimizu H, et al: Relation between 

severity of magnesium deficiency and frequency of 

anginal attacks in men with variant angina. J Am 


14. Cermuzynski L, Gebalska J, Wolk R, Makowska E: 

Hypomagnesemia in heart failure with ventricular 

arrhythmias. Beneficial effects of magnesium supplementation. 

J Intern Med 247:78, 2000. 

15. Sheu JR, Hsiao G, Shen MY, et al. Mechanisms involved 

in the antiplatelet activity of magnesium in 

human platelets. Br J Haematol 119:1033, 2002. 

16. Ravn HB. Pharmacological effects of magnesium 

on arterial thrombosis-mechanisms of action? 

Magnes Res 12 : 191, 1999. 

17. Shechter M: The role of magnesium as antithrombotic 

therapy. Wien Med Wochenschr 150:343, 2000. 

18. Sherer Y, Bitzur R, Cohen H, et al: Mechanisms of 

action of the anti-atherogenic effect of magnesium: 

Lessons from a mouse model. Magnes Res 14:173, 

2001. 

19. Shechter M, Sharir M, Labrador MJ, et al: Oral 

magnesium therapy improves endothelial function 

in patients with coronary artery disease. Circulation 

102:2353, 2000. 

20. Mazur A, Maier JA, Rock E, et al. Magnesium and 

the inflammatory response: potential physiopathological 

implications. Arch Biochem Biophys 458: 48, 

2007. 

21. Leary WP, Reyes AJ, Lockett CJ, et al: Magnesium 

and deaths ascribed to ischaemic heart disease in 

South Africa. A preliminary report. S Afr Med J 



12-1


64:775, 1983. 

22. Yamori Y, Mizushima S: A review of the link between 

dietary magnesium and cardiovascular risk. 

J Cardiovasc Risk 7:31, 2000. 

23. Chipperfield B, Chipperfield JR: Heart-muscle 

magnesium, potassium, and zinc concentrations 

after sudden death from heart-disease. Lancet 

2:293, 1973. 

24. Johnson CJ, Peterson DR, Smith EK: Myocardial 

tissue concentrations of magnesium and potassium 

in men dying suddenly from ischemic heart 

disease. Am J Clin Nutr 32:967, 1979. 

25. Abraham AS, Bar-On E, Eylath U: Changes in the 

magnesium content of tissues following myocardial 

damage in rats. Med Biol 59:99; 1981. 

26. Chang C, Bloom S: Interrelationship of dietary 

magnesium intake and electrolyte homeostasis in 

hamsters: I. Severe magnesium deficiency, electrolyte 

homeostasis, and myocardial necrosis. J Am 

Coll Nutr 4:173, 1985. 

27. Chakraborti S, Chakraborti T, Mandal M, et al. 

Protective role of magnesium in cardiovascular 

diseases: a review. Mol Cell Biochem 238:163, 2002. 

28. Steurer G, Yang P, Rao V, et al: Acute myocardial 

infarction, reperfusion injury, and intravenous 

magnesium therapy: Basic concepts and clinical 

implications. Am Heart J 132: 478, 496, 1996. 

29. Teo KK, Yusuf S, Collins R, et al: Effects of intravenous 

magnesium in suspected acute myocardial 

infarction: Overview of randomised trials. BMJ 

303:1499, 1991. 

30. Woods KL, Fletcher S, Roffe C, Haider Y: Intravenous 

magnesium sulphate in suspected acute myocardial 

infarction: Results of the second Leicester 

Intravenous Magnesium Intervention Trial (LIM- 

IT-2). Lancet 339:1553, 1992. 

31. ISIS-4: A randomized factorial trial assessing early 

oral captopril, oral mononitrate, and intravenous 

magnesium sulphate in 58,050 patients with suspected 

acute myocardial infarction. ISIS-4 (Fourth 

International Study of Infarct Survival) Collaborative 

Group. Lancet 345:669, 1995. 

32. Ziegelstein RC, Hilbe JM, French WJ, et al: Magnesium 

use in the treatment of acute myocardial 

infarction in the United States (Observations from 

the Second National Registry of Myocardial Infarction). 

Am J Cardiol 87:7, 2001. 

33. Woods KL, Fletcher S: Long-term outcome after intravenous 

magnesium sulphate in suspected acute 

myocardial infarction: The second Leicester Intravenous 

magnesium Intervention Trial (LIMIT-2). 

Lancet 343:816, 1994. 

34. Roffe C, Fletcher S, Woods KL: Investigation of 

the effects of intravenous magnesium sulphate on 

cardiac rhythm in acute myocardial infarction. Br 

Heart J 71:141, 1994. 

35. Shechter M, Hod H, Kaplinsky E, Rabinowitz B: 

The rationale of magnesium as alternative therapy 

for patients with acute myocardial infarction without 

thrombolytic therapy. Am Heart J 132:483, 

1996. 

36. Antman EM: Magnesium in acute myocardial infarction: 

Overview of available evidence. Am Heart 

J 132:487, 1996. 

37. Woods KL, Abrams K: The importance of effect 

mechanism in the design and interpretation of clinical 

trials: The role magnesium in acute myocardial 

infarction. Prog Cardiovasc Dis 44:267, 2002. 

38. Shechter M, Hod H, Chouraqui P, et al: Magnesium 

therapy in acute myocardial infarction when patients 

are not candidates for thrombolytic therapy. 

Am J Cardiol 75:321, 1995. 

39. Caspi J, Rudis E, Bar I, et al: Effects of magnesium 

on myocardial function after coronary artery bypass 

grafting. Ann Thorac Surg 59:942, 1995. 

40. Toraman F, Karabulut EH, Alhan HC, et al: Magnesium 

infusion dramatically decreases the incidence 

of atrial fibrillation after coronary artery bypass 

grafting. Ann Thorac Surg 72:1256, 2001. 

41. Kinoshita K, Oe M, Tokunaga K: Superior protective 

effect of low-calcium, magnesium-free 

potassium cardioplegic solution on ischemic myocardium. 

Clinical study in comparison with St. 

Thomas’ Hospital solution. J Thorac Cardiovasc 

Surg 101:695, 1991. 

42. Demmy TL, Haggerty SP, Boley TM, Curtis JJ: Lack 

of cardioplegia uniformity in clinical myocardial 

preservation. Ann Thorac Surg 57:648, 1994. 

43. Santoro GM, Antoniucci D, Bolognese L, et al: A 

randomized study of intravenous magnesium in 

acute myocardial infarction treated with direct 

coronary angioplasty. Am Heart J 140:891, 2000. 

44. Magnesium in Coronaries (MAGIC) Trial Investigators. 

Early administration of intravenous magnesium 

to high-risk patients with acute myocardial 

infarction in the Magnesium in Coronaries (MAG- 

IC) Trial: a randomised controlled trial. Lancet 

360:1189, 2002. 

45. Antman EM, Anbe DT, Armstrong PW, et al. ACC/ 

AHA Guidelines for the Management of Patients 

With ST-Elevation Myocardial Infarction—Executive 

Summary. Circulation. 110:588, 2004. 

46. Li J, Zhang Q, Zhang M, Egger M. Intravenous 

magnesium for acute myocardial infarction. Cochrane 

Database Syst Rev 18: (2): CD002755, 2007. 

47. Jackson CE, Meier DW: Routine serum magnesium 

analysis. Correlation with clinical state in 5,100 patients. 

Ann Int Med 69:743, 1968.

48. Tosiello L: Hypomagnesemia and diabetes mellitus. 

A review of clinical implications. Arch Intern Med 

156:1143, 1996. 

49. Lima MD, Cruz T, Pousada JC, et al: The effect of 

magnesium supplementation in increasing doses 

on the control of type 2 diabetes. Diabetes Care 

21:682, 1998. 

50. Sjogren A, Floren CH, Nilsson A: Magnesium, potassium 

and zinc deficiency in subjects with type II 

diabetes mellitus. Acta Med Scand 224:461, 1988. 

51. Agus ZS: Hypomagnesemia. J Am Soc Nephrol 

10:1616, 1999. 

52. Leier CV, Dei Cas L, Metra M: Clinical relevance 

and management of the major electrolyte abnormalities 

in congestive heart failure: Hyponatremia, 

hypokalemia, and hypomagnesemia. Am Heart J 

128:564, 1994. 

53. Cohen N, Alon I, Almoznino-Sarafian D, et al: 

Metabolic and clinical effects of oral magnesium 

supplementation in furosemide-treated patients 

with severe congestive heart failure. Clin Cardiol 

23:433, 2000. 

54. Wester PO, Dyckner T: Diuretic treatment and 

magnesium losses. Acta Med Scand 647(Suppl):145, 

1981. 

55. Chase LR, Slatopolsky E: Secretion and metabolic 

efficiency of parathyroid hormone in patients with 

severe hypomagnesemia. J Clin Endocrinol Metab 

38:363, 1974. 

56. Leicht E, Schmidt-Gayk H, Langer HJ, et al: Hypomagnesaemia-induced 

hypocalcaemia: Concentrations 

of parathyroid hormone, prolactin and 

1,25-dihydroxyvitamin D during magnesium replenishment. 

Magnes Res 5:33, 1992. 

57. Dyckner T, Wester PO, Widman L. Amiloride prevents 

thiazide-induced intracellular potassium and 

magnesium losses. Acta Med Scand 224: 25, 1988. 

58. Bo S, Pisu E. Role of dietary magnesium in cardiovascular 

disease prevention, insulin sensitivity and 

diabetes. Curr Opin Lipidol 19:50, 2008. 

59. Belin RJ, He K. Magnesium physiology and pathogenic 

mechanisms that contribute to the development 

of the metabolic syndrome. Magnes Res 20: 

107, 2007. 

60. Wester PO: Electrolyte balance in heart failure and 

the role for magnesium ions. Am J Cardiol 70:44C, 

1992. 

61. Eichhorn EJ, Tandon PK, DiBianco R, et al: Clinical 

and prognostic significance of serum magnesium 

concentration in patients with severe chronic 

congestive heart failure: The PROMISE Study. J Am 


61a. Peacock JM, Ohira T, Post W, et al: Serum magnesium 

and risk of sudden cardiac death in the Ath- 


erosclerosis Risk in Communities (ARIC) study. 

Am Heart J 160: 464, 2010. 

62. Gottlieb SS, Fisher ML, Pressel MD, et al: Effects of 

intravenous magnesium sulfate on arrhythmias in 

patients with congestive heart failure. Am Heart J 

125:1645, 1993. 

63. Sueta CA, Clarke SW, Dunlap SH, et al: Effect of 

acute magnesium administration on the frequency 

of ventricular arrhythmia in patients with heart 

failure. Circulation 89:660, 1994. 

64. Bashir Y, Sneddon JF, Staunton HA, et al: Effects 

of long-term oral magnesium chloride replacement 

in congestive heart failure secondary to coronary 


65. Cohen L, Kitzes R: Magnesium sulfate and digitalis-toxic 

arrhythmias. JAMA 249:2808, 1983. 

66. Crippa G, Sverzellati E, Giorgi-Pierfranceschi M, 

Carrara GC: Magnesium and cardiovascular drugs: 

Interactions and therapeutic role. Ann Ital Med Int 

14:40, 1999. 

67. Dyckner T, Wester PO: Ventricular extrasystoles 

and intracellular electrolytes before and after potassium 

and magnesium infusions in patients on 

diuretic treatment. Am Heart J 97:12, 1979. 

68. McLean RM: Magnesium and its therapeutic uses: 

A review. Am J Med 96:63, 1994. 

69. Ho KM. Intravenous magnesium for cardiac arrhythmias: 

jack of all trades. Magnes Res 21: 65, 

2008. 

70. Hirahara K, Matsubayashi T, Matsuura H, Ehara T: 

Intracellular magnesium depletion depresses the 

delayed rectifier potassium current in guinea pig 

ventricular myocytes. Jpn J Physiol 48:81, 1998. 

71. Ghani MF, Rabah M: Effect of magnesium chloride 

on electrical stability of the heart. Isr Heart J 

94:600, 1977. 

72. McDaniel WC, Curtis JJ, Walls JT, Madsen RW. Effects 

of magnesium sulfate on electrical ventricular 

defibrillation of dogs. J Electrocardiol 31:137, 1998. 

73. Dyckner T, Wester PO: Magnesium deficiency 

contributing to ventricular tachycardia. Two case 

reports. Acta Med Scand 212:89, 1982. 

74. Iseri LT: Magnesium and cardiac arrhythmias. 

Magnesium 5:111, 1986. 

75. Tsuji H, Venditti FJ Jr., Evans JC, et al: The association 

of levels of serum potassium and magnesium 

with ventricular premature complexes (the Framingham 

Heart Study). Am J Cardiol 74: 232, 1994. 

76. Shiga T, Wajima Z, Inoue T, Ogawa R: Magnesium 

prophylaxis for arrhythmias after cardiac surgery: a 

meta-analysis of randomized controlled trial. Am J 

Med 117: 325, 2004. 

77. Hoes AW, Grobbee DE, Lubsen J, et al: Diuretics, 

β-blockers, and the risk for sudden cardiac death


in hypertensive patients. Ann Intern Med 123:481, 

1995. 

78. Allegra J, Lavery R, Cody R, et al: Magnesium sulfate 

in the treatment of refractory ventricular fibrillation 

in the pre-hospital setting. Resuscitation 

49:245, 2001. 

79. Allen BJ, Brodsky MA, Capparelli EV, et al: Magnesium 

sulfate therapy for sustained monomorphic 

ventricular tachycardia. Am J Cardiol 15:64:1202, 

1989. 

80. Ramee SR, White CJ, Svinarich JT, et al: Torsades 

de pointes and magnesium deficiency. Am Heart J 

109:164, 1985. 

81. Tzivoni D, Banai S, Schuger C, et al: Treatment of 

torsades de pointes with magnesium sulfate. Circulation 

77:392, 1988. 

82. Shingu T, Matsuura H, Kusaka M, et al: Significance 

of intracellular free calcium and magnesium 

and calcium-regulating hormones with sodium 

chloride loading in patients with essential hypertension. 

J Hypertens 9:1021, 1991. 

83. Hatzistavri LS, Sarafidis PA, Georgianos PI, et al: 

Oral magnesium supplementation reduces ambulatory 

blood pressure in patients with mild hypertension. 


84. McCarron DA: Calcium and magnesium nutrition 

in human hypertension. Ann Intern Med 98:800, 

1983. 

85. Joffres MR, Reed DM, Yano K: Relationship of 

magnesium intake and other dietary factors to 

blood pressure: The Honolulu Heart Study. Am J 

Clin Nutr 45:469; 1987. 

86. Peacock JM, Folsom AR, Arnett DK, et al: Relationship 

of serum and dietary magnesium to incident 

hypertension: The Atherosclerosis Risk in 

Communities (ARIC) Study. Ann Epidemiol 9:159, 

1999. 

87. Houston MC, Harper KJ. Potassium, magnesium, 

and calcium: their role in both the cause and treatment 

of hypertension. J Clin Hypertens (Greenwich) 

10(7 Suppl 2):3, 2008. 

88. Resnick LM, Gupta RK, Laragh JH: Intracellular 

free magnesium in erythrocytes of essential hypertension: 

Relation to blood pressure and serum 

divalent cations. Proc Natl Acad Sci U S A 81: 6511, 

1984. 

89. Vollmer WM, Sacks FM, Ard J, et al: Effects of diet 

and sodium intake on blood pressure: Subgroup 

analysis of the DASH-Sodium Trial. Ann Intern 

Med 135:1019, 2001. 

90. Ascherio A, Hennekens C, Willett WC, et al: Prospective 

study of nutritional factors, blood pressure, 

and hypertension among US women. Hypertension 

27:1065, 1996. 

91. Yamamoto ME, Applegate WB, Klag MJ, et al: Lack 

of blood pressure effect with calcium and magnesium 

supplementation in adults with high-normal 

blood pressure. Results from Phase I of the Trials 

of Hypertension Prevention (TOHP). Trials of Hypertension 

Prevention (TOHP) Collaborative Research 

Group. Ann Epidemiol 5:96, 1995. 

92. Lind L, Lithell H, Pollare T, Ljunghall S: Blood 

pressure response during long-term treatment with 

magnesium is dependent on magnesium status. A 

double-blind, placebo-controlled study in essential 

hypertension and in subjects with high normal 

blood pressure. Am J Hypertens 4:674, 1991. 

93. Cappuccio FP, Markandu ND, Benynon GW, et al: 

Lack of effect of oral magnesium on high blood 

pressure: A double blind study. BMJ 291:235, 1985. 

94. Henderson DG, Schierup J, Schodt J: Effect of magnesium 

supplementation on blood pressure and 

electrolyte concentrations in hypertensive patients 

receiving long-term diuretic treatment. BMJ 293: 

664, 1986. 

95. Nowson CA, Morgan TO: Magnesium supplementation 

in mild hypertensive patients on a moderately 

low sodium diet. Clin Exp Pharmacol Toxicol 

16:299, 1989. 

96. Ferrara LA, Iannuzzi R, Castaldo A, et al: Longterm 

magnesium supplementation in essential hypertension. 

Cardiology 81:25, 1992. 

97. Hatzistavri LS, Sarafidis PA, Georgianos PI, et al. 

Oral magnesium supplementation reduces ambulatory 

blood pressure in patients with mild hypertension. 


98. Harlan WR, Harlan LC: Blood pressure and calcium 

and magnesium intake. In: Laragh JH, Brenner 

BM, eds. Hypertension: Pathophysiology, Diagnosis 

and Management. New York: Raven Press, 

1995:1143. 

99. Lu JF, Nightingale CH: Magnesium sulfate in eclampsia 

and pre-eclampsia: Pharmacokinetic principles. 


100. Witlin AG, Sibai BM: Magnesium sulfate in preeclampsia 

and eclampsia. Obstet Gynecol 92:883, 

1998. 

101. Simunic M, Rumboldt Z, Ljutic D, et al. Ramipril 

decreases chlorthalidone-induced loss of magnesium 

and potassium in hypertensive patients. J Clin 

Pharmacol 35:1150, 1995. 

102. Keyrouz SG, Diringer MN. Clinical review: Prevention 

and therapy of vasospasm in subarachnoid 

hemorrhage. Crit Care 11; 220, 2007 

103. Vink R, Cook NL, van den Heuvel C. Magnesium 

in acute and chronic brain injury: an update. 

Magnes Res 22:158S, 2009. 

104. Larsson SC, Virtanen MJ, Mars M, et al: Magne-

sium, calcium, potassium, and sodium intakes and 

risk of stroke in male smokers. Arch Intern Med 

168: 459, 2008. 

105. Muir KW: Magnesium for neuroprotection in ischaemic 

stroke: Rationale for use and evidence of effectiveness. 

CNS Drugs 15:921, 2001. 

106. Lampl Y, Gilad R, Geva D, et al: Intravenous administration 

of magnesium sulfate in acute stroke: 

A randomized double-blind study. Clin Neuropharmacol 

24:1, 2001. 

107. Cortés YE, Moses L. Magnesium disturbances in 

critically ill patients. Compend Contin Educ Vet 29: 

420, 2007. 

108. Elliott C, Newman N, Madan A: Gentamicin effects 

on urinary electrolyte excretion in healthy subjects. 


109. Kingston ME, Al-Siba’i MB, Skooge WC: Clinical 

manifestations of hypomagnesemia. Crit Care Med 

14:950, 1986. 

110. Gettes LS: Electrolyte abnormalities underlying 

lethal and ventricular arrhythmias. Circulation 

85(Suppl I):I70, 1992. 

111. Chen WC, Fu XX, Pan ZJ, Qian SZ: ECG changes 

in early stage of magnesium deficiency. Am Heart J 

104:1115, 1982. 

112. Iseri LT, Freed J, Bures AR: Magnesium deficiency 

and cardiac disorders. Am J Med 58:837, 1975. 

113. Gullestad L, Midtvedt K, Dolva LO, et al: The magnesium-loading 

test: Reference values in healthy 

subjects. Scand J Clin Lab Invest 54:23, 1994. 

114. Rob PM, Dick K, Bley N, et al: Can one really measure 

magnesium deficiency using the short-term 

magnesium loading test? J Intern Med 246:373, 

1999. 

115. Martin KJ, González EA, Slatopolsky E. Clinical 

consequences and management of hypomagnesemia. 

J Am Soc Nephrol 20:2291, 2009. 

116. He K, Liu K, Daviglus ML, et al: Magnesium intake 

and incidence of metabolic syndrome among 

young adults. Circulation 113: 1675, 2006. 

117. Sica DA, Struthers AD, Cushman WC, et al: Importance 

of potassium in cardiovascular disease. J Clin 

Hypertens 4:1, 2002. 

117a. Bowling CB, Pitt B, Ahmed MI, et al: Hypokalemia 

and outcomes in patients with chronic heart 

failure and chronic kidney disease. Findings from 

propensity-matched studies. Circ Heart Fail 3: 253, 

2010. 

117b. Chatterjee R, Yeh H-C, Shafi T, et al: Serum and dietary 

potassium and risk of incident type 2 diabetes 

mellitus. The Atherosclerosis Risk in Communities 

(ARIC) Study. Arch Intern Med 170: 1745, 2010. 

118. Young DB: Control, cardiovascular, and renal effects 

of potassium. In: Laragh JH, Brenner BM, 


eds. Hypertension: Pathophysiology, Diagnosis and 

Management. New York: Raven Press, 1995:1503. 

119. Young DB, Lin H, McCabe RD: Potassium’s cardiovascular 

protective mechanisms. Am J Physiol 

268:R825, 1995. 

120. Fang J, Madhavan S, Alderman MH: Dietary potassium 

intake and stroke mortality. Stroke 31:1532, 

2000. 

121. Bazzano LA, he J, Ogden LG, et al: Dietary potassium 

intake and risk of stroke in US men and women. 

National Health and Nutrition Examination 

Survey I Epidemiologic Follow-Up Study. Stroke 

32:1473, 2001. 

122. Cohen HW, Madhavan S, Alderman MH: High and 

low serum potassium associated with cardiovascular 

events in diuretic-treated patients. J Hypertens 

19:1315, 2001. 

123. Franse LV, Pahor M, DiBari M, et al: Hypokalemia 

associated with diuretic use and cardiovascular 


Program. Hypertension 35:1025, 2000. 

124. Sanguinetti MC: Modulation of potassium channels 

by antiarrhythmic and antihypertensive drugs. 


125. Singh H, Linas SL: Potassium therapy and hypertension. 

Miner Electrolyte Metab 19:57, 1993. 

126. Morris RC Jr, Sebastian A: Potassium-responsive 

hypertension. In: Laragh, JH, Brenner BM, eds. 

Hypertension: Pathophysiology, Diagnosis and 

Management, 2nd ed. New York: Raven Press, 

1995:2715. 

127. Tobian L: The protective effects of high-potassium 

diets in hypertension, and the mechanisms by 

which high-NaCl diets produce hypertension— 

a personal view. In: Laragh JH, Brenner BM, eds. 

Hypertension: Pathophysiology, Diagnosis and Management, 

2nd ed. New York: Raven Press, 1995:299. 

128. Siani A, Strazzullo P: Relevance of dietary potassium 

intake to antihypertensive drug treatment. In: 

Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, 

Diagnosis and Management, 2nd ed. 

New York: Raven Press, 1995:2727. 

129. Khaw KT, Barrett-Connor E: Dietary potassium 

and blood pressure in a population. Am J Clin Nutr 

39: 963; 1984. 

130. Khaw KT, Rose G: Population study of blood pressure 

and associated factors in St. Lucia, West Indies. 

Int J Epidemiol 11:372, 1982. 

131. Reed D, McGee D, Yano K, Hankin J: Diet, blood 

pressure, and multicollinearity. Hypertension 7:405, 

1985. 

132. Cook NR, Obarzanek E, Cutler JA, et al. Trials of 

Hypertension Prevention Collaborative Research 

Group. Joint effects of sodium and potassium in-


take on subsequent cardiovascular disease: the Trials 

of Hypertension Prevention follow-up study. 


133. Pietinen PI, Wong O, Altschul AM: Electrolyte output, 

blood pressure, and family history of hypertension. 

Am J Clin Nutr 32:997, 1979. 

134. Grim CE, Luft FC, Miller JZ, et al: Racial differences 

in blood pressure in Evans County, Georgia: 

Relationship to sodium and potassium intake and 

plasma renin activity. J Chronic Dis 33:87, 1980. 

135. Turban S, Miller ER 3rd, Ange B, Appel LJ. Racial 

differences in urinary potassium excretion. J Am 

Soc Nephrol 19:1396, 2008. 

136. Whelton PK: Potassium and blood pressure. In 

Izzo JL Jr., Sica DA, Black HR (eds): Hypertension 

Primer 4th ed. American Heart Assn, Dallas 2008: 

305. 

137. Appel LJ, on behalf of the American Society of Hypertension 

Writing Group: ASH position paper: 

dietary approaches to lower blood pressure. J Clin 

Hypertens 11: 358: 2009. 

138. Fujita T, Ando K: Hemodynamic and endocrine 

changes associated with potassium supplementation 

in sodium-loaded hypertensives. Hypertension 

6:184, 1984. 

139. Young DB, McCaa RE, Pan YJ, Guyton AC: The natriuretic 

and hypotensive effects of potassium. Circ 

Res 38(Suppl 2):84, 1976. 

140. Wilson DK, Sica DA, Miller SB: Effects of potassium 

on blood pressure in salt-sensitive and saltresistant 

black adolescents. Hypertension 34:181, 

1999. 

141. Cappuccio FP, MacGregor GA: Does potassium 

supplementation lower blood pressure? A metaanalysis 

of published trials. J Hypertens 9:465, 1991. 

142. Kawano Y, Minami J, Takishita S, Omae T: Effects 

of potassium supplementation on office, home, and 

24-h blood pressure in patients with essential hypertension. 


143. Gu D, He J, Wu X, et al: Effect of potassium supplementation 

on blood pressure in Chinese: A 

randomized, placebo-controlled trial. J Hypertens 

19:1325, 2001. 

144. Whelton PK, He J, Cutler JA, et al: Effects of oral 

potassium on blood pressure. Meta-analysis of randomized 

controlled clinical trials. JAMA 277:1624, 

1997. 

145. Smith SR, Klotman PE, Svetkey LP: Potassium 

chloride lowers blood pressure and causes natriuresis 

in older patients with hypertension. J Am Soc 

Nephrol 2:1302, 1992. 

146. Fotherby MD, Potter JF: Potassium supplementation 

reduces clinic and ambulatory blood pressure 

in elderly patients. J Hypertens 10:1403, 1992. 

147. Svetkey LP, Simons-Morton D, Vollmer WM, et al: 

Effects of dietary patterns on blood pressure: subgroup 

analysis of the Dietary Approaches to Stop 

Hypertension (DASH) randomized clinical trial. 


148. Sacks FM, Svetkey LP, Vollmer WM, et al: Effects 

on blood pressure of reduced dietary sodium and 

the Dietary Approaches to Stop Hypertension 

(DASH) diet. DASH-Sodium Collaborative Research 

Group. N Engl J Med 344:3, 2001. 

149. Kaplan NM, Carnegie A, Ruskin P, et al: Potassium 

supplementation in hypertensive patients 

with diuretic-induced hypokalemia. N Engl J Med 

312:746, 1985. 

150. Salvetti A, Bishisao E, Caiazza A, et al: The combination 

of a low Na/high K salt with metoprolol 

in the treatment of mild-moderate hypertension. A 

multicenter study. Am J Hypertens 1:201S, 1988. 

151. Khaw KT, Barrett-Connor E: Dietary potassium 

and stroke-associated mortality. A 12-year prospective 

population study. N Engl J Med 316:235, 

1987. 

152. Ascherio A, Rimm EB, Hernan MA, et al: Intake 

of potassium, magnesium, calcium, and fiber and 

risk of stroke among US men. Circulation 98:1198, 

1998. 

153. Fang J, Madhavan S, Alderman MH: Dietary potassium 

intake and stroke mortality. Stroke 31:1532, 

2000. 

154. Larsson SC, Virtanen MJ, Mars M, Männistö S, et 

al. Magnesium, calcium, potassium, and sodium 

intakes and risk of stroke in male smokers. Arch 

Intern Med 168: 459, 2008. 

155. US FDA Center for Food Safety and Applied Nutrition 

Health claim notification for potassiumcontaining 

foods. Available at http://www.fda.gov/ 

Food/LabelingNutrition/LabelClaims/ FDA Modernization 

Act FD AMAClaims/ucm073606.htm. 

Accessed 1/31/10. 

156. Steinberg D, Parthasarathy S, Carew TE, et al: Beyond 

cholesterol. Modifications of low-density lipoprotein 

that increase its atherogenicity. N Engl J 

Med 320:915, 1989. 

157. Steinbrecher UP, Zhang H, Longheed M: Role of 

oxidative modification of low-density lipoprotein 

in atherosclerosis. Free Radic Biol Med 9: 155, 1990. 

158. Tobian L, Jahner TM, Johnson MA: High potassium 

diets markedly reduce atherosclerotic cholesterol 

ester deposition in aortas of rats with hypercholesterolemia 

and hypertension. Am J Hypertens 3:133, 

1990. 

159. Young DB, Ma G: Vascular protective effects of potassium. 

Semin Nephrol 19:477, 1999. 

160. Cavusoglu E, Chopra V, Gupta A, et al: Relation of

aseline serum potassium levels to angiographic 

findings in patients with known or suspected coronary 

artery disease. Am J Hypertens 22: 754, 2009. 

161. Fang J, Madhavan S, Cohen H, Alderman MH: Serum 

potassium and cardiovascular mortality. J Gen 

Intern Med 15: 885, 2000. 

162. Rardon DP, Fisch C: Electrolytes and the heart. In: 

Schlant RC, Alexander RW, eds. Hurst’s The Heart, 

8th ed. New York: McGraw Hill, 1994:768. 

163. Diercks DB, Shumaik GM, Harrigan RA, et al. 

Electrocardiographic manifestations: electrolyte 

abnormalities. J Emerg Med 27:153, 2004. 

164. Surawicz B: Electrolytes, hormones, temperature, 

and miscellaneous factors. In: Electrophysiologic 

Basis of ECG and Cardiac Arrhythmias. Baltimore: 

Williams Wilkins, 1995:426. 

165. Wahr JA, Parks R, Boisvert D, et al: Preoperative 

serum potassium levels and perioperative outcomes 

in cardiac surgery patients. Multicenter 

Study of Perioperative Ischemia Research Group. 

JAMA 281:2203, 1999. 

166. Reid JL, Whyte KF, Struthers AD: Epinephrineinduced 

hypokalemia: The role of beta adrenoceptors. 

Am J Cardiol 57:23F, 1986. 

167. Newhouse MT, Chapman KR, McCallum AL, et al: 

Cardiovascular safety of high doses of inhaled fenoterol 

and albuterol in acute severe asthma. Chest 

110:595, 1996. 

168. Salerno DM, Murakami M, Elsperger KJ: Effects of 

pretreatment with propranolol on potassium, calcium, 

and magnesium shifts after ventricular fibrillation 

in dogs. J Lab Clin Med 114:595, 1989. 

169. Wijesinghe M, Weatherall M, Perrin K, et al. Risk 

of mortality associated with formoterol: a systematic 

review and meta-analysis. Eur Respir J 34: 803, 

2009. 

170. Cohn JN, Kowey PR, Whelton PK, Prisant LM: 

New guidelines for potassium replacement in clinical 

practice: A contemporary review by the National 

Council on potassium in Clinical Practice. Arch 

Intern Med 160: 2429, 2000. 

171. Norris W, Kunzelman KS, Bussell S, et al Potassium 

supplementation, diet vs pills. A randomized trial 

of postoperative cardiac surgery patients. Chest 

125: 404, 2004. 

172. Perezella MA: Drug-induced hyperkalemia: Old 

culprits and new offenders. Am J Med 109:307, 

2000. 

173. Schepkens H, Vanholder R, Billiouw JM, Lameire 

N: Life-threatening hyperkalemia during combined 

therapy with angiotensin-converting enzyme 

inhibitors and spironolactone: An analysis of 25 

cases. Am J Med 110:438, 2001. 

174. Kruse JA, Clark VL, Carlson RW, Geheb MA: Con- 


centrated potassium chloride infusions in critically 

ill patients with hypokalemia. J Clin Pharmacol 

34:1077, 1994. 

175. Kruse JA, Carlson RW: Rapid correction of hypokalemia 

using concentrated intravenous potassium 

chloride infusions. Arch Intern Med 150:613, 1990. 

176. Famularo G, Corsi FM, Giacanelli M: Iatrogenic 

worsening of hypokalemia and neuromuscular paralysis 

associated with the use of glucose solutions 

for potassium replacement in a young woman with 

licorice intoxication and furosemide abuse. Acad 

Emerg Med 6:960, 1999. 

177. He FJ, MacGregor GA: Beneficial effects of potassium. 

BMJ 323:497, 2001. 

178. Gennari FJ: Hypokalemia. N Engl J Med 339:451, 

1998. 

179. Macdonald JE, Struthers AD: What is the optimal 

serum potassium level in cardiovascular patients? J 


180. Hatton DC, Young EW, Bukoski RD, McCarron 

DA: Calcium metabolism in experimental genetic 

hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: 

Pathophysiology, Diagnosis and Management. 

New York: Raven Press, 1995:1193. 

181. Oparil S: Diet-micronutrients—special foods. In: 

Oparil S, Weber M, eds. Hypertension: A Companion 

to the Kidney. Philadelphia: Saunders, 2000:433. 

182. Fleckenstein-Grun G, Frey M, Thimm F, et al: 

Calcium overload—an important cellular mechanism 

in hypertension and arteriosclerosis. Drugs 

44(Suppl 1):23, 1992. 

183. Sowers JR, Standley PR, Tuck ML, Ram JL: Calcium 

and calcium-regulatory hormones in hypertension. 

In: Laragh JH, Brenner BM, eds. Hypertension: 

Pathophysiology, Diagnosis and Management. New 

York: Raven Press, 1995:1155. 

184. Zemel MB: Calcium modulation of hypertension 

and obesity: Mechanisms and implications. J Am 

Coll Nutr 20 (Suppl 5): 428S, 2001. 

185. Sica DA, Harford AM, Zawada ET: Hypercalcemic 

hypertension in hemodialysis. Clin Nephrol 22:102, 

1984. 

186. Quereda C, Orte L, Sabater J, et al: Urinary calcium 

excretion in treated and untreated essential hypertension. 

J Am Soc Nephrol 7:1058, 1996. 

187. Yamakawa H, Suzuki H, Nakamura M, et al: Disturbed 

calcium metabolism in offspring of hypertensive 

parents. Hypertension 19:528, 1992. 

188. Jorde R, Sundsfjord J, Haug E, Bonaa KH: Relation 

between low calcium intake, parathyroid hormone, 

and blood pressure. Hypertension 35:1154, 2000. 

189. Jorde R, Bonaa KH, Sundsfjord J: Population based 

study on serum ionized calcium, serum parathyroid 

hormone, and blood pressure. The Tromso


study. Eur J Endocrinol 141:350, 1999. 

190. Hagstrom E, Hellman P, Larsson TE, et al: Plasma 

parathyroid hormone and the risk of cardiovascular 

mortality in the community. Circulation 119: 

2765, 2009. 

191. Bucher HC, Cook RJ, Guyatt GH, et al: Effects of 

dietary calcium supplementation on blood pressure. 

A meta-analysis of randomized controlled 

trials. JAMA 275:1016, 1996. 

192. Allender PS, Cutler JA, Follmann D, et al: Dietary 

calcium and blood pressure: A meta-analysis of 

randomized clinical trials. Ann Intern Med 124:825, 

1996. 

193. Pikilidou MI, Befani CD, Sarafidis PA, Oral calcium 

supplementation ambulatory blood pressure 

and relation to changes in intracellular ions and sodium-hydrogen 

exchange. Am J Hypertens 22:1263, 

2009. 

194. Griffith LE, Guyatt GH, Cook RJ, et al: The influence 

of dietary and non-dietary calcium supplementation 

on blood pressure: An updated meta-analysis 

of randomized controlled trials. Am J Hypertens 

12:84, 1999. 

195. Domrongkitchaiporn S, Ongphiphadhanakul B, 

Stitchantrakul W, et al: Risk of calcium oxalate 

nephrolithiasis after calcium or combined calcium 

and calcitriol supplementation in postmenopausal 

women. Osteoporosis Int 11:486, 2000. 

196. Bucher HC, Guyatt GH, Cook RJ, et al: Effect of 

calcium supplementation on pregnancy-induced 

hypertension and preeclampsia: A meta-analysis 

of randomized controlled trials. JAMA 275:1113, 

1996. 

197. Niromanesh S, Laghaii S, Mosavi-Jarrahi A: Supplementary 

calcium in prevention of pre-eclampsia. 

Int J Gynaecol Obstet 74:17, 2001. 

198. Hofmyr GJ, Duley L, Atallah A. Dietary calcium 

supplementation for prevention of pre-eclampsia 

and related problems: a systematic review and 

commentary. BJOG 114:933, 2007. 

199. LeWinter MM, Osol G: Normal physiology of the 

cardiovascular system. In: Fuster V, Alexander RW, 

O’Rourke RA, eds. Hurst’s the Heart, 10th ed. New 

York: McGraw Hill, 2001:63–94. 

200. Figueredo VM, Camacho SA: Basic mechanisms of 

myocardial dysfunction: Cellular pathophysiology 

of heart failure. Curr Opinion Cardiol 9:272, 1994. 

201. Dhalla NS, Afzal N, Beamish RE, et al: Pathophysiology 

of cardiac dysfunction in congestive heart 

failure. Can J Cardiol 9:873, 1993. 

202. Ornato JP, Gonzalez ER, Morkunas AR, et al: Treatment 

of presumed asystole during pre-hospital cardiac 

arrest: Superiority of electrical countershock 

Am J Emer Med 3:395, 1985. 

203. Stempien A, Katz AM, Messineo FC: Calcium and 

cardiac arrest. Ann Intern Med 105:603, 1986. 

204. Kelsch T, Kikuchi K, Vahdat S, Frishman WH: Innovative 

pharmacologic approaches to cardiopulmonary 

resuscitation. Heart Dis 3:46, 2001. 

205. Kirsch JR, Dean JM, Rogers MC: Current concepts 

in brain resuscitation. Arch Intern Med 146:1413, 

1986. 

206. Dembo DH: Calcium in advanced life support. Crit 

Care Med 9:358, 1981. 

207. Follette DM, Fey K, Buckberg GD, et al: Reducing 

postischemic damage by temporary modification 

of reperfusate calcium, potassium, pH, and osmolarity. 

J Thorac Cardiovasc Surg 82:221, 1981. 

208. Hessen SE, Michelson EL: Mechanisms of ventricular 

arrhythmias: From laboratory to bedside. Am 

Coll Cardiol Curr J Rev 4:11, 1995. 

209. White RD, Goldsmith RS, Rodriguez R, et al: Plasma 

ionic calcium levels following injection of chloride, 

gluconate, and gluceptate salts of calcium. J


Inotropic Agents 

Thierry H. LeJemtel, MD 

Marc Klapholz, MD 



1. Warner Stevenson L: Inotropic therapy for heart 

failure. N Engl J Med 339:1848, 1998. 

2. ACC/AHA 2005 guideline update for the diagnosis 

and management of chronic heart failure in the 

adult. A report of the American College of Cardiology/American 

Heart Association Task Force on 

Practice Guidelines (Writing Committee to Update 

the 2001 Guidelines for the Evaluation and Management 

of Heart Failure: J Am Coll Cardiol 46: e1, 

2005. 

2a. Jefferies JL, Towbin JA: Dilated cardiomyopathy. 

Lancet 375: 752, 2010. 

2b. Goldhaber JI, Hamilton MA: Role of inotropic 

agents in the treatment of heart failure. Circulation 

121: 1655, 2010. 

3. LeJemtel TH, Sonnenblick EH, Frishman WH: Diagnosis 

and management of heart failure. In: Fuster 


Heart, 11th ed. New York: McGraw-Hill, 2004:723. 

4. Ferguson DW: Digitalis and neurohormonal abnormalities 

in heart failure and implications for 

therapy. Am J Cardiol 69:24G, 1992. 

5. Felker GM, O’Connor CM: Inotropic therapy for 

heart failure: An evidence-based approach. Am 

Heart J 142:393, 2001. 

6. Burger AJ, Elkayam U, Neibaur MT, et al: Comparison 

of the occurrence of ventricular arrhythmias in 

patients with acutely decompensated congestive 

heart failure receiving dobutamine versus nesiritide 

therapy. Am J Cardiol 88:35, 2001. 

7. Patel MB, Kaplan IV, Patni RN, et al: Sustained 

improvement in flow mediated vasodilation after 

short-term administration of dobutamine in patients 

with severe congestive heart failure. Circulation 

99:60, 1999. 

8. Drazner MH, Solomon MA, Thompson B, Yancy 

CW: Tailored therapy using dobutamine and nitroglycerin 

in advanced heart failure. Am J Cardiol 

84:941, 1999. 

9. Withering W: An Account of the Foxglove, And 

Some of Its Medical Uses: With Practical Remarks 

on Dropsy and other Diseases. London: GGJ and J 

Robinson, 1785. 

10. Fothergill JM: Digitalis: Its Mode of Action. London, 

1871. 

11. Dock W, Tainter ML: The circulatory changes after 

full therapeutic doses of digitalis, with critical 

discussion of views on cardiac output. J Clin Invest 

8:467, 1929. 

12. Fisch C: William Withering: An account of the foxglove 

and some of its medical uses, 1785–1985. J 

Am Coll Cardiol 5:1A, 1985. 

13. Gillis RA, Quest JA: The role of the nervous system 

in the cardiovascular effects of digitalis. Pharmacol 

Rev 31:19, 1980. 

14. Rahimtoola SH, Tak T: The use of digitalis in heart 

failure. Curr Probl Cardiol 21:785, 1996. 

15. Fozzard HA, Sheets MF: Cellular mechanism of action 

of cardiac glycosides. J Am Coll Cardiol 5:10A, 

1985. 

16. Charlemagne D: Molecular and cellular level of action 

of digitalis. Herz 18:79, 1993. 

17. Scholz H: Inotropic drugs and their mechanisms of 

action. J Am Coll Cardiol 4:389, 1984. 

18. Siri FM, Krueger JW, Nordin C, et al: Depressed 

intracellular calcium transients and contraction in 

myocytes from hypertrophied and failing guinea 

pig hearts. Am J Physiol 261:H514, 1991. 

19. Li P, Park C, Micheletti R, et al: Myocyte performance 

during evolution of myocardial infarction 

in rats: Effects of propionyl-L-carnitine. Am J 



13-1


Physiol 268:H1702, 1995. 

20. Rosen MR: Cellular electrophysiology of digitalis 

toxicity. J Am Coll Cardiol 5:22A, 1985. 

21. Smith TW, Antman EM, Friedman PL, et al: Digitalis 

glycosides: Mechanisms and manifestations of 

toxicity. Parts I, II, III. Prog Cardiovasc Dis 26:413, 

495; 27:21, 1984. 

22. Wantanabe AM: Digitalis and the autonomic nervous 

system. J Am Coll Cardiol 5:35A, 1985. 

23. Newton GE, Tong JH, Schofield AM, et al: Digoxin 

reduces cardiac sympathetic activity in severe 

congestive heart failure. J Am Coll Cardiol 28:155, 

1996. 

24. Wenger T, Butler VP Jr., Haber E, Smith TW: 

Digoxin-specific antibody treatment of digitalis 

toxicity. In: Erdmann E, Greeff K, Skou JC, eds. Update 

in Cardiac Glycosides 1785–1985. New York: 

Springer-Verlag, 1986:377–388. 

25. Braunwald E, Ross J Jr, Sonnenblick EH: Mechanisms 

of Contraction of the Normal and Failing 

Heart, 2nd ed. Boston: Little, Brown, 1976. 

26. Mason DT, Braunwald E, Karsh RB, Bullock FA: 

Studies on digitalis. X: Effects of ouabain on forearm 

vascular resistance and venous tone in normal 

subjects and in patients with heart failure. J Clin 

Invest 43:532, 1964. 

27. Eberhardt RT, Frishman WH, Landau A, et al: Increased 

mortality incidence in elderly individuals 

receiving digoxin therapy: Results of the Bronx 

Longitudinal Aging Study. Cardiol Elderly 3:177, 

1995. 

28. Packer M, Gheorghiade M, Young JB, et al: Withdrawal 

of digoxin from patients with chronic heart 

failure treated with angiotensin-converting-enzyme 

inhibitors. RADIANCE Study. N Engl J Med 

329:1, 1993. 

29. Uretsky BF, Young JB, Shahidi FE, et al: Randomized 

study assessing the effect of digoxin withdrawal 

in patients with mild to moderate chronic 

congestive heart failure: Results of the PROVED 

Trial. J Am Coll Cardiol 22:955, 1995. 

30. Adams KF Jr, Gheorghiade M, Uretsky BF, et al: 

Clinical predictors of worsening heart failure during 

withdrawal from digoxin therapy. Am Heart J 

135:389–397, 1998. 

31. Captopril-Digoxin Multicenter Research Group: 

Comparative effects of therapy with captopril and 

digoxin in patients with mild to moderate heart 

failure. JAMA 259:539, 1988. 

32. Tauke J, Goldstein S, Gheorghiade M: Digoxin 

for chronic heart failure: A review of the randomized 

controlled trials with special attention to the 

PROVED and RADIANCE Trials. Prog Cardiovasc 

Dis 37:49, 1994. 

33. Kraus F, Rudolph C, Rudolph W: Efficacy of digi- 

talis in patients with chronic congestive heart failure 

and sinus rhythm: An overview of randomized, 

double-blind, placebo-controlled studies. Herz 

18:95, 1993. 

34. The Digitalis Investigation Group: The effect of digoxin 

on mortality and morbidity in patients with 


35. Wirth KE: Relevant metabolism of cardiac glycosides. 

In: Erdmann E, Greeff K, Skou JC, eds. Update 

in Cardiac Glycosides, 1785–1985. New York: 

Springer-Verlag, 1986:257–262. 

36. Adams KF Jr., Gheorghiade M, Uretsky BF, et al: 

Clinical benefits of low serum digoxin concentrations 

in heart failure. J Am Coll Cardiol 39:946, 

2002. 

37. van Veldhuisen DJ: Low-dose digoxin in patients 

with heart failure: Less toxic and at least as effective? 


38. Marcus FI: Pharmacokinetic interactions between 

digoxin and other drugs. J Am Coll Cardiol 5:82A, 

1985. 

39. Sonnenblick EH, LeJemtel TH: Heart failure: Its 

progression and its therapy. Hosp Pract 28:121, 

1993. 

40. Fauchier L, Grimard C, Pierre B, et al: Comparison 

of beta blocker and digoxin alone and in combination 

for management of patients with atrial fibrillation 

and heart failure. Am J Cardiol 103: 248, 2009. 

41. Hauptman PJ, Kelly RA: Digitalis. Circulation 

99:1265, 1999. 

42. Muller JE, Turi ZG, Stone PH, et al for the MILIS 

Group: Digoxin therapy and mortality following 

confirmed or suspected myocardial infarction: experience 

in the MILIS Study. In: Erdmann E, Greeff 

JC, Skou JC, eds. Update in Cardiac Glycosides 

1785–1985. New York: Springer-Verlag, 1986:493. 

43. Ahmed A, Gambassi G, Weaver MT, et al: Effects of 

discontinuation of digoxin versus continuation at 

low serum digoxin concentrations in chronic heart 

failure. Am J Cardiol 100: 280, 2007. 

44. Spargias KS, Hall AS, Ball SG: Safety concerns 

about digoxin after acute myocardial infarction. 

Lancet 354:391, 1999. 

45. Lewis RP: Clinical use of serum digoxin concentrations. 

Am J Cardiol 69:97G, 1992. 

46. Steimer W, Muller C, Eber B: Digoxin assays: Frequent, 

substantial and potentially dangerous interference 

by spironoactone, canrenone, and other 

steroids. Clin Chem 48:507, 2002. 

47. Kelley RA, Smith TW: Recognition and treatment 

of digitalis toxicity. Am J Cardiol 69:108G, 1992. 

48. Marcus FI: Digitalis. In: Schlant RC, Alexander 

RW, eds. Hurst’s The Heart, 8th ed. New York: Mc- 

Graw-Hill, 1994:573–588. 

49. Williamson KM, Thrasher KA, Fulton KB, et al:

Digoxin toxicity. An evaluation in current clinical 

practice. Arch Intern Med 158:2444, 1998. 

50. Cardiac glycosides interact with many drugs. Drugs 

Ther Perspect 6(3):11, 1995. 

51. Eddleston M, Rajapakse S, Rajakanthan SJ, et 

al: Anti-digoxin Fab fragments in cardiotoxicity 

induced by ingestion of yellow oleander: A randomised 


52. Marik PE, Fromm L: A case series of hospitalized 

patients with elevated digoxin levels. Am J Med 

105:110, 1998. 

53. Benovic JL, Bouvier M, Caron MG, Lefkowitz RJ: 

Regulation of adenyl cyclase-coupled β-adrenergic 

receptors. Am Rev Cell Biol 4:405, 1988. 

54. Kelly RB: Storage and release of neurotransmitters. 

Cell/Neuron 72(Suppl. 72):443, 1993. 

55. Hoffman BB, Taylor P: Neurotransmission. In: 

Hardman JG, Limbird LE, eds. Goodman & Gilman’s 

The Pharmacological Basis of Therapeutics, 

10th ed. New York: McGraw-Hill, 2001:115–153. 

56. Spann JF, Sonnenblick EH, Cooper T, et al: Cardiac 

norepinephrine stores and the contractile state of 

the heart. Circ Res 19:317, 1966. 

57. Francis GS, Goldsmith SR, Levine TB, et al: The 

neurohumoral axis in congestive heart failure. Ann 

Intern Med 101:370, 1984. 

58. Insel PA: Adrenergic receptors—evolving concepts 

and clinical implications. N Engl J Med 334:580, 

1996. 

59. Movsesian MA: Beta-adrenergic receptor agonists 

and cyclic nucleotide phosphodiesterase inhibitors: 

Shifting the focus from inotropy to cyclic adenosine 

monophosphate J Am Coll Cardiol 34:318–324, 

1999. 

60. Pagel PS, Haikala H, Pentikainen PJ, et al: Pharmacology 

of levosimendan: A new myofilament calcium 

sensitizer. Cardiovasc Drugs Rev 14:286, 1996. 

61 Micheletti R, Mattera GG, Rocchetti M, et al. Pharmacological 

profile of the novel inotropic agent 

(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17dione 

hydrochloride (PST2744). J Pharm Exp 

Thera 303:592, 2002. 

62. Goldberg LI, Rajfer SI: Dopamine receptors: Applications 

in clinical cardiology. Circulation 72:245, 

1985. 

63. Leclerc KM, Steele NP, Levy WC: Norepinephrine 

alters exercise oxygen consumption in heart failure 

patients. Med Sci Sports Exerc 32:2029, 2000. 

64. van de Borne P, Oren R, Somers VK: Dopamine 

depresses minute ventilation in patients with heart 

failure. Circulation 98:126, 1998. 

65. Elkayam U, Ng TMH, Hatamizadeh P, et al: Renal 

vasodilatory action of dopamine in patients with 

heart failure. Magnitude of effect and site of action. 

Circulation 117: 200, 2008. 


66. Hoogenberg K, Smit AJ, Girbes ARJ: Effects of 

low-dose dopamine on renal and systemic hemodynamics 

during incremental norepinephrine infusion 

in healthy volunteers. Crit Care Med 26:260, 

1998. 

67. Australian and New Zealand Intensive Care Society 

(ANZICS) Clinical Trials Group: Low-dose 

dopamine in patients with early renal dysfunction: 

A placebo-controlled randomised trial. Lancet 

356:2139, 2000. 

68. DeBacker D, Biston P, Devriendt J, et al for the 

SOAP II Investigators: Comparison of dopamine 

and norepinephrine in the treatment of shock. N 

Engl J Med 362: 779, 2010. 

69. Ruffolo RR Jr.: Review: The pharmacology of dobutamine. 

Am J Med Sci 294:244, 1987. 

70. Sonnenblick EH, Frishman WH, LeJemtel TH: 

Dobutamine: A new synthetic cardioactive sympathetic 

amine. N Engl J Med 300:17, 1979. 

71. Tisdale JE, Patel R, Webb CR, et al: Electrophysiologic 

and proarrhythmic effects of intravenous inotropic 

agents. Progr Cardiovasc Dis 38:167, 1995. 

72. Oliva F, Latini R, Politi A, et al for the DICE (Dobutamina 

nell’-Insufficienza Cardiaca Estrema) 

Investigators: Intermittent 6-month low-dose dobutamine 

infusion in severe heart failure: DICE 

Multicenter Trial. Am Heart J 138:247, 1999. 

73. Silver MA: Intermittent inotropes for advanced 

heart failure: Inquiring minds want to know. Am 

Heart J 138:191, 1999. 

74. Nanas JN, Kontoyannis DA, Alexopoulos GP, et al: 

Long-term intermittent dobutamine infusion combined 

with oral amiodarone improves the survival 

of patients with severe congestive heart failure. 

Chest 119:1173, 2001. 

75. Parmley WW, Sonnenblick EH: A role for glucagon 

in cardiac therapy. Am J Med Sci 258:224, 1969. 

76. Braunwald E, Sonnenblick EH, Chakrin LW, 

Schwarz RP Jr., eds. Milrinone Investigation: A New 

Inotropic Therapy for Congestive Heart Failure. New 

York: Raven Press, 1984. 

77. Grose R, Strain J, Greenberg M, LeJemtel TH: Systemic 

and coronary effects of intravenous milrinone 

and dobutamine in congestive heart failure. J 


78. Harris AL, Silver PJ, Lemp BM, Evans DB: The vasorelaxant 

effects of milrinone and other vasodilators 

are attenuated by ouabain. Eur J Pharmacol 

145:133–139, 1988. 

79. Nielsen-Kudsk JE, Aldershvile J: Will calcium sensitizers 

play a role in the treatment of heart failure? 

J Cardiovasc Pharmacol 26 (Suppl 1):577, 1995. 

80. Packer M, Carver JR, Rodeheffer RJ, et al: Effect of 

oral milrinone on mortality in severe chronic heart 

failure. N Engl J Med 325:1468, 1991.


81. Fleming GA, Murray KT, Yu C, et al: Milrinone use 

is associated with postoperative atrial fibrillation 

after cardiac surgery. Circulation 118: 1619, 2008. 

82. Baruch L, Patacsil P, Hameed A, et al: Pharmacodynamic 

effects of milrinone with and without a 

bolus loading infusion. Am Heart J e6:141, 2000. 

83. Givertz MM, Hare JM, Loh E, et al: Effect of bolus 

milrinone on hemodynamic variables and pulmonary 

vascular resistance in patients with severe left 

ventricular dysfunction: A rapid test for reversibility 

of pulmonary hypertension. J Am Coll Cardiol 

28:1775, 1996. 

84. Yano M, Kohno M, Ohkusa T, et al: Effect of milrinone 

on left ventricular relaxation and Ca 2+ uptake 

function of cardiac sarcoplasmic reticulum. Am J 

Physiol 279:H1898, 2000. 

85. Tanigawa T, Yano M, Kohno M, et al: Mechanism 

of preserved positive lusitropy by cAMP-dependent 

drugs in heart failure. Am J Physiol 278:H313, 

2000. 

86. Hatzizacharias A, Makris T, Krespi P, et al: Intermittent 

milrinone effect on long-term hemodynamic 

profile in patients with severe congestive 

heart failure. Am Heart J 138:241, 1999. 

87. Milfred-LaForest SK, Shubert J, Mendoza B, et al: 

Tolerability of extended duration intravenous milrinone 

in patients hospitalized for advanced heart 

failure and the usefulness of uptitration of oral 

angiotensin-converting enzyme inhibitors. Am J 

Cardiol 84:894, 1999. 

88. Ewy GA: Inotropic infusions for chronic congestive 

heart failure. Medical miracles or misguided medicinals? 


89. Cesario D, Clark J, Maisel A: Beneficial effects of 

intermittent home administration of the inotrope/ 

vasodilator milrinone in patients with end-stage 

congestive heart failure: A preliminary study. Am 

Heart J 135:121, 1998. 

90. Mehra MR, Ventura HO, Kapoor C, et al: Safety 

and clinical utility of long-term intravenous milrinone 

in advanced heart failure. Am J Cardiol 80:61, 

1997. 

91. Canver CC, Chanda J: Milrinone for long-term 

pharmacologic support of the status of heart 

transplant candidates. Ann Thorac Surg 69:1823, 

2000. 

92. Cusick DA, Pfeifer PB, Quigg RJ: Effects of intravenous 

milrinone followed by titration of high-dose 

oral vasodilator therapy on clinical outcome and 

rehospitalization rates in patients with severe heart 

failure. Am J Cardiol 82:1060, 1998. 

93. Cuffe MS, Califf RM, Adams KF Jr. et al: Shortterm 

intravenous milrinone for acute exacerbation 

of chronic heart failure. A randomized, controlled 

trial. JAMA 287:1541, 2002. 

94. Lowes BD, Higginbotham M, Petrovich L, et al: 

Low-dose enoximone improves exercise capacity 

in chronic heart failure. J Am Coll Cardiol 36:501, 

2000. 

95. Shakar SF, Bristow MR: Low-level inotropic stimulation 

with type III phosphodiesterase inhibitors in 

patients with advanced symptomatic chronic heart 

failure receiving β-blocking agents. Curr Cardiol 

Rep 3:224, 2001. 

96. Metra M. ESSENTIAL: the Studies of Oral Enoximone 

Therapy in Advanced Heart Failure. Presented 

at: European Society of Cardiology Congress; September 

5–8, 2005; Stockholm, Sweden: Late Breaking 

Clinical Trials. 

97. Cavusoglu E, Frishman WH, Klapholz M: Vesnarinone: 

A new inotropic agent for treating congestive 

heart failure. J Card Fail 1:249, 1995. 

98. Matsumori A, Shioi T, Yamada T, et al: Vesnarinone, 

a new inotropic agent, inhibits cytokine production 

by stimulated human blood from patients 

with heart failure. Circulation 89:955, 1994. 

99. OPC 8212 Multicenter Research Group: A placebo-controlled, 

randomized, double-blind study of 

OPC 8212 in patients with mild chronic heart failure. 

Cardiovasc Drugs Ther 4:419, 1990. 

100. Feldman AM, Bristow MR, Parmley WW, et al for 

the Vesnarinone Study Group: Effects of vesnarinone 

on morbidity and mortality in patients with 


101. Cohn JN, Goldstein SO, Greenberg BH et al: A 

dose-dependent increase in mortality with vesnarinone 

among patients with severe heart failure. N 

Engl J Med 339:1810, 1998. 

102. Sugiyama A, Satoh Y, Hashimoto K: Electropharmacologic 

effects of a new phosphodiesterase III 

inhibitor, toborinone (OPC-18790), assessed in 

an in vivo canine model. J Cardiovasc Pharmacol 

38:268, 2001. 

103. Yu Y, Mizushige K, Ueda T, et al: Effect of olprinone, 

phosphodiesterase III inhibitor, on cerebral 

blood flow assessed with technetium-99m-ECD 

SPECT. J Cardiovasc Pharmacol 35:422, 2000. 

104. Slawsky MT, Colucci WS, Gottlieb SS, et al: Acute 

hemodynamic and clinical effects of levosimendan 

in patients with severe heart failure. Circulation 

102:2222, 2001. 

105. Kivikko M, Lehtonen L, Colucci WS, et al. Sustained 

hemodynamic effects of intravenous levosimendan. 

Circulation 2003;107:81-6. 

106. Fuhrmann JT, Schmeisser A, Schulze MR, et al: Levosimendan 

is superior to enoximone in refractory 

cardiogenic shock complicating acute myocardial 

infarction. Crit Care Med 36: 2257, 2008. 

107. Russ MA, Prondzinsky R, Christoph A, et al: Hemodynamic 

improvement following levosimendan

treatment in patients with acute myocardial infarction 

and cardiogenic shock. Crit Care Med 35: 

2732, 2007. 

108. Lehtonen L: Levosimendan: A promising agent for 

the treatment of hospitalized patients with decompensated 

heart failure. Curr Cardiol Rep 2:233, 2000. 

109. Figgitt DP, Gillies PS, Goa KL: Levosimendan. 

Drugs 61:613, 2001. 

110. Folláth F, Hinkka S, Jäger D, et al: Dose-ranging and 

safety with intravenous levosimendan in low-output 

heart failure: Experience in three pilot studies and 

outline of the levosimendan infusion versus dobutamine 

(LIDO) trial. Am J Cardiol 83:21I, 1999. 

111. Ukkonen H, Saraste M, Akkila J, et al: Myocardial 

efficiency during levosimendan infusion in congestive 

heart failure. Clin Pharmacol Ther 68:522, 

2000. 

112. Harjola V-P, Peuhkurinen K, Nieminen MS, et al: 

Oral levosimendan improves cardiac function and 

hemodynamics in patients with severe congestive 

heart failure. Am J Cardiol 83:4I, 1999. 

113. Nijhawan N, Nicolosi AC, Montgomery MW, et al: 

Levosimendan enhances cardiac performance after 

cardiopulmonary bypass: A prospective, randomized 

placebo-controlled trial. J Cardiovasc Pharmacol 

34:219, 1999. 

114. Hosenpud JD, for the Oral Levosimendan Study 

Group: Levosimendan, a novel myofilament calcium 

sensitizer, allows weaning of parenteral inotropic 

therapy in patients with severe congestive heart 

failure. Am J Cardiol 83:9I, 1999. 

115. Follath F, Cleland JGF, Just H, et al: Efficacy and 

safety of intravenous levosimendan compared with 

dobutamine in severe low-output heart failure (the 

LIDO study): A randomised double-blind study. 

Lancet 360:196, 2002. 

116. Moiseyev VS, Põder P, Andrejevs N, et al. Safety 

and efficacy of a novel calcium sensitizer, levosimendan, 

in patients with left ventricular failure due 

to an acute myocardial infarction. A randomized, 

placebo-controlled, double-blind study (RUSS- 

LAN). Eur Heart J 23:1422, 2002. 

117. Lehtonen L, Pöder P: The utility of levosimendan in 

the treatment of heart failure. Ann Med 39: 2, 2007. 

117a. REVIVE-II summary data. http://www.cardiosource.com/pops/trialSum.asp?trialID=1378;accessed 

February 17, 2010. 

118. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan 

vs dobutamine for patients with acute 

decompensated heart failure: the SURVIVE randomized 

trial. JAMA 297:1883, 2007. 

119. Fujimoto S, Matsuda T. Effects of pimobendan, a 

cardiotonic and vasodilating agent with phosphodiesterase 

inhibiting properties, on isolated arteries 

and veins of rats. J Pharmacol Exp Ther 1990; 


252(3): 1304-11. 

120. Matsui K, Kiyosue T, Wang JC, et al. Effects of 

pimobendan on the L-type Ca2+ current and developed 

tension in guinea-pig ventricular myocytes 

and papillary muscle: comparison with IBMX, 

milrinone, and cilostazol. Cardiovasc Drugs Ther 

13:105, 1999. 

121. Kuriya S, Ohmori S, Hino M, et al. Identification 

of cytochrome P-450 isoform(s) responsible for the 

metabolism of pimobendan in human liver microsomes. 


122. Chu KM, Shieh SM, Hu OY. Pharmacokinetics and 

pharmacodynamics of enantiomers of pimobendan 

in patients with dilated cardiomyopathy and 

congestive heart failure after single and repeated 

oral dosing. Clin Pharmacol Ther 57: 610, 1995. 

123. Chu KM, Shieh SM, Hu OY. Pharmacokinetics and 

pharmacodynamics of enantiomers of pimobendan 

in patients with dilated cardiomyopathy and 

congestive heart failure after single and repeated 

oral dosing. Clin Pharmacol Ther 57: 610, 1995. 

124. Hagemeijer F. Calcium sensitization with pimobendan: 

pharmacology, haemodynamic improvement, 

and sudden death in patients with chronic 

congestive heart failure. Eur Heart J 14:551, 1993. 

125. Sasayama S, Asanoi H, Kihara Y, et al. Clinical effects 

of long-term administration of pimobendan 

in patients with moderate congestive heart failure. 

Heart Vessels 9:113, 1994. 

126. Katz SD, Kubo SH, Jessup M, et al. A multicenter, 

randomized, double-blind, placebo-controlled trial 

of pimobendan, a new cardiotonic and vasodilator 

agent, in patients with severe congestive heart failure. 

Am Heart J 123:95, 1992. 

127. Kubo SH, Gollub S, Bourge R, et al. Beneficial effects 

of pimobendan on exercise tolerance and 

quality of life in patients with heart failure: results 

of a multicenter trial. The Pimobendan Multicenter 

Research Group. Circulation 85:942, 1992. 

128. The Pimobendan in Congestive Heart Failure 

(PICO) investigators. Effect of pimobendan on exercise 

capacity in patients with heart failure: main 

results from the Pimobendan in Congestive Heart 

Failure (PICO) trial. Heart 76:223, 1996. 

129. The EPOCH study group. Effects of pimobendan 

on adverse cardiac events and physical activities in 

patients with mild to moderate chronic heart failure 

– The Effects of Pimobendan on Chronic Heart 

Failure Study (EPOCH Study). Circ J 66:149,2002. 

130. Sasaki T, Kubo T, Komamura K, Nishikimi T. Effects 

of long-term treatment with pimobendan 

on neurohormonal factors in patients with nonischemic 

chronic moderate heart failure. J Cardiol 

33:317,1999. 

131. Iwasaki A, Matsumori A, Yamada T, et al: Pimo-


bendan inhibits the production of proinflammatory 

cytokines and gene expression of inducible 

nitric oxide synthase in a murine model of viral 

myocarditis. J Am Coll Cardiol 33:1400, 1999. 

132. Dorigo P, Floreani M, Santostasi G, et al: Pharmacological 

characterization of a new Ca 2+ sensitizer. J 


133. Brixius K, Reicke S, Reuter H, Schwinger RH. Effects 

of the Ca 2+ sensitizers EMD 57033 and CGP 

48506 on myocardial contractility and Ca2+ transients 

in human ventricular and atrial myocardium. 

Z Kardiol 91:312,2002 

134. Yang G, Liu L, Xu J, Li T. Effects of MCI-154 on 

vascular reactivity and its mechanisms after hemorrhagic 

shock in rats. J Cardiovasc Pharmacol 

47:751, 2006. 

135. Müller-Ehmsen J, Brixius K, Schwinger RHG: Positive 

inotropic effects of a novel Na+-channel modulator 

BDF 9198 in human nonfailing and failing 

myocardium. J Cardiovasc Pharmacol 31:684, 1998. 

136. Doggrell S.A.: Effects of BDF 9198 on left ventricular 

contractility in advanced spontaneously hypertensive 

rats with heart failure. J Pharmacy Pharmacol 

54: 1097, 2002. 

137. Satoh N, Sato T, Shimada M, et al. Lusitropic effect 

of MCC-135 is associated with improvement 

of sarcoplasmic reticulum function in ventricular 

muscles of rats with diabetic cardiomyopathy. J 

Pharm Exper Ther298:1161, 2001. 

138. Kawasumi H, Satoh N, Kitada Y: Caldaret, an intracellular 

Ca 2+ handling modulator, limits infarct 

size of reperfused canine heart. J Pharmacol Sci 

103: 222, 2007. 

139. Bär FW, Tzivoni D, Dirksen MT, et al. Results of the 

first clinical study of adjunctive Caldaret (MCC- 

135) in patients undergoing primary percutaneous 

coronary intervention for ST-elevation myocardial 

infarction: the randomized multicentre CASTEMI 

study. Eur Heart J 27:2516,2006. 

140. Tzivoni D, Balkin J, Bär FW, et al: Effect of Caldaret 

on the incidence of severe left ventricular dysfunction 

in patients with ST-elevation myocardial 

infarction undergoing primary coronary intervention. 

Am J Cardiol 103; 1,2009. 

141. Shah SJ, Blair JEA, Filippatos GS, et al for the HO- 

RIZON-HF Investigators: Effects of istaroxime on 

diastolic stiffness in acute heart failure syndromes: 

results from the hemodynamic, echocardiographic, 

and neurohormonal effects of istaroxime, a novel 

intravenous inotropic and lusitropic agent: a randomized 

controlled trial in patients hospitalized 

with heart failure (HORIZON-HF) trial. Am Heart 

J 157: 1035, 2009. 

142. Micheletti R, Mattera GG, Rocchetti M, et al. Pharmacological 

profile of the novel inotropic agent 

(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17dione 

hydrochloride (PST2744). J Pharm Exp 

Thera 303:592,2002. 

143. Adamson PB, Vanoli E, Mattera GG, et al. Hemodynamic 

effects of a new inotropic compound, 

PST-2744, in dogs with chronic ischemic heart failure. 

J Cardiovasc Pharmacol 42:169,2003. 

144. Gheorghiade M, Blair JEA, Filippatos GS, et al. 

Hemodynamic, echocardiographic, and neurohormonal 

effects of istaroxime, a novel intravenous 

inotropic and lusitropic agent. J Am Coll Cardiol 

51:2276,2008. 

145. McMurray J, Pfeffer MA: New therapeutic options 

in congestive heart failure, Part II. Circulation 

105:2223, 2002. 

146. Maurice JP, Hata JA, Shah AS, et al: Enhancement 

of cardiac function after adenoviral-mediated in 

vivo intracoronary β 2 -adrenergic receptor gene delivery. 

J Clin Invest 104:21, 1999. 

147. Weig H-J, Laugwitz K-L, Moretti A, et al: Enhanced 

cardiac contractility after gene transfer of V2 vasopressin 

receptors in vivo by ultrasound-guided 

injection or transcoronary delivery. Circulation 

101:1578, 2000. 

148. del Monte F, Harding SE, Schmidt U, et al: Restoration 

of contractile function in isolated cardiomyocytes 

from failing human hearts by gene transfer of 

SERCA2a. Circulation 100:2308, 1999. 

149. del Monte F, Williams E, Lebeche D, et al: Improvement 

in survival and cardiac metabolism after gene 

transfer of sarcoplasmic reticulum Ca 2+ -ATPase in 

a rat model of heart failure. Circulation 104:1424, 

2001. 

150. Sakata S, Lebeche D, Sakata Y, et al: Transcoronary 

gene transfer of SERCA2a increases coronary 

blood flow and decreases cardiomyocyte size in a 

type 2 diabetic rat model. Am J Physiol Heart Circ 

Physiol. 292:H1204,2007. 

151. Sakata S, Lebeche D, Sakata N, et al: Targeted gene 

transfer increases contractility and decreases oxygen 

cost of contractility in normal rat hearts. Am J 

Physiol Heart Circ Physiol. 292:H2356,2007. 

152. Sakata S, Lebeche D, Sakata N, et al: Restoration of 

mechanical and energetic function in failing aortic-banded 

rat hearts by gene transfer of calcium 

cycling proteins. J Mol Cell Cardiol. 42:852,2007. 

153. Calcium Up-Regulation by Percutaneous Administration 

of Gene therapy In Cardiac Disease (CU- 

PID Trial) -Presented at American Heart Association 

Meeting 2008. J Card Fail 14:355,2008. 

154. Late Breaking Clinical Trials. Circulation 

118:2309,2008. 

155. Leri A, Anversa P, Frishman WH: Cardiovascular 

Regeneration and Stem Cell Therapy. UK: Blackwell


The Organic Nitrates and Nitroprusside 

Jonathan Abrams, MD 


Publishing, 2007. 

1. Fung H-L, Chung S-J, Bauer JA, et al: Biochemical 

mechanism of organic nitrate action. Am J Cardiol 

70:4B, 1992. 

2. Kukovetz WR, Holzmann S, Schmidt K: Cellular 

mechanisms of action therapeutic nitric oxide donors. 

Eur Heart J 12(suppl E):16, 1991. 

3. Harrison DG, Bates JN: The nitrovasodilators: New 

ideas about old drugs. Circulation 87:1461, 1993. 

4. Torfgard KE, Ahlner J: Mechanisms of action of nitrates. 


5. Loscalzo J: Antiplatelet and antithrombotic effects 

of organic nitrates. Am J Cardiol 70:18B, 1992. 

6. Diodati J, Theroux P, Latour J-G, et al: Effects of 

nitroglycerin at therapeutic doses on platelet aggregation 

in unstable angina pectoris and acute myocardial 

infarction. Am J Cardiol 66:683, 1996. 

7. Folts JD, Stamler J, Loscalzo J: Intravenous nitroglycerin 

infusion inhibits blood flow responses 

caused by periodic platelet thrombus formation 

in stenosed canine coronary arteries. Circulation 

83:2122, 1991. 

8. Lam JYT, Chesebro JH, Fuster V: Platelets, vasoconstriction 

and nitroglycerin during arterial wall 

injury: A new antithrombotic role for an old drug. 


9. Fye WB: Nitroglycerin: A homeopathic remedy. 


10. Whitmont RD, Mamtani R: Homeopathy with a 

special focus on treatment of cardio-vascular diseases. 

In Frishman WH, Weintraub MI, Micozzi 

MS: Complementary and Integrative Therapies for 

Cardiovascular Disease. St. Louis: Elsevier/Mosby 

2005: 232-47. 

11. Seth P, Fung H-L: Biochemical characterization of 

a membrane-bound enzyme responsible for gen- 

erating nitric oxide from nitroglycerin in vascular 

smooth muscle cells. Biochem Pharmacol 64:1481, 

1993. 

12. Watanabe H, Kakihana M, Ohtsuka S, et al: Platelet 

cyclic GMP. A potentially useful indicator to evaluate 

the effects of nitroglycerin and nitrate tolerance. 


13. Gori T, Parker JD: The puzzle of nitrate tolerance. 

Pieces smaller than we thought? Circulation 106: 

2404, 2002. 

14. Gori T, Parker JD: Nitrate tolerance. A unifying hypothesis. 

Circulation 106: 2510, 2002. 

15. Sage PR, de la Lande IS, Stafford I: Nitroglycerin 

tolerance in human vessels. Evidence for impaired 

nitroglycerin bioconversion. Circulation 102:2810, 

2000. 

16. Boesgaard S, Aldershvile J, Lofts S, et al: Nitrate 

tolerance in vivo is not associated with depletion 

of arterial or venous thiol levels. Circ Res 74:115, 

1994. 

16a. Fung H-L: Personal Communication. 

16b. Munzel T, Wenzel P, Daiber A: Do we still need organic 

nitrates? (editorial comment). J Am Coll Cardiol 

49: 1296: 2007. 

17. Kim D, Rybalkin SD, Pi X, et al: Upregulation of 

phosphodiesterase 1A1 expression is associated 

with the development of nitrate tolerance. Circulation 

104:2338, 2001. 

18. Bassenge E: Coronary vasomotor responses: Role 

of endothelium and nitrovasodilators. Cardiovasc 

Drugs Ther 8:601, 1994. 

19. Kurz MA, Lamping KG, Bates JN, et al: Mechanisms 

responsible for the heterogeneous coronary 

microvascular response to nitroglycerin. Circ Res 

68:847, 1991. 

20. Chiariello M, Gold HK, Leinbach RC, et al: Com- 



14-1


parison between the effects of nitroprusside and 

nitroglycerin on ischemic injury during acute 

myocardial infarction. Circulation 54:766, 1976. 

21. Abrams J: Mechanisms of action of the organic nitrates 

in the treatment of myocardial ischemia. Am 

J Cardiol 70:30B, 1992. 

22. Loos D, Schneider R, Schorner W: Changes in regional 

body blood volume caused by nitroglycerin. 

Z Kardiol 72(Suppl 3):29, 1983. 

23. Vatner SF, Pagani M, Rutherford JD, et al: Effects of 

nitroglycerin on cardiac performance and regional 

blood flows distribution in conscious dogs. Am J 

Physiol 234(3):H244, 1978. 

24. Leier CV, Huss P, Bambach D, et al: Central and regional 

hemodynamic effects of intravenous isosorbide 

dinitrate, nitroglycerin and nitroprusside in 

patients with congestive heart failure. Am J Cardiol 

48:1115, 1981. 

25. Abrams J: Beneficial actions of nitrates in cardiovascular 

disease. Am J Cardiol 77:31C, 1996. 

26. Pupita G, Maseri A, Kaski JC, et al: Myocardial ischemia 

caused distal coronary-artery constriction in 

stable angina pectoris. N Engl J Med 323:514, 1990. 

27. Brown BG, Bolson EL, Dodgett T: Dynamic mechanisms 

in human coronary stenosis. Circulation 

70:917, 1984. 

28. Bassenge E, Zanzinger J: Nitrates in different vascular 

beds, nitrate tolerance, and interactions with 

endothelial function. Am J Cardiol 70:23B, 1992. 

29. Dupuis J: Nitrates in congestive heart failure. Cardiovasc 

Drugs Ther 8:501, 1994. 

30. Schwarz M, Katz SD, Demopoulos L, et al: Enhancement 

of endothelium dependent vasodilation 

by low-dose nitroglycerin in patients with congestive 


31. Luscher TF, Noll G: The endothelium in coronary 

vascular control, update 3. In: Braunwald E, ed. 

Heart Disease. Philadelphia: Saunders, 1995:1. 

32. Gage JE, Hess OM, Murakami T, et al: Vasoconstriction 

of stenotic coronary arteries during dynamic 

exercise in patients with classic angina 

pectoris: Reversibility by nitroglycerin. Circulation 

73:865, 1986. 

33. Ludmer PL, Selwyn AP, Shook TL, et al: Paradoxical 

vasoconstriction induced by acetycholine in 

atherosclerotic arteries. N Engl J Med 315:1046, 

1986. 

34. Paulus WJ: Endothelial control of vascular and 

myocardial function in heart failure. Cardiovasc 

Drugs Ther 8:437, 1994. 

35. Sonnenblick EH, Lejemtel TH, Frishman WH: Inotropic 

agents. In Frishman WH, Sonnenblick EH, 

Sica DA (eds): Cardiovascular Pharmacotherapeutics 

2nd ed. New York: McGraw Hill 2003: 191. 

36. Rafflenbeul W, Bassenge E, Lichtlen P: Competition 

between endothelium-dependent and nitroglycerin-induced 

coronary vasodilation. Z Kardiol 

78(Suppl 2):45, 1989. 

37. Luscher TF: Endothelium-derived nitric oxide: The 

endogenous nitrovasodilator in the human cardiovascular 

system. Eur Heart J 12(Suppl E):2, 1991. 

38. Münzel T, Giaid A, Kurz S, et al: Evidence for a role 

of endothelin 1 and protein kinase C in nitroglycerin 

tolerance. Proc Natl Acad Sci USA 92:5244, 

1995. 

39. Gori T, Mak SS, Kelly S, Parker JD: Evidence supporting 

abnormalities in nitric oxide synthase 

function induced by nitroglycerin in humans. J Am 

Coll Cardiol 38:1096, 2001. 

40. Münzel T, Sayegh H, Freeman BA, et al: Evidence 

for enhanced vascular superoxide anion production 

in nitrate tolerance. A novel mechanism underlying 

tolerance and cross-tolerance. J Clin Invest 

95 (1):187, 1995. 

41. Heizer T, Just H, Brockhoff C et al: Long-term 

nitroglycerin treatment is associated with supersensitivity 

to vasoconstrictors in men with stable 

coronary artery disease: Prevention by concomitant 

treatment with captopril. J Am Coll Cardiol 

31(1):83, 1998. 

42. Caramori PR, Adelman AG, Azevedo ER, et al: 

Therapy with nitroglycerin increases coronary vasoconstriction 

in response to acetylcholine. J Am 

Coll Cardiol 32(7):1969, 1998. 

43. Gori T, Parker JD: Nitrate-induced toxicity and 

preconditioning. A rationale for reconsidering the 

use of these drugs. J Am Coll Cardiol 52: 251, 2008. 

44. Jugdutt BI, Tymchak WJ, Burton JR: Preservation 

of left ventricular geometry and function after late 

reperfusion and intravenous nitroglycerin in acute 

transmural myocardial infarction. Circulation 

84:II-683, 1991. 

45. McDonald KM, Francis GS, Matthews J, et al: 

Long-term oral nitrate therapy prevents chronic 

ventricular remodeling in the dog. J Am Coll Cardiol 

21:514, 1993. 

46. Jugdutt BI, Warnica JW: Intravenous nitroglycerin 

therapy to limit myocardial infarct size, expansion, 

and complications: Effect on timing, dosage and 

infarct location. Circulation 78:906, 1988. 

47. Yusuf S, Collins R, MacMahon S, Peto R: Effect of 

intravenous nitrates on mortality in acute myocardial 

infarction: An overview of the randomized trials. 

Lancet 2:1088, 1988. 

48. Beltrame JF, Stewart S, Leslie S, et al: Resolution 

of ST segment elevation following intravenous administration 

of nitroglycerin and verapamil. Am J 

Cardiol 89:452, 2002.

49. Gruppo Italiano per lo Studio della Supravivenza 

nellInfarcto Miocardico (GISSI-3): Effects of lisinopril 

and transdermal glyceryl trinitrate singly 

and together on 6-week mortality and ventricular 

function after acute myocardial infarction. Lancet 

343:1115, 1994. 

50. ISIS-4 (Fourth International Study of Infarct Survival) 

Collaborative Group (ISIS-4): A randomized 

factorial trial assessing early oral captopril, oral 

mononitrate, and intravenous magnesium sulphate 

in 58,050 patients with suspected acute myocardial 


51. Leesar MA, Stoddard MF, Dawn B, et al: Delayed 

preconditioning-mimetic action of nitroglycerin in 

patients undergoing coronary angioplasty. Circulation 

103:2935, 2001. 

52. Heusch G: Nitroglycerin and delayed preconditioning 

in humans. Yet another new mechanism 

for an old drug? Circulation 103:2876, 2001. 

53. Henrikson CA, Howell EE, Bush DE, et al: Chest 

pain relief by nitroglycerin does not predict active 

coronary artery disease. Ann Intern Med 139: 979, 

2003. 

54. Nesbitt SD: Nitrates as adjunct hypertensive treatment. 

A possible answer to resistant systolic hypertension. 


55. Pickering TG: Why don’t we use nitrates to treat 

older hypertensive patients? J Clin Hypertens 7: 

685, 2005. 

56. Duchier J, Iannascoli F, Safor M: Antihypertensive 

effect of sustained release isosorbide dinitrate for 

isolated systolic systemic hypertension in the elderly. 

Am J Cardiol 60:99, 1987. 

57. Ito Y, Isotani E, Mizuno Y, et al: Effective improvement 

of the cerebral vasospasm after subarachnoid 

hemorrhage with low-dose nitroglycerin. J Cardiovasc 

Pharmacol 35:45, 2000. 

58. Abrams J, Schroeder J, Frishman WH, Freedman 

J: Pharmacologic options for treatment of ischemic 

disease. In Antman EM (ed): Cardiovascular Therapeutics. 

A Companion to Braunwald’s Heart Disease, 

3rd ed.. Philadelphia: Saunders/Elsevier 2007: 

77. 

59. Abrams J: Nitrates and nitrate tolerance in congestive 

heart failure. Coron Artery Dis 4:27, 1993. 

60. Mehra A, Ostrzega E, Shotan A, et al: Persistent hemodynamic 

improvement with short-term nitrate 

therapy in patients with chronic congestive heart 

failure already treated with captopril. Am J Cardiol 

70:1310, 1992. 

61. Parker JD, Parker JO: Effect of therapy with an angiotensin 

converting enzyme inhibitor on hemodynamic 

and counterregulators responses during 

continuous therapy with nitroglycerin. J Am Coll 


Cardiol 21:1445, 1993. 

62. Elkayam U, Johnson JV, Shotan A, et al: Doubleblind, 

placebo-controlled study to evaluate the 

effect of organic nitrates in patients with chronic 

heart failure treated with angiotensin-converting 

enzyme inhibition. Circulation 99:2652, 1999. 

63. Elkayam U, Mehra A, Shotan A, Ostrzega E: Nitrate 

resistance and tolerance: Potential limitations 

in the treatment of congestive heart failure. Am J 

Cardiol 70:98B, 1992. 

64. Abrams J: The mystery of nitrate resistance. Am J 

Cardiol 68: 1393, 1991. 

65. Leier CB, Magorien RD, Desch CE, et al: Hydralazine 

and isosorbide dinitrate: comparative central 

and regional hemodynamic effects when administered 

alone or in combination. Circulation 63: 102: 

1981. 

66. Gogia H, Mehra A, Parikh S, et al: Prevention of 

tolerance to hemodynamic effects of nitrates with 

concomitant use of hydralazine in patients with 

chronic heart failure. J Am Coll Cardiol 26: 1575, 

1995. 

67. Elkayam U, Canetti M, Wani DR, et al: Hydralazine 

induced prevention of nitrate tolerance: experimental 

and clinical evidence and potential mechanism. 

Am J Cardiol 81; 44A, 1998. 

68. Munzel T, Kurz S, Rajagopalan S, et al: Hydralazine 

prevents nitroglycerin tolerance by inhibiting activation 

of a membrane-bound NADH oxidase: a 

new action for an old drug. J Clin Invest 98: 1465, 

1996. 

69. Daiber A, Oelze M, Coldewey M, et al: Hydralazine 

is a powerful inhibitor of peroxy-nitrite formation 

as a possible explanation for its beneficial effects on 

prognosis in patients with congestive heart failure. 

Biochem Biophys Res Commun 338: 1865, 2005. 



heart failure: Results of a Veterans Administration 

Cooperative Study. N Engl J Med 314:1547, 

1986. 

71. Cohn JN, Johnson G, Ziesche S, et al: A comparison 

of enalapril with hydralazine-isosorbide dinitrate 

in the treatment of chronic congestive heart 


72. Carson P, Ziesche S, Johnson G, Cohn JN: Racial 

differences in response to therapy for heart failure: 

analysis of the vasodilator-heart failure trials. Vasodilator-Heart 

Failure Trial Study Group. J Card Fail 

5: 178, 1999. 

73. Cheng JW: A review of isosorbide dinitrate and 

hydralazine in the management of heart failure in 

black patients, with a focus on a new fixed-dose 

combination. Clin Ther 28: 666, 2006.


74. Taylor AL, Ziesche S, Yancy C, et al, African-American 

Heart Failure Trial Investigators: Combination 

of isosobide dinitrate and hydralazine in blacks 

with heart failure. N Engl J Med 351: 2049, 2004. 

75. Mullens W, Abrahams Z, Francis GS, et al: Usefulness 

of isosorbide dinitrate and hydralazine as addon 

therapy in patients discharged for advanced 

decompensated heart failure. Am J Cardiol 103: 

1113, 2009. 

76. Carmody MS, Anderson JR: BiDil (isosorbide dinitrate 

and hydralazine): a new fixed-dose combination 

of two older medications for the treatment of 

heart failure in black patients. Cardiol in Rev 15: 46, 

2007. 

77. Temple R, Stockbridge NL: BiDil for heart failure in 

black patients: the US Food and Drug Administration 

perspective. Ann Intern Med 146: 57, 2007. 

78. Wilson RM, DeSilva DS, Sato K, et al: Effects of 

fixed-dose isosorbide dinitrate/hydralazine on diastolic 

function and exercise capacity in hypertension-induced 

diastolic heart failure. Hypertension 

54: 583, 2009. 

79. Mahmarian JJ, Fenimore NL, Marks GF, et al: 

Transdermal nitroglycerin patch therapy reduces 

the extent of exercise-induced myocardial ischemia: 

Results of a double-blind, placebo-controlled 

trial using quantitative thallium-201 tomography. J 

Am Cardiol 24:25, 1994. 

80. Fallen EL, Nahmia SC, Scheffel A, et al: Redistribution 

of myocardial blood flow with topical nitroglycerin 

in patients with coronary arterial disease. 


81. Parker JO, Amies MH, Hawkinson RW, et al: Intermittent 

transdermal nitroglycerin therapy in angina 

pectoris: Clinically effective without tolerance 

or rebound. Circulation 91:1368, 1995. 

82. DeMots H, Glasser SP: Intermittent transdermal 

nitroglycerin therapy in the treatment of chronic 

stable angina. J Am Coll Cardiol 13:786, 1989. 

83. Freedman SB, Daxini BV, Noyce D, Kelly DT: Intermittent 

transdermal nitrates do not improve ischemia 

in patients taking beta-blockers or calcium 

antagonists: Potential role of rebound ischemia 

during the nitrate-free period. J Am Coll Cardiol 

25:349, 1995. 

84. Bogaert MG: Clinical pharmacokinetics of nitrates. 


85. Schaumann W: Pharmacokinetics of isosorbide 

dinitrate and isosorbide-5-mononitrate. Int J Clin 

Pharmacol Ther Toxical 27:445, 1989. 

86. Parker JO and the Isosorbide-5-Mononitrate Study 

Group: Eccentric dosing with isosorbide-5-mononitrate 

in angina pectoris. Am J Cardiol 73:871, 

1993. 

87. Abrams J: The role of nitrates in coronary heart disease. 


88. Gunasekara NS, Noble S: Isosorbide 5-mononitrate. 

A review of a sustained-release formulation 

(Imdur) in stable angina pectoris. Drugs 57:261, 

1999. 

89. Chrysant SG, Glasser SP, Bittar N, et al: Efficacy 

and safety of extended release isosorbide mononitrate 

for stable effort angina pectoris. Am J Cardiol 

72:1249, 1993. 

90. Prakash A, Markham A: Long-acting isosorbide 

mononitrate. Drugs 57:93, 1999. 

91. Waller DG: Optimal nitrate therapy with a oncedaily 

sustained-release formulation of isosorbide 

mononitrate. J Cardiovasc Pharmacol 34 (Suppl 

2):S21, 1999. 

92. Webb DJ, Miurhead GJ, Wulff M, et al: Sildenafil 

citrate potentiates the hypotensive effect of nitric 

oxide donor drugs in male patients with stable angina. 


93. Col J, Col-Debeys C, Lavenne-Pardonge E, et al: 

Propylene glycol induced heparin resistance during 

nitroglycerin infusion. Am Heart J 110:171, 

1986. 

94. Becker RC, Jeanne CM, Corrao JM, et al: Intravenous 

nitroglycerin induced heparin resistance: A 

qualitative antithrombin III abnormality. Am Heart 

J 119:1254, 1990. 

95. Bode V, Weizel D, Franz G, et al: Absence of drug 

interaction between heparin and nitroglycerin: 

Randomized placebo-controlled crossover study. 

Arch Intern Med 150(10):2117, 1990. 

96. Nicolini FA, Ferrini D, Ottani F, et al: Concurrent 

nitroglycerin therapy impairs tissue-type plasminogen 

activator–induced thrombolysis in patients 

with acute myocardial infarction. Am J Cardiol 

74:662, 1994. 

97. Death AK, Nakhla S, McGrath KCY, et al: Nitroglycerin 

upregulates matrix metalloproteinase expression 

in human macrophages. J Am Coll Cardiol 

39:1943, 2002. 

98. Thadani U, Ripley TL:Side effects of using nitrates 

to treat heart failure and the acute coronary syndromes, 

unstable angina and acute myocardial infarction. 

Expert Opin Drug Saf 6: 385, 2007. 

99. Elkayam V: Tolerance to organic nitrates: Evidence, 

mechanisms, clinical relevance, and strategies for 

prevention. Ann Intern Med 114: 667, 1991. 

100. Fung H-L, Bauer JA: Mechanisms of nitrate tolerance. 

Cardiovasc Drugs Ther 94–8:489, 1993. 

101. Steering Committee, Transdermal Nitroglycerin 

Cooperative Study: Acute and chronic antianginal 

efficacy in continuous twenty-four hour application 

of transdermal nitroglycerin. Am J Cardiol

68:1263, 1991. 

102. Thadani U, Fung H-L, Darke AC, Parker JO: Oral 

isosorbide dinitrate in angina pectoris: Comparison 

of duration of action and dose response relationship 

during acute and sustained therapy. Am J 

Cardiol 49:411, 1982. 

103. Münzel T, Mollnau H, Hartmann M et al: Effects of 

a nitrate-free interval on tolerance, vasoconstrictor 

sensitivity and vascular superoxide production. J 

Am Coll Cardiol 36(2):628, 2000. 

104. Abrams J, Elkayam U, Thadani U, Fung H: Nitrate 

tolerance: An historical overview. Am J Cardiol 

81(1A):3-14A, 1998. 

105. Glasser S: Prospects for therapy of nitrate tolerance. 

Lancet 353:1545, 1999. 

106. Elkayam U, Roth A, Mehra A, et al: Randomized 

study to evaluate the relation between oral isosorbide 

dinitrate dosing interval and the development 

of early tolerance to its effect on left ventricular filling 

pressure in patients with chronic heart failure. 


107. Frishman WH: Tolerance, rebound and time-zero 

effect of nitrate therapy. Am J Cardiol 70:436, 1992. 

108. Ferratini M, Pirelli S, Merlini P, et al: Intermittent 

transdermal nitroglycerin monotherapy in stable 

exercise-induced angina: A comparison with a 

continuous schedule. Eur Heart J 10:998, 1989. 

109. Abou-Mohamed G, Kaesemeyer WH, Caldwell 

RB, Caldwell RW: Role of L-arginine in the vascular 

actions and development of tolerance to nitroglycerin. 

Br J Pharmacol 130(2):211, 2000. 

110. Gruhn N, Aldershvile J, Boesgaard S: Tetrahydrobiopterin 

improves endothelium-dependent 

vasodilation in nitroglycerin-tolerant rats. Eur J 

Pharmacol 416(3):245, 2001. 

111. Milone SD, Pace-Asciak CR, Reynaud D, et al: Biochemical, 

hemodynamic, and vascular evidence 

concerning the free radical hypothesis of nitrate 

tolerance. J Cardiovasc Pharmacol 33(5):685, 1999. 

112. Dikalov S, Fink B, Skatchkov M, Bassenge E: Comparison 

of glyceryl trinitrate-induced with pentaerythrityl 

tetranitrate-induced in vivo formation of 

superoxide radicals: Effect of vitamin C. Free Radic 

Biol Med 27(1–2):170, 1999. 

113. Bassenge E, Fink N, Skatchkov M, Fink B: Dietary 

supplement with vitamin C prevents nitrate tolerance. 

J Clin Invest 102(1):67, 1998. 

114. Watanabe H, Kakihana M, Ohtsuka S, Sugishita 

Y: Randomized, double-blind, placebo-controlled 

study of the preventive effect of supplemental oral 

vitamin C on attenuation of development of nitrate 

tolerance. J Am Coll Cardiol 31(6):1323, 1998. 

115. Gori T, Burstein JM, Ahmed S, et al: Folic acid prevents 

nitroglycerin-induced nitric oxide synthase 


dysfunction and nitrate tolerance. Circulation 

104:1119, 2001. 

116. Loscalzo J: Folate and nitrate-induced endothelial 

dysfunction: A simple treatment for complex pathology. 

Circulation 104:1086, 2001. 

117. Hirai N, Kawano H, Yasue H, et al: Attenuation of 

nitrate tolerance and oxidative stress by an angiotensin 

II receptor blocker in patients with coronary 

spastic angina. Circulation 108: 1446, 2003. 

118. Zimmet JM, Hare JM: Nitroso-redox interactions 

in the cardiovascular system. Circulation 114: 1531, 

2006. 

119. Thomas GR, DiFabio JM, Gori T, Parker JD: Once 

daily therapy with isosorbide-5-mononitrate 

causes endothelial dysfunction in humans. J Am 

Coll Cardiol 49: 1289, 2007. 

120. Berkenboom G, Fontaine D, Unger P, et al: Absence 

of nitrate tolerance after long-term treatment with 

ramipril: An endothelium-dependent mechanism. 


121. Munzel T: Does nitroglycerin therapy hit the endothelium? 

(editorial). J Am Coll Cardiol 38:1102, 

2001. 

122. Hebert D, Lam JYT: Nitroglycerin rebound associated 

with vascular, rather than platelet, hypersensitivity. 


123. Kanamasa K, Hayashi T, Takenaka T, et al: Continuous 

long-term dosing with oral slow-release 

isosorbide dinitrate does not reduce incidence of 

cardiac events in patients with healed myocardial 

infarction. Clin Cardiol 24:608, 2001. 

124. Nakamura Y, Moss AJ, Brown MW, et al: Longterm 

nitrate use may be deleterious in ischemic 

heart disease: A study using the databases from 

two large-scale post-infarction studies. Multicenter 

Myocardial Ischemia Research Group. Am Heart J 

138:577, 1999. 

125. Khot WN, Novaro GM, Popvic ZB, et al: Nitroprusside 

in critically ill patients with left ventricular 

dysfunction and aortic stenosis. N Engl J Med 

348: 1756, 2003. 

126. Miller RR, Vismara LA, Zelis R, et al: Clinical use 

of sodium nitroprusside in chronic ischemic heart 

disease: Effect on peripheral vascular resistance 

and venous tone on ventricular volume, pump and 

mechanical performance. Circulation 51:328, 1975. 

127. Mullens W, Abrahams Z, Francis GS: Sodium nitroprusside 

for advanced low-output heart failure. 


128. Zile MR, Gaasch WH: Heart failure in aortic stenosis 

– improving diagnosis and treatment. N Engl J 

Med 348: 1735, 2003. 

129. Mann T, Cohn P, Holman BL, et al: Effect of nitroprusside 

on regional myocardial blood flow in


coronary artery disease: Results in 25 patients and 

comparison with nitroglycerin. Circulation 52:732, 

1978. 

130. Macho P, Vatner SF: Effects of nitroglycerin and nitroprusside 

on large and small coronary vessels in 

conscious dogs. Circulation 64:1101, 1981. 

131. Flaherty JT, Magee PA, Gardner TJ, et al: Comparison 

of intravenous nitroglycerin and sodium nitoprusside 

for the treatment of acute hypertension 

developing after coronary artery bypass surgery. 


132. Cohn JN, Franciosa JA, Francis GS, et al: Effect of 

short-term infusion of sodium nitroprusside on 

mortality rate in acute myocardial infarction complicated 

by left ventricular failure. N Engl J Med 

306:1129, 1982. 

133. Durrer JD, Lie KI, van Chapelle FJL, Durrer D: Effect 

of sodium nitroprusside on mortality in acute 

myocardial infarction. N Engl J Med 306:1121, 

1982. 

134. Flaherty JT: Role of nitrates in acute myocardial 

infarction. In: Abrams J, Pepine C, Thadani U, eds. 

Medical Therapy of Ischemic Heart Disease. Boston, 

Little Brown, 1992:309. 

135. Antman EM, Anbe DT, Armstrong PW, et al: ACC/ 

AHA guidelines for the management of patients 

with ST elevation myocardial infarction – executive 

summary of a report of the American College 

of Cardiology/American Heart Association Task 

Force on Practice Guidelines (writing committee 

to revise the 1999 guidelines for the management 

of patients with acute myocardial infarction). J Am 

Coll Cardiol 44: 671, 2004. 

136. Darius H: Role of nitrates for the therapy of coronary 

artery disease patients in the years beyond 

2000. J Cardiovasc Pharmacol 34(Suppl 2): S15, 

1999.


Ranolazine 

A Piperazine Derivative 


James J. Nawarskas, PharmD 

Joe R. Anderson, PharmD 

1. American Heart Association. Heart disease and 

stroke statistics – 2005 update. Dallas, TX: American 

Heart Association; 2005. 

2. Fraker TD Jr., Fihn SD. Focused update of the 

2002 ACC/AHA guidelines for the management 

of patients with chronic stable angina: a report of 



Writing Group to develop the focused update 

of the 2002 guidelines. J Am Coll Cardiol 50: 2264, 

2007. 

3. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/ 

AHA 2002 guideline update for the management 

of patients with chronic stable angina: a report of 



(Committee on the Management of Patients 

With Chronic Stable Angina). J Am Coll Cardiol 41: 

159, 2003. 

4. Hueb W, Soares PR, Gersh BJ, et al. The medicine, 

angioplasty, or surgery study (MASS-II): a randomized, 

controlled clinical trial of three therapeutic 

strategies for multivessel coronary artery disease. 

One year results. J Am Coll Cardiol 43:1743,2004. 

5. Holubkov R, Laskey WK, Haviland A. Angina 1 

year after percutaneous coronary intervention: 

a report from the NHLBI dynamic registry. Am 

Heart J 144:826,2002. 

6. Anderson JR, Nawarskas JJ: Ranolazine. A metabolic 

modulator for the treatment of chronic stable 

angina. Cardiol in Rev 13: 202, 2005. 

7. Goldschmidt M, Frishman WH: Ranolazine: a new 

anti-ischemic drug which affects myocardial energetics. 

Am J Therap 2: 269, 1995. 

8. Frishman WH, Retter A, Misailidis, et al: Innova- 

tive pharmacologic approaches to the treatment of 

myocardial ischemia. In Frishman WH, Sonnenblick 

EH, Sica DA (eds): Cardiovascular Pharmacotherapeutics 

2nd ed. New York: McGraw Hill 2003: 

855. 

9. Siddiqui MAA, Keam SJ: Ranolazine. A review of 

its use in chronic stable angina pectoris. Drugs 66: 

693, 2006. 

10. Keating GM: Ranolazine. A review of its use in 

chronic stable angina. Drugs 68: 2483, 2008. 

11. Scirica BM, Morrow DA: Ranolazine in patients 

with angina and coronary artery disease. Curr Cardiol 

Rep 9: 272, 2007. 

12. Shyrock JC, Belardinelli L: Inhibition of late sodium 

current to reduce electrical and mechanical 

dysfunction of ischaemic myocardium. Br J Pharmacol 

153: 1128, 2008. 

13. Hale SL, Shyrock JC, Belardinelli L, et al: Late sodium 

current inhibition as a new cardioprotective 

approach. J Molec Cell Cardiol 44: 954, 2008.13a. 

Hwang H, Arcidi JM Jr., Hale SL, et al: Ranolazine 

as a cardioplegia additive improves recovery of 

diastolic function in isolated rat hearts. Circulation 

120 Suppl 1: S16, 2009. 

14. Saint DA: The cardiac persistent sodium current: 

an appealing therapeutic target? Br J Pharmacol 

153: 1133, 2008. 

15. Theroux P. Protection of the myocardial cell during 

ischemia. Am J Cardiol 83;3G,1999. 

16. Stanley WC, Chandler MP. Energy metabolism in 

the normal and failing heart: potential for therapeutic 

interventions. Heart Fail Rev 7:115,2002. 

17. Hutter JF, Piper HM, Spieckermann PG. Effects of 

fatty acid oxidation on efficiency of energy production 

in rat heart. Am J Physiol 249:H723,1985. 

18. Lopaschuk GD, Belke DD, Gamble J, et al. Regu- 



15-1


lation of fatty acid oxidation in the mammalian 

heart in health and disease. Biochem Biophys Acta 

1994;1213;263,1994. 

19. Steinberg D, Khoo JC. Hormone-sensitive lipase of 

adipose tissue. Fed Proc 36: 1986,1977. 

20. MacInnes A, Fairman DA, Binding P, et al: The 

antianginal agent trimetazidine does not exert its 

functional benefit via inhibition of mitochondrial 

long-chain-3-ketoacyl coenzyme A thiolase. Circ 

Res 93: e26, 2003. 

21. Wang P, Fraser H, Lloyd SG, et al: A comparison 

between ranolazine and CVT-4325, a novel inhibitor 

of fatty acid oxidation, on cardiac metabolism 

and left ventricular function in rat isolated perfused 

heart during ischemia and reperfusion. J 

Pharmacol Exp Ther 321: 213, 2007. 

22. Létienne R, Vié B, Puech A, et al: Evidence that 

ranolazine behaves as a weak b1- and b2-adrenoceptor 

antagonist in the rat cardiovascular system. 

Naunyn Schmiedebergs Arch Pharmacol 363: 464, 

2001. 

23. Pepine CJ, Wolff AA: A controlled trial with a novel 

anti-ischemic agent, ranolazine, in chronic stable 

angina pectoris that is response to conventional 

antianginal agents. Ranolazine Study Group. Am J 

Cardiol 84:46, 1999. 

24. Rousseau MF, Pouleur H, Cocco G, et al: Comparative 

efficacy of ranolazine versus atenolol for 

chronic angina pectoris. Am J Cardiol 95: 311, 2005. 

25. Sossalla S, Wagner S, Rasenack ECL, et al: Ranolazine 

improves diastolic dysfunction in isolated 

myocardium from failing human hearts: role of 

late sodium current and intracellular ion accumulation. 

J Molec Cell Cardiol 45: 32, 2008. 

26. Moss AJ, Zareba W, Schwarz KQ, et al: Ranolazine 

shortens repolarization in patients with sustained 

inward sodium current due to type-3 long-QT syndrome. 

J Cardiovasc Electrophysiol 19:1294, 2008. 

27. Chaitman BR, Skettino SL, Parker JO, et al. Antiischemic 

effects and long-term survival during 

ranolazine monotherapy in patients with chronic 

severe angina. J Am Coll Cardiol 43:1375, 2004. 

28. Chaitman BR, Pepine CJ, Parker JO, et al. Effects 

of ranolazine with atenolol, amlodipine, or diltiazem 

on exercise tolerance and angina frequency in 

patients with severe chronic angina: a randomized 


29. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. 

Electrophysiological effects of ranolazine, a novel 

antianginal agent with antiarrhythmic properties. 

Circulation 110:904,2004. 

30. Wu L, Shryock JC, Song Y, et al. Antiarrhythmic 

effects of ranolazine in a guinea pig in vitro model 

of long-QT syndrome. JPET 310:599,2004. 

31. Song Y, Shryock JC, Wu L, Belardinelli L. Antagonism 

by ranolazine of the pro-arrhythmic effects of 

increasing late I Na in guinea pig ventricular myocytes. 

J Cardiovasc Pharmacol 44:192,2004. 

31a. Carvas M, Nascimento BCG, Acar M, et al: Intrapericardial 

ranolazine prolongs atrial refractory 

period and markedly reduces atrial fibrillation inducibility 

in the intact porcine heart. J Cardiovasc 

Pharmacol 55: 286, 2010. 

32. Fenichel RR, Malik M, Antzelevitch C, et al. Druginduced 

torsades de pointes and implications for 

drug development. J Cardiovasc Electrophysiol 

15:475,2004. 

33. Belardinelli L, Antzelevitch C, Vos MA. Assessing 

predictors of drug-induced torsade de pointes. 

Trends Pharmacol Sci 24:619,2003. 

34. Cocco G, Rousseau MF, Bouvy T, et al. Effects of a 

new metabolic modulator, ranolazine, on exercise 

tolerance in angina pectoris patients treated with 

b-blocker or diltiazem. J Cardiovasc Pharmacol 

20:131,1992. 

35. Herron WJ, Eadie J, Penman AD. Estimation of ranolazine 

and eleven phase I metabolites in human 

plasma by liquid chromatography-atmospheric 

pressure chemical ionization mass spectrometry 

with selected-ion monitoring. J Chromatogr A 

712:55,1995. 

36. Pepine CJ, Wolff AA. A controlled trial with a novel 

anti-ischemic agent, ranolazine, in chronic stable 

angina pectoris that is responsive to conventional 

antianginal agents. Am J Cardiol. 84:46,1999. 

37. Anderson JR, Khou S, Nawarskas JJ. Ranolazine: a 

potential new treatment for chronic stable angina. 

Heart Dis 3:263,2001. 

38. Jain D, Dasgupta P, Hughes LO, et al. Ranolazine 

(RS-43285): A preliminary study of a new antianginal 

agent with selective effect of ischaemic myocardium. 

Eur J Clin Pharmacol 38:111,1990. 

39. Thadani U, Ezekowitz M, Fenney L, et al. Doubleblind 

efficacy and safety study of a novel anti-ischemic 

agent, ranolazine, versus placebo in patients 

with chronic stable angina pectoris. Circulation 

90:726,1994. 

40. Rousseau MF, Pouleur H, Cocco G, Wolff AA. 

Comparative efficacy of ranolazine versus atenolol 

for chronic angina pectoris. Am J Cardiol 95; 311, 

2005. 

41. Stone PH, Gratsiansky NA, Blokhin A, et al: Antianinal 

efficacy of ranolazine when added to treatment 

with amlodipine: the ERICA (Efficacy of 

Ranolazine in Chronic Angina) trial. J Am Coll 

Cardiol 48: 566, 2006. 

42. Morrow DA, Scirica BM, Karwatowska-Prokopczuk 

E, et al: Effects of ranolazine on recurrent

cardiovascular events in patients with non-ST-elevation 

acute coronary syndromes: the MERLIN- 

TIMI 36 randomized trial. JAMA 297: 1775, 2007. 

43. DeQuattro V, Skettino S, Chaitman BR, et al. Comparative 

antianginal efficacy and tolerability of 

ranolazine in diabetic and nondiabetic patients: 

results of the MARISA trial. J Am Coll Cardiol 37: 

338A,2001. 

44. Chaitman BR, Skettino S, DeQuattro V. Improved 

exercise performance on ranolazine in patients 

with chronic angina and a history of heart failure: 

the MARISA trial. J Am Coll Cardiol 37 :149A,2001. 

45. Koren MJ, Crager MR, Sweeney M: Long-term 

safety of a novel antianginal agent in patients with 

severe chronic stable angina: the Ranolazine Open 

Label Experience (ROLE). J Am Coll Cardiol 49: 

1027, 2007. 

46. Chaitman BR, Skettino S, Pepine CJ, et al. Ranolazine 

increases exercise performance and decreases 

hemoglobin A1C in angina patients with diabetes. 

J Am Coll Cardiol 41: 378A, 2003. 

47. White HD, Skettino S, Chaitman BR, et al. Antianginal 

efficacy of ranolazine addition to beta 

blocker or calcium antagonist therapy in patients 

with a history of heart failure. Circulation 

106:II-349,2002. 

48. Scirica BM, Morrow DA, Hod H, et al: Effect of 

ranolazine, an antianginal agent with novel electrophysioloical 

properties, on the incidence of 

arrhythmias in patients with non ST-segment elevation 

acute coronary syndromes: results from 

the Metabolic Efficiency with Ranolazine for Less 

Ischemia in Non ST-Elevation Acute Coronary 

Syndrome Thrombolysis In Myocardial Infarction 

36 (MERLIN-TIMI 36) randomized controlled 

trial. Circulation 116: 1647, 2007. 

49. Scirica BM, Morrow DA, Budaj A, et al: Ischemic 

detected on continuous electrocardiography after 

acute coronary syndrome: observations from the 

MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine 

for Less Ischemia in Non-ST-Elevation 

Acute Coronary Syndrome-Thrombolysis in Myocardial 

Infarction 36) trial J Am Coll Cardiol 53: 


1411, 2009. 

50. Wilson SR, Scirica BM, Braunwld E, et al: Efficacy 

of ranolazine in patients with chronic angina: observations 

from the randomized, double-blind, 

placebo-controlled MERLIN-TIMI 36 (Metabolic 

Efficiency with Ranolazine for Less Ischemia in 

Non-ST-elevation Acute Coronary Syndromes 36) 

trial. J Am Coll Cardiol 53: 1510, 2009. 

51. Mega JL, Hochman JS, Scirica BM, et al: Clinical 

features and outcomes of women with unstable 

ischemic heart failure. Observations from Metabolic 

Efficiency with Ranolazine for Less Ischemia 

in Non-ST-Elevation Acute Coronary Syndromes- 

Thrombolysis in Myocardial Infarction 36 (MER- 

LIN-TIMI36). Circulation 121: 1809, 2010. 

52. Morrow DA, Scirica BM, Sabatine MS, et al: B-type 

natriuretic peptide and the effect of ranolazine in 

patients with non-ST-segment elevation acute coronary 

syndromes. J Am Coll Cardiol 55: 1189, 2010. 

53. Morrow DA, Scirica BM, Chaitman BR, et al: Evaluation 

of the glycometabolic effects of ranolazine 

in patients with and without diabetes mellitus in 

the MERLIN-TIMI 36 randomized controlled trial. 

Circulation 119: 2032, 2009. 

54. Sabbah HN, Mishima T, Biesiadecki BJ, et al. Ranolazine 

improves left ventricular performance in 

dogs with chronic heart failure. J Am Coll Cardiol 

34(Suppl A): 218A,2000. 

55. CV Therapeutics, Inc. CV Therapeutics announces 

preclinical data evaluating ranolazine and dobutmaine 

in a model of CHF. Available at http://www. 

cvt.com. 

56. Wenger NK, Chaitman B, Vetrovec GW: Gender 

comparison of efficacy and safety of ranolazine for 

chronic angina pectoris in 4 randomized clinical 

trial. Am J Cardiol 99: 11, 2007. 

57. Rich MW, Crager M, McKay CR: Safety and efficacy 

of extended-release ranolazine in patients aged 

70 years or older with chronic stable angina pectoris. 

Am J Geriatr Cardiol 16: 216, 2007. 

58. Reddy BM, Weintraub HS, Schwartzbard AZ: Ranolazine. 

A new approach to treating an old problem. 

Texas Heart Insti J 37: 641, 2010.


Nonspecific Antihypertensive 

Vasodilators 

Lawrence R. Krakoff, MD 


1. McVeigh GE, Bratteli, CW, Morgan DJ, et al: Agerelated 

abnormalities in arterial compliance identified 

by pressure pulse contour analysis: Aging and 

arterial compliance. Hypertension 33:1392, 1999. 

2. Hoffman BB: Therapy of hypertension. In Brunton 

LL, Lazo JS, Parker KL (eds): Goodman & Gilman’s 

The Pharmacological Basis of Therapeutics, 11th ed. 

NY: McGraw-Hill, 2006: 845. 

3. Sica DA, Gehr TW: Pharmacologic treatment of 

hypertension. In Antman EM (ed): Cardiovascular 

Therapeutics. A companion to Braunwald’s Heart 

Disease 3rd ed. Philadelphia, Saunders: 2007, 578. 

4. Ram CVS, Fenves A: Direct arterial dilators. In Izzo 

JL Jr, Black HR, eds. Hypertension Primer, 4th ed. 

Dallas, American Heart Association, 2008, 469. 

5. Chobanian AV, Bakris GL, Black HR, et al and the 

National High Blood Pressure Education Program 

Coordinating Committee: The Seventh Report of 

the Joint National Committee on Prevention, Detection, 

Evaluation, and Treatment of High Blood 

Pressure. The JNC 7 Report. JAMA 289: 2560, 2003. 

6. Guidelines Subcommittee: 1999 World Health Organization—International 

Society of Hypertension 

Guidelines for the Management of Hypertension. J 

Hypertens 17:151, 1999. 

7. Seedat YK: Hypertension in developing nations 

in Sub-Saharan Africa. J Hum Hypertens 14:739, 

2001. 

8. Frishman WH, Schlocke SJ, Awad K, Tejani N: 

Pathophysiology and medical management of systemic 

hypertension in pregnancy. Cardiol in Rev 

13: 274, 2005. 

9. Calhoun DA: Hypertensive crisis. In Oparil S, 

Weber MA (eds): Hypertension: A Companion to 

Brenner and Rector’s The Kidney. Philadelphia: 

Saunders, 2000; 715. 

10. Abalos E, Duley L, Steyn DW, Henderson-Smart 

DJ: Antihypertensive drug therapy for mild to 

moderate hypertension during pregnancy (Cochrane 

Review). The Cochrane Library, 2007. 



heart failure: Results of a Veterans Administration 

Cooperative Study. N Engl J Med 314:1547, 

1986. 

12. Cohn JN, Johnson G, Ziesche S, et al: A comparison 

of enalapril with hydralazine-isosorbide dinitrate 

in the treatment of chronic congestive heart 


13. Carmody MS, Anderson JR: BiDil (isosorbide dinitrate 

and hydralazine): a new fixed-dose combination 

of two older medications for the treatment of 

heart failure in black patients. Cardiol in Rev 15: 46, 

2007. 

14. Frishman WH, Lee BY, Galandauer I, Phan AH: Potassium-channel 

openers and sodium/hydrogenchannel 

effectors. In Frishman WH, Sonnenblick 

EH, Sica DA (eds): Cardiovascular Pharmacotherapeutics 


15. Clapham JC, Trail BK, Hamilton TC: K + channel 

activators, acute glucose tolerance and glibenclamide-induced 

hypoglycemia in the hypertensive 

rat. Eur J Pharmacol 257:79, 1994. 

16. Stone CK, Wellington KL, Willick A, et al: Acute 

hemodynamic effects of pinacidil in hypertensive 

patients with and without propranolol treatment. J 


17. Krusell LR, Jespersen LT, Thomsen K, Pedersen 

OL: Proximal renal tubular pressure-natriuresis in 

essential hypertensives following acute vasodilation. 

Blood Press 2:40, 1993. 



16-1


18. Lundeen TE, Dolan DR, Ram CV: Pericardial effusion 

associated with minoxidil therapy. Postgrad 

Med 70: 98, 1981. 

19. Frohlich ED: Other adrenergic inhibitors and 

the direct-acting smooth muscle vasodilators. In 

Oparil S, Weber MA (eds): Hypertension: A Companion 

to Brenner and Rector’s The Kidney. Philadelphia: 

Saunders, 2000; 637.


Antiarrhythmic Drugs 

Peter Zimetbaum, MD 

Peter R. Kowey, MD 

Eric L. Michelson, MD 

1. Members of the Sicilian Gambit: New approaches 

to antiarrhythmic therapy, Part 1. Emerging therapeutic 

applications of the cell biology of cardiac arrhythmias. 

Circulation 104:2865, 2001. 

2. Members of the Sicilian Gambit: New approaches 

to antiarrhythmic therapy, Part II. Emerging therapeutic 

applications of the cell biology of cardiac arrhythmias. 

Circulation 104:2990, 2001. 

3. Lau W, Newman D, Dorian P: Can antiarrhythmic 

agents be selected based on mechanism of action? 

Drugs 60:1315, 2000. 

4. Harrison DC: Antiarrhythmic drug classification: 

New science and practical applications. Am J Cardiol 

50:185, 1985. 

5. The Task Force of the Working Group on Arrhythmias 

of the European Society of Cardiology: The 

Sicilian gambit: A new approach to the classification 

of antiarrhythmic drugs based on their actions 

on arrhythmogenic mechanisms. Circulation 

84:1831, 1991. 

6. The Cardiac Arrhythmia Suppression Trial 

(CAST) Investigators: Preliminary report: Effect 

of encainide and flecainide on mortality in a randomized 

trial of arrhythmia suppression after myocardial 


7. ACC/AHA/ESC Guidelines for the Management 

of Patients With Atrial Fibrillation: Circulation 

2006;114:e257-354. 

8. Wyse D, Waldo A, DiMarco J et al. A comparison 

of rate control and rhythm control in patients with 

atrial fibrillation. N Engl J Med 2002;347:1825-33. 

9. Ellenbogen KA, Clemo HF, Stambler BS, et al: Efficacy 

of ibutilide for termination ofatrial fibrillation 

and flutter. Am J Cardiol 78(8A):42, 1996. 

10. Natale A, Newby KH, Pisano E, et al: Prospective 

randomized comparison of antiarrhythmic therapy 

versus first-line radiofrequency ablation in patients 

with atrial flutter. J Am Coll Cardiol 35:1898, 2000. 

11. Bauernfeind RA, Amat-y-Leon F, Dhingra RC, et 

al: Chronic nonparoxysmal sinus tachycardia in 

otherwise healthy persons. Ann Intern Med 91:702, 

1979. 

12. Kastor J: Multifocal atrial tachycardia. N Engl J Med 

322(24):1713, 1990. 

13. Cannom DS, Prystowsky EN: Management of ventricular 

arrhythmias. Detection, drugs and devices. 

JAMA 281:172, 1999. 

14. Buxton AE, Lee K, Fisher JD, et al: A Randomized 

study of the prevention of sudden death in patients 

with coronary artery disease. N Engl J Med 

341:1882, 1999. 

15. Kuck K-H, Cappato R, Siebels J: Randomized 

comparison of antiarrhythmic drug therapy with 

implantable defibrillators in patients resuscitated 

from cardiac arrest. The Cardiac Arrest Study 

Hamburg (CASH). Circulation 102:748, 2000. 

16. The Antiarrhythmics versus Implantable 

Defibrillators(AVID) Investigators: A Comparison 

of antiarrhythmic-drug therapy with implantable 

defibrillators in patients resuscitated from near-fatal 

ventricular arrhythmias. N Engl J Med 337:1576, 

1997. 

17. Pacifico A, Hohnloser SH, Williams JH, et al: 

Prevention of implantable-defibrillator shocks by 

treatment with sotalol. d, l—Sotalol Implantable 

Cardioverter–Defibrillator Study Group. N Engl J 

Med 340(24)1885, 1999. 

18. Hoffman BF, Rosen MR, Wit AL: Electrophysiology 

and pharmacology of cardiac arrhythmias: VII. 

Cardiac effects of quinidine and procainamide. Am 

Heart J 90:117, 1975. 



17-1


19. Ueda CT, Williamson BJ, Dzindzio BS: Absolute 

quinidine bioavailability. Clin Pharmacol Ther 

20:260, 1976. 

20. Kessler KM, Humphries WC, Black M, Spann J: 

Quinidine pharmacokinetics in patients with cirrhosis 

receiving propranolol. Am Heart J 96:627, 

1978. 

21. Drayer DE, Hughes M, Lorenzo B, Reidenberg M: 

Prevalence of high (S)-3-hydroxyquinidine/quinidine 

ratios in serum, and clearance of quinidine 

in cardiac patients with age. Clin Pharmacol Ther 

27:72, 1980. 

22. Kessler KM, Lowenthal DT, Warner H, et al: 

Quinidine elimination in patients with congestive 

heart failure or poor renal function. N Engl J Med 

290:706, 1974. 

23. Uematsu T, Sato R, Vozeh S, et al: Relative electrophysiological 

potencies of quinidine, 3-OH quinidine 

and quinidine-N-oxide in guinea-pig heart. 

Arch Intern Pharmacodyn Ther 297:29, 1989. 

24. DiMarco JP, Garan H, Ruskin JN: Efficacy of quinidine 

in the treatment of ventricular arrhythmias: 

The role of electrophysiologic testing. Circulation 

64(Suppl IV):38, 1981. 

25. Ruskin JN, DiMarco JP, Garan H: Out-of-hospital 

cardiac arrest: Electrophysiologic observations and 

selection of long-term antiarrhythmic therapy. N 

Engl J Med 303:607, 1980. 

26. Lown B, Wolf M: Approaches to sudden death from 

coronary heart disease. Circulation 44:130, 1971. 

27. Farringer JA, McWay-Hess K, Clementi WA: Cimetidine-quinidine 

interaction. Clin Pharm 3:81, 

1984. 

28. Leahey EB, Reiffel JA, Drusin RE, et al: Interaction 

between quinidine and digoxin. JAMA 240:533, 

1978. 

29. Schenck-Gustafsson K, Jogestrand T, Norlander R, 

Dahlqvist TR: Effect of quinidine on digoxin concentration 

skeletal muscle and serum in patients 

with atrial fibrillation: Evidence for reduced binding 

of digoxin in muscle. N Engl J Med 305:209, 

1981. 

30. Funck-Brentano C, Turgeon J, Woosley RL, Roden 

DM: Effect of low dose quinidine on encainide 

pharmacokinetics and pharmacodynamics: Influence 

of genetic polymorphism. J Pharmacol Exp 

Ther 249:134, 1989. 

31. Funck-Brentano C, Kroener HK, Pavlou H, et 

al: Genetically determined interaction between 

propafenone and low dose quinidine: Role of active 

metabolites in modulating net drug effect. Br J Clin 

Pharmacol 27:435, 1989. 

32. Lau C-P, Chow MSS, Tse H-F, et al: Control of 

paroxysmal atrial fibrillation recurrence using 

combined administration of propafenone and 

quinidine. Am J Cardiol 86:1327, 2000. 

33. Mark LC, Kayden HJ, Steele JM, et al: The physiological 

disposition and cardiac effects of procainamide. 


34. Miller H, Nathanson MH, Griffith GC: The action 

of procainamide in cardiac arrhythmias. JAMA 

146:1004, 1951. 

35. Josephson ME, Caracta AR, Ricciutti MA, et al: 

Electrophysiologic properties of procainamide in 

man. Am J Cardiol 33:596, 1974. 

36. Manion CV, Lalka D, Baer DT, Meyer MB: Absorption, 

kinetics of procainamide in humans. J Pharm 

Sci 66:981, 1977. 

37. Karlsson E: Clinical pharmacokinetics of procainamide. 


38. Singh S, Gelband H, Mehta AV, et al: Procainamide 

elimination kinetics in pediatric patients. Clin 


39. Kluger J, Leech S, Reidenberg MM, et al: Longterm 

antiarrhythmic therapy with acetylprocainamide. 

Am J Cardiol 48:1124, 1981. 

40. Bigger JT, Heissenbuttel RH: The use of procainamide 

and lidocaine in the treatment of cardiac arrhythmias. 


41. Waxman HL, Buxton AE, Sadowski LM, Josephson 

ME: The response to procainamide during 

electrophysiologic study for sustained ventricular 

tachyarrhythmias predicts the response to other 

medications. Circulation 67:30, 1983. 

42. Rae AP, Sokoloff NM, Webb CR, et al: Limitations 

of failure of procainamide during electrophysiological 

testing to predict response to other medical 

therapy. J Am Coll Cardiol 6:410, 1985. 

43. Ellrodt AG, Murata GH, Riedinger MS, et al: Severe 

neutropenia associated with sustained-release 

procainamide. Ann Intern Med 100:197, 1984. 

44. Sim E: Drug-induced immune-complex disease. 

Comp Inflamm 6:119, 1989. 

45. Adams LE, Sanders CE, Budinsky RA, et al: Immunomodulatory 

effects of procainamide metabolites: 

Their implications in drug-related lupus. J Lab Clin 

Med 113:482, 1989. 

46. Asherson RA, Zulman J, Hughes GR: Pulmonary 

thromboembolism associated with procainamide 

induced lupus syndrome and anticardiolipin antibodies. 

Ann Rheum Dis 48:232, 1989. 

47. Li GC, Greenberg CS, Currie MS: Procainamideinduced 

lupus anticoagulants and thrombosis. 

South Med J 81:262, 1988. 

48. Heyman MR, Flores RH, Edelman BB, Carliner 

NH: Procainamide-induced lupus anticoagulant. 

South Med J 81:934, 1988. 

49. Kosoglou T, Rocci ML, Vlasses PH: Trimethoprim

alters the disposition of procainamide and N-acetylprocainamide. 


50. Lai MY, Jiang FM, Chung CH, et al: Dose dependent 

effect of cimetidine on procainamide disposition 

in man. Int J Clin Pharmacol Ther Toxicol 

26:118, 1988. 

51. Christian CD, Meredith CG, Speeg KV: Cimetidine 

inhibits renal procainamide clearance. Clin Pharmacol 

Ther 36:221, 1984. 

52. Danilo P Jr, Hordoff AJ, Rosen MR: Effects of disopyramide 

on electrophysiologic properties of canine 

cardiac Purkinje fibers. J Pharmacol Exp Ther 

201:701, 1977. 

53. Sasyniuk BI, Kus T: Cellular electrophysiologic 

changes induced by disopyramide in normal and 

infarcted hearts. J Int Med Res 4 (Suppl I): 20, 1976. 

54. Kidwell GA, Lima JJ, Schaal SF, Muir WW: Hemodynamic 

and electrophysiologic effects of disopyramide 

enantiomers in a canine blood superfusion 

model. J Cardiovasc Pharmacol 13:644, 1989. 

55. Birkhead JS, Vaughan Williams EM: Dual effect of 

disopyramide on atrial and atrioventricular conduction 

and refractory periods. Br Heart J 39:657, 

1977. 

56. Morady F, Scheinman MM, Desai J: Disopyramide. 


57. Bexton RS, Hellestrand KJ, Cory-Pearce R, et al: 

The direct electrophysiologic effects of disopyramide 

phosphate in the transplanted human heart. 


58. Katoh T, Karagueuzian HS, Jordan J, Mandel JW: 

The cellular electrophysiologic mechanism of the 

dual actions of disopyramide on rabbit sinus node 

dysfunction. Circulation 66:1216, 1979. 

59. Dubetz DK, Brown NN, Hooper WD, et al: Disopyramide: 

Pharmacokinetics and bioavailability. Br 


60. Capparelli EV, DiPersio DM, Zhao H, et al: Clinical 

pharmacokinetics of controlled-release disopyramide 

in patients with cardiac arrhythmias. J Clin 

Pharmacol 28:306, 1988. 

61. Bonde J, Jensen NM, Pedersen LE, et al: Elimination 

kinetics and urinary excretion of disopyramide 

in human healthy volunteers. Pharmacol 

Toxicol 62:298, 1988. 

62. Lima JJ, Boudoulas H, Blanford M: Concentrationdependence 

of disopyramide binding to plasma 

protein and its influence on kinetics and dynamics. 


63. Leach AJ, Brown JE, Armstrong PW: Cardiac depression 

by intravenous disopyramide in patients 

with left ventricular dysfunction. Am J Med 68:839, 

1980. 

64. Podrid PJ, Schoeneberger A, Lown B: Congestive 


heart failure caused by oral disopyramide. N Engl J 

Med 302:614, 1980. 

65. Yoshida Y, Hirai M, Yamada T, et al: Antiarrhythmic 

efficacy of dipyridamole in treatment of reperfusion 

arrhythmias. Evidence for cAMP-mediated 

triggered activity as a mechanism responsible for 

reperfusion arrhythmias. Circulation 101:624, 

2000. 

66. Jennings G, Jones MBS, Besterman EMM, et al: 

Oral disopyramide in prophylaxis of arrhythmias 

following myocardial infarction. Lancet 1:51, 1976. 

67. Vismara LA, Mason DT, Amsterdam EA: Disopyramide 

phosphate: Clinical efficacy of a new oral 

antiarrhythmic drug. Am Heart J 16:330, 1974. 

68. Jonason T, Ringqvist I, Bandh S, et al: Propafenone 

versus disopyramide for treatment of 

chronic symptomatic ventricular arrhythmias: A 

multicenter study. Acta Med Scand 223:515, 1988. 

69. Ueda CT, Dzindzio BS, Vosik WM: Serum disopyramide 

concentrations and suppression of ventricular 

premature contractions. Clin Pharmacol 

Ther 36:326, 1984. 

70. Vismara LA, Vera Z, Miller RR, Mason DT: Efficacy 

of disopyramide phosphate in the treatment 

of refractory ventricular tachycardia. Am J Cardiol 

39:1027, 1977. 

71. Kim SG, Mercando AD, Tam S, Fisher JD: Combination 

of disopyramide and mexiletine for better 

tolerance and additive effects for treatment of 

ventricular arrhythmias. J Am Coll Cardiol 13:659, 

1989. 

72. Della-Bella P, Tondo C, Marenzi G, et al: Facilitating 

influence of disopyramide on atrial flutter 

termination by overdrive pacing. Am J Cardiol 

61:1046, 1988. 

73. Karlson BW, Torstensson I, Jansson SO, Peterson 

LE: Disopyramide in the maintenance of sinus 

rhythm after electroconversion of atrial fibrillation: 

A placebo-controlled one-year follow-up study. 

Eur Heart J 9:284, 1988. 

74. Fujimura O, Klein GJ, Sharma AD, et al: Acute effect 

of disopyramide on atrial fibrillation in the 

Wolff-Parkinson-White syndrome. J Am Coll Cardiol 

13:1133, 1989. 

75. Morillo CA, Leitch JW, Yee R, Klein GJ: A placebo-controlled 

trial of intravenous and oral disopyramide 

for prevention of neurally mediated 

syncope induced by head-up tilt. J Am Coll Cardiol 

22(7):1843, 1993. 

76. Nicholson WJ, Martin CE, Gracey JG, Knoch HR: 

Disopyramide induced ventricular fibrillation. Am 

J Cardiol 43:1053, 1979. 

77. Nakabayashi H, Ito T, Igawa T, et al: Disopyramide 

induces insulin secretion and plasma glucose dimi-


nution: Studies using the in situ canine pancreas. 


78. Ragosta M, Wiehl AC, Rosenfeld LE: Potentially 

fatal interaction between erythromycin and disopyramide. 

Am J Med 86:465, 1989. 

79. Harrison DC, Sprouse JH, Morrow AG: The antiarrhythmic 

properties of lidocaine and procainamide. 


80. Harrison DC, Alderman EL: The pharmacology 

and clinical use of lidocaine as an antiarrhythmic 

drug. Modern Treatment 9:139, 1972. 

81. Rosen KM, Lau SH, Weiss MB, Damato AN: The 

effect of lidocaine on atrioventricular and intraventricular 

conduction in man. Am J Cardiol 25:1, 

1970. 

82. Singh BN, Vaughn Williams EM: Effect of altering 

potassium concentration on the action of lidocaine 

and di phenylhydantoin on rabbit atrial and ventricular 

muscle. Circ Res 29:286, 1971. 

83. Lichtstein E, Chadda KD, Gupta PK: Atrioventricular 

block with lidocaine therapy. Am J Cardiol 

31:277, 1973. 

84. DeBoer AG, Breimer DD, Mattie H, et al: Rectal 

bioavailability of lidocaine in man: Partial avoidance 

of first-pass metabolism. Clin Pharmacol Ther 

26:701, 1979. 

85. Drayer DE, Lorenzo B, Werns S, Reidenberg MM: 

Plasma levels, protein binding, and elimination 

data of lidocaine and active metabolites in cardiac 

patients of various ages. Clin Pharmacol Ther 34:14, 

1983. 

86. Routledge PA, Barchowsky A, Bjornsson TD, et al: 

Lidocaine plasma protein binding. Clin Pharmacol 

Ther 27:347, 1980. 

87. Stenson RE, Constantino RT, Harrison DC: Interrelationships 

of hepatic blood flow, cardiac output, 

and blood levels of lidocaine in man. Circulation 

43:205, 1971. 

88. Rowland M, Thomson PD, Guichard A, Melmon 

KL: Disposition kinetics of lidocaine in normal 

subjects. Ann NY Acad Sci 179:383, 1971. 

89. Thomson PD, Melmon KL, Richardson JA, et al: 

Lidocaine pharmacokinetics in advanced heart 

failure, liver disease, and renal failure in humans. 


90. LeLorier J, Grenon D, Latour Y, et al: Pharmacokinetics 

of lidocaine after prolonged intravenous 

infusion in uncomplicated myocardial infarction. 


91. Narang PK, Crouthamel WG, Carliner NH: Lidocaine 

and its active metabolites. Clin Pharmacol 

Ther 24:654, 1978. 

92. Teo KK, Yusuf S, Furberg CD: Effects of prophylactic 

antiarrhythmic drug therapy in acute myo- 

cardial infarction. An overview of results from 

randomized controlled trials. JAMA 270(13):1589, 

1993. 

93. Yusuf S, Wittes J, Friedman L: Overview of results 

of randomized clinical trials in heart disease: I. 

Treatments following myocardial infarction. JAMA 

260:2088, 1988. 

94. Noneman JW, Jones MR: Lidocaine in drug treatment 

of cardiac arrhythmias. In: Goupd LA, ed. 

Drug Treatment of Cardiac Arrhythmias. Mt. Kisco, 

NY: Futura, 1983:193. 

95. Ochs HR, Carstens G, Greenblatt DJ: Reduction 

in lidocaine clearance during continuous infusion 

and by coadministration of propranolol. N Engl J 

Med 303:373, 1980. 

96. Feely J, Wilkinson GR, McAllister CB, Wood AJJ: 

Increased toxicity and reduced clearance of lidocaine 

by cimetidine. Ann Intern Med 96:592, 1982. 

97. Boyce JR, Cervenko FW, Wright FJ: Effects of halothane 

on the pharmacokinetics of lidocaine in digitalis-toxic 

dogs. Can Anaesth Soc J 25:323, 1978. 

98. Koster RW, Dunning AJ: Intramuscular lidocaine 

for prevention of lethal arrhythmias in the prehospitalization 

phase of acute myocardial infarction. N 

Engl J Med 313:1105, 1985. 

99. Singh BN, Vaughn Williams EM: Investigations of 

the mode of action of a new antidysrhythmic drug, 

Ko 1173. Br J Pharmacol 44:1, 1972. 

100. Allen JD, Kofi Ekue JM, et al: The effect of Ko 1173, 

a new anticonvulsant agent, on experimental cardiac 

arrhythmias. Br J Pharmacol 45:561, 1972. 

101. Weld FM, Bigger JT, Swistel D, et al: Electrophysiologic 

effects of mexiletine (Ko 1173) on bovine cardiac 

Purkinje fibres. J Pharmacol Exp Ther 210:222, 

1979. 

102. Arita M, Goto M, Nagamoto Y, Saikawa T: Electrophysiological 

actions of mexiletine (Ko 1173) on 

canine Purkinje fibers and ventricular muscle. Br J 

Pharmacol 67:143, 1979. 

103. Campbell NPS, Pantridge JF, Adgey AAJ: Longterm 

antiarrhythmic therapy with mexiletine. Br 

Heart J 40:796, 1978. 

104. Nora MO, Chandrasekaran K, Hammill SC, Reeder 

GS: Prolongation of ventricular depolarization: 

ECG manifestation of mexiletine toxicity. Chest 

95:925, 1989. 

105. Prescott LF, Clements JA, Pottage A: Absorption, 

distribution and elimination of mexiletine. Postgrad 

Med J 53(Suppl I):50, 1977. 

106. Middleton D: Baseline pharmacology, electrophysiology 

and pharmacokinetics of mexiletine. Acta 

Cardiol 25(Suppl): 45, 1980. 

107. Horowitz JD, Anavekar SN, Morris PM, et al: Comparative 

trial of mexiletine and lidocaine in treat-

ment of early ventricular tachyarrhythmias after 

acute myocardial infarction. J Cardiovasc Pharmacol 

3:409, 1981. 

108. Stein J, Podrid PJ, Lampert S, Hirshowitz GH: 

Long-term mexiletine for ventricular arrhythmia. 

Am Heart J 107:1091, 1984. 

109. Whitford EG, McGovern B, Schoenfeld MH, et 

al: Long-term efficacy of mexiletine alone and in 

combination with a class Ia antiarrhythmic drugs 

for refractory ventricular arrhythmias. Am Heart J 

115:360, 1988. 

110. Duff HJ: Mexiletine-quinidine combination: Enhanced 

antiarrhythmic and electrophysiologic activity 

in the dog. J Pharmacol Exp Ther 249:617, 

1989. 

111. Kim SG, Mercando AD, Tam S, Fisher JD: Combination 

of disopyramide and mexiletine for better 

tolerance and additive effects for treatment of 


1989. 

112. Kim SG, Felder SD, Waspe LE, Fisher JD: Electrophysiologic 

effects and clinical efficacy of mexiletine 

used alone or in combination with class Ia 

agents for refractory recurrent ventricular tachycardias 

or ventricular fibrillation. Am J Cardiol 

58:485, 1986. 

113. Achuff SC, Campbell RWF, Pottage A, et al: Mexiletine 

in the prevention of ventricular arrhythmias 

in acute myocardial infarction. Postgrad Med J 

53(Suppl I):163, 1977. 

114. Campbell RWF, Dolder MA, Prescott LF, et al: 

Comparison of procaineamide and mexiletine in 

prevention of ventricular arrhythmias after acute 

myocardial infarction. Lancet 1:1257, 1975. 

115 Murray KT, Barbet JT, Kopelman HA, et al: Mexiletine 

and tocainide: A comparison of antiarrhythmic 

efficacy, adverse effects, and predictive value 

of lidocaine testing. Clin Pharmacol Ther 45:553, 

1989. 

116. Zehender M, Geibel A, Tresse N, et al: Prediction 

of efficacy and tolerance of oral mexiletine by intravenous 

lidocaine application. Clin Pharmacol Ther 

44:389, 1988. 

117. Banitt EH, Coyne WE, Schmid JR, Mendel A: 

Antiarrhythmics. N-aminoalkylene) trifluoroethoxybenzamides 

and N-(aminoalkylene) trifluoroethoxynaphthamides. 

J Med Chem 18:1130, 

1975. 

118. Seipel L, Abendroth PR, Breithart G: Electrophysiologische 

Effekte des neuen Antiarrhythmikums 

Flecainid (R818) beim Menschen. Z Kardiol 

70:524, 1981. 

119. Vik-Mo H, Ohm O-J, Lund-Johansen P: Electrophysiologic 

effects of flecainide acetate in patients 


with sinus node dysfunction. Am J Cardiol 50:1090, 

1982. 

120. Hodess AB, Follanshee WT, Spear JF: Electrophysiological 

effects of a new antiarrhythmic agent, 

flecainide, in the intact canine heart. J Cardiovasc 

Pharmacol 1:427, 1979. 

121. Hellestrand KJ, Bexton RS, Nathan AW, et al: Acute 

electrophysiologic effects of flecainide acetate on 

cardiac conduction and refractoriness in man. Br 

Heart J 48:140, 1982. 

122. Conrad GJ, Ober RE: Metabolism of flecainide. Am 

J Cardiol 53:4B, 1982. 

123. Anderson JL, Stewart JR, Perry BA, et al: Oral flecainide 

acetate for the treatment of ventricular arrhythmias. 

N Engl J Med 305:473, 1981. 

124. Hodges M, Haugland JM, Granrud G, et al: Suppression 

of ventricular ectopic depolarizations by 

flecainide acetate, a new antiarrhythmic agent. Circulation 

65:879, 1982. 

125. Forland SC, Cutler RE, McQuinn RL, et al: Flecainide 

pharmacokinetics after multiple dosing in 

patients with impaired renal function. J Clin Pharmacol 

28:727, 1988. 

126. McQuinn RL, Pentikainen PJ, Chang SF, Conrad 

GJ: Pharmacokinetics of flecainide in patients with 

cirrhosis of the liver. Clin Pharmacol Ther 44:566, 

1988. 

127. Cohen AA, Daru V, Covelli G, et al: Hemodynamic 

effects of intravenous flecainide in acute uncomplicated 

myocardial infarction. Am Heart J 110:1193, 

1985. 

128. Webb CR, Morganroth J, Senior S, et al: Safety and 

efficacy of antiarrhythmic therapy with flecainide 

for patients with ventricular tachycardia and ventricular 

dysfunction. Clin Res 32:685A, 1984. 

129. Josephson MA, Ikeda N, Singh BN: Effects of flecainide 

on ventricular function: Clinical and experimental 

correlations. Am J Cardiol 53:945B, 

1984. 

130. Van Wijk LM, den Heijer P, Crijns HJ, et al: Flecainide 

versus quinidine in the prevention of 

paroxysms of atrial fibrillation. J Cardiovasc Pharmacol 

13:32, 1989. 

131. Wafa SS, Ward DE, Parker DJ, Camm AJ: Efficacy 

of flecainide acetate for atrial arrhythmias following 

coronary artery bypass grafting. Am J Cardiol 

63:1058, 1989. 

132. Gavaghan TP, Koegh AM, Kelly RP, et al: Flecainide 

compared with a combination of digoxin and disopyramide 

for acute atrial arrhythmias after cardiopulmonary 

bypass. Br Heart J 60:497, 1988. 

133. Van Wijk LM, Crijns HJ, van Gilst WH, et al: Flecainide 

acetate in the treatment of supraventricular 

tachycardias: Value of programmed electrical


stimulation for long-term prognosis. Am Heart J 

117:365, 1989. 

134. Zee Cheng CS, Kim SS, Ruffy R: Flecainide acetate 

for treatment of bypass tract mediated reentrant 

tachycardia. Am J Cardiol 62:23D, 1988. 

135. Kim SS, Smith P, Ruffy R: Treatment of atrial 

tachyarrhythmias and preexcitation syndrome 

with flecainide acetate. Am J Cardiol 62:29D, 1988. 

136. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators: 

Effects of encainide, flecainide, imipramine 

and moricizine on ventricular arrhythmias 

during the year after acute myocardial infarction: 

The CAPS. Am J Cardiol 61:501, 1988. 

137. Capparelli EV, Kluger J, Regnier JC, Chow MS: 

Clinical and electrophysiologic effects of flecainide 

in patients with refractory ventricular tachycardia. 


138. Flecainide-Quinidine Research Group: Flecainide 

versus quinidine for treatment of chronic ventricular 

arrhythmias: A multicenter clinical trial. Circulation 

67:1117, 1983. 

139. Morganroth J, Price B: Flecainide vs quinidine: Efficacy 

and tolerance in patients with chronic stable 

ventricular ectopy. Am J Cardiol 49:1015, 1982. 

140. Viswanathan PC, Bezzina CR, George AL Jr, et al: 

Gating-dependent mechanisms for flecainide action 

in SCH5A-linked arrhrythmia syndromes. 

Circulation 104:1200, 2001. 

141. Lal R, Chapman PO, Naccarrelli GV, et al: Short- 

and long-term experience with flecainide acetate in 

the management of refractory life threatening ventricular 

arrhythmias. J Am Coll Cardiol 6:772, 1985. 

142. Chimienti M, Cullen MT, Casadei G: Safety of 

long-term flecainide and propafenone in the management 

of patients with symptomatic paroxysmal 

atrial fibrillation: Report from the Flecainide and 

Propafenone Italian Study Investigators. Am J Cardiol 

77:60A, 1996. 

143. Reid PR, Griffith LSC, Platia EV, Ord SE: Evaluation 

of flecainide acetate in the management of patients 

at high risk of sudden cardiac death. Am J 

Cardiol 53:108B, 1983. 

144. Hellestand KJ, Burnett PJ, Milne JR, et al: Effect 

of the antiarrhythmic agent flecainide acetate on 

acute and chronic pacing thresholds. PACE 6:892, 

1983. 

145. Kohlhardt M: Basic electrophysiological action of 

propafenone in heart muscle. In: Schlepper M, Olssen 

B, eds. Cardiac Arrhythmias: Diagnosis, Prognosis 

and Therapy: Proceedings of 1st International 

Rhythmonorm Congress. New York: Springer-Verlag, 

1983:91. 

146. Zeiler RH, Grough WB, El-Sherif N: Electrophysiologic 

effects of propafenone on canine ischemic 

cardiac cells. Am J Cardiol 54:424, 1984. 

147. Rudolph W, Petri H, Kafka W, Hall D: Effects of 

propafenone on the accessory pathway in patients 

with WPW syndrome. Am J Cardiol 43:430, 1979. 

148. Dubuc M, Kus T, Campa MA, et al: Electrophysiologic 

effects of intravenous propafenone in Wolff- 

Parkinson-White syndrome. Am Heart J 117:370, 

1989. 

149. Kroemer HK, Funck-Brentano C, Silberstein DJ, et 

al: Stereoselective disposition and pharmacologic 

activity of propafenone enantiomers. Circulation 

79:1068, 1989. 

150. Karagueuzian HS, Katoh T, McCullen A, et al: 

Electrophysiologic and hemodynamic effects of 

propafenone, a new antiarrhythmic agent, on the 

anesthetized, closed-Chest dog: Comparative study 

with lidocaine. Am Heart J 107:418, 1984. 

151. Chilson DA, Heger JJ, Zipes DP, et al: Electrophysiologic 

effects and clinical efficacy of oral 

propafenone therapy in patients with ventricular 

tachycardia. J Am Coll Cardiol 5:1407, 1985. 

152. Connolly ST, Kates RE, Labsack CS, et al: Clinical 

efficacy and electrophysiology of oral propafenone 

for ventricular tachycardia. Am J Cardiol 52:1208, 

1983. 

153. Connolly SJ, Kates RE, Lebsack CS, et al: Clinical 

pharmacology of propafenone. Circulation 68:589, 

1983. 

154. Siddoway LA, Thompson KA, McAllister CB, et 

al: Polymorphism of propafenone metabolism and 

disposition in man: Clinical and pharmacokinetic 

consequences. Circulation 75:785, 1987. 

155. Baker BJ, Dinh H, Kroskey D, et al: Effect of 

propafenone on left ventricular ejection fraction. 

Am J Cardiol 54:20D, 1984. 

156. Podrid PJ, Cytryn R, Lown B: Propafenone: Noninvasive 

evaluation of efficacy. Am J Cardiol 54:53D, 

1984. 

157. Henze E, Roth J, Haerer W, et al: Long term inotropic 

effects of flecainide and propafenone. Eur J Nucl 

Med 13:568, 1988. 

158. Shen EN, Sung RJ, Morady F, et al: Electrophysiologic 

and hemodynamic effects of intravenous 

propafenone in patients with recurrent ventricular 

tachycardia. J Am Coll Cardiol 3:1291, 1984. 

159. Singh BN, Kaplinsky E, Kirsten E, Guerrero J: Effects 

of propafenone on ventricular arrhythmias: 

Double-blind, parallel, randomized, placebo-controlled 

dose-ranging study. Am Heart J 116:1542, 

1988. 

160. Dinh H, Baker BJ, deSoyza N, Murphy ML: Sustained 

therapeutic efficacy and safety of oral 

propafenone for treatment of chronic ventricular 

arrhythmias: A 2-year experience. Am Heart J

115(1Pt 1):92, 1988. 

161. Prystowsky EN, Heger JJ, Chilson DA, et al: Antiarrhythmic 

and electrophysiologic effects of oral 

propafenone. Am J Cardiol 54:26D, 1984. 

162. Connolly SJ, Hoffert DL: Usefulness of propafenone 

for recurrent paroxysmal atrial fibrillation. 

Am J Cardiol 63:817, 1989. 

163. Aliot E, Denjoy I: Comparison of the safety and efficacy 

of flecainide versus propafenone in hospital 

out-patients with symptomatic praroxysmal atrial 

fibrillation/flutter: The Flecainide AF French Study 

Group. Am J Cardiol 77:66A, 1996. 

164. KatesRE, Yee Y-G, Kirsten EB: Interaction between 

warfarin and propafenone in healthy volunteer 

subjects. Clin Pharmacol Ther 42:305, 1987. 

165. Capucci A, Boriani G, Botto GL, Lenzi T, et al: Conversion 

of recent-onset atrial fibrillation by a single 

oral loading dose of propafenone or flecainide. Am 

J Cardiol 74(5):503, 1994. 

166. Wit AL, Hoffman BF, Rosen MR: Electrophysiology 

and pharmacology of cardiac arrhythmias: IX. 

Cardiac electrophysiologic effects of beta adrenergic 

receptor stimulation and blockade (Part B). Am 

Heart J 90:665, 1975. 

167. Frishman WH: Beta-adrenoreceptor antagonists: 

New drugs and new indications. N Engl J Med 

305:500, 1981. 

168. Wit AL, Hoffman BF, Rosen MR: Electrophysiology 

and pharmacology of cardiac arrhythmias: IX. 

Cardiac electrophysiologic effects of beta adrenergic 

receptor stimulation and blockade (Part C). Am 

Heart J 90:795, 1975. 

169. Josephson ME, Seides SF: Clinical Cardiac Electrophysiology. 

Philadelphia: Lea & Febiger, 1979, p 68. 

170. Frishman WH, Cavusoglu E: β-Adrenergic blockers 

and their role in the therapy of arrhythmias. In: 

Podrid PJ, Kowey PR, eds. Cardiac Arrhythmias– 

Mechanisms, Diagnosis and Management. Baltimore: 

Williams & Wilkins, 1995:421. 

171. Huikure HV, Cox M, Interian A, et al: Efficacy of 

intravenous propranolol for suppression of inducibility 

of ventricular tachyarrhythmias with different 

electrophysiologic characteristics in coronary 


172. Sectral package insert. Philadelphia: Wyeth-Ayerst, 

1999. 

173. De Soyza N, Shapiro W, Chandraratra PAN, et al: 

Acebutolol therapy for ventricular arrhythmia: 

A randomized, placebo-controlled, double blind 

multicenter study. Circulation 65:1129, 1982. 

174. Boissel J-P, Leizorovicz A., Picolet H, Ducruet T, 

and the APSI investigators: Efficacy of acebutolol 

after acute myocardial infarction (the APSI trial). 

Am J Cardiol 66:24C, 1990. 


175. Greenspan AM, Spielman SR, Horowitz LN, et al: 

The electrophysiologic properties of esmolol, a 

short acting beta-blocker. Int J Clin Pharmacol Ther 

Toxicol 26:209, 1988. 

176. Gorczynski RJ: Basic pharmacology of esmolol. 

Am J Cardiol 56:3F, 1985. 

177. Frishman WH, Murthy VS, Strom JA, Hershman 

DL: Ultrashort-acting beta-adrenoreceptor blocking 

drug: Esmolol. In: Messerli FH, ed. Cardiovascular 

Drug Therapy, 2d ed. Philadelphia: Saunders, 

1996. 

178. Shaffer JE, Quon CY, Gorczynski RJ: Beta-adrenoreceptor 

antagonist potency and pharmacodynamics 

of ASL-8123, the primary acid metabolite of 

esmolol. J Cardiovasc Pharmacol 11:187, 1988. 

179. Morganroth J, Horowitz LN, Anderson J, et al: 

Comparative efficacy and tolerance of esmolol 

to propranolol for control of supraventricular 

tachyarrhythmia. Am J Cardiol 56:33F, 1985. 

180. Platia EV, Michelson EL, Porterfield JK, Das G: 

Esmolol versus verapamil in the acute treatment 

of atrial fibrillation or atrial flutter. Am J Cardiol 

63:925, 1989. 

181. Kloner RA, Kirshenbaum J, Lange R, et al: Experimental 

and clinical observations on the efficacy 

of esmolol in myocardial infarction. Am J Cardiol 

56:40F, 1985. 

182. Singh BN, Vaughn Williams EM: The effect of 

amiodarone, a new antianginal drug, on cardiac 

muscle. Br J Pharmacol 39:657, 1970. 

183. Levine JH, Moore EN, Kadish AH, et al: Mechanisms 

of depressed conduction from long-term 

amiodarone therapy in canine myocardium. Circulation 

78:684, 1988. 

184. Kamiya K, Nishiyama A, Yasui K, et al: Short- and 

long-term effects of amiodarone on the two components 

of cardiac delayed rectifier K + current. Circulation 

103:1317, 2001. 

185. Rosenbaum MB, Chiale PA, Ryba D, Elizazri 

MV: Control of tachyarrhythmias associated with 

Wolff-Parkinson-White syndrome by amiodarone 

hydrochloride. Am J Cardiol 34: 215, 1974. 

186. Mitchell LB, Wyse DG, Gillis AM, Duff HJ: Electropharmacology 

of amiodarone therapy initiation: 

Time courses of onset of electrophysiologic and antiarrhythmic 

effects. Circulation 80:34, 1989. 

187. Marcus FI: Clinical pharmacology of amiodarone. 

Ann NY Acad Sci 427:112, 1984. 

188. Connolly SJ: Evidence-based analysis of amiodarone 

efficacy and safety. Circulation 100:2025, 1999. 

189. Munoz A, Karila P, Gallay P, et al: A randomized 

hemodynamic comparison of intravenous amiodarone 

with and without Tween 80. Eur Heart J 9:142, 

1988.


190. Cushing DJ, Adams MP, Cooper WD, et al: Evaluation 

of the effects of PM101, a cyclodextrin-based 

formulation of intravenous amiodarone, on blood 

pressure in healthy humans. Am J Cardiol 104: 

1152, 2009. 

191. Block PJ, Winkle RA: Hemodynamic effects of antiarrhythmic 

drugs. Am J Cardiol 52:14C, 1983. 

192. Roy D, Talajic M, Dorian P, et al for the Canadian 

Trial of Atrial Fibrillation Investigators: Amiodarone 

to prevent recurrence of atrial fibrillation. N 

Engl J Med 342:913, 2000. 

193. Giri S, White CM, Dunn AB, et al: Oral amiodarone 

for prevention of atrial fibrillation after open 

heart surgery, the Atrial Fibrillation Suppression 

Trial (AFIST): A randomised, placebo-controlled 

trial. Lancet 357:830, 2001. 

194. Gold RL, Haffajee CL, Charos G, et al: Amiodarone 

for refractory atrail fibrillation. Am J Cardiol 

57:124, 1986. 

195. Brodsky MA, Allen BJ, Walker CJ III, et al: Amiodarone 

for maintenance of sinus rhythm after 

conversion of atrial fibrillation in the setting of a 

dilated left atrium. Am J Cardiol 60:572, 1987. 

196. The Canadian Trial of Atrial Fibrillation Investigators: 

Amiodarone to prevent recurrence of atrial 

fibrillation. N Engl J Med 342:913, 2000. 

197. Heger JE, Prystowsky E, Zipes DP: Clinical efficacy 

of amiodarone in treatment of recurrent ventricular 

tachycardia and ventricular fibrillation. Am 

Heart J 106:887, 1983. 

198. Greenspon AJ, Volosin KJ, Greenberg RM, et al: 

Amiodarone therapy: Role of early and late electrophysiologic 

studies. J Am Coll Cardiol 11:117, 1988. 

199. Cairns JA, Connolly SJ, Roberts R, et al: Canadian 

amiodarone myocardial infarction arrhythmia trial 

(CAMIAT): Rationale and protocol. Am J Cardiol 

72:87F, 1993. 

200. Camm AJ, Julian D, Munoz A, et al: The European 

myocardial infarct amiodarone trial (EMIAT). Am 

J Cardiol 72:95F, 1993. 

201. Singh SN, Fletcher RD, Fisher S, et al: Veterans affairs 

congestive heart failure antiarrhythmic trial: 

CHF STAT investigators. Am J Cardiol 72:99F, 

1993. 

202. Kowey PR, Levine JH, Herre JM, et al: Randomized, 

double-blind comparison of intravenous amiodarone 

and bretylium in the treatment of patients 

with recurrent, hemodynamically destabilizing 

ventricular tachycardia or fibrillation. Circulation 

92:3255, 1995. 

203. Scheinman MM, Levine JH, Cannom DS, et al: 

Dose-ranging study of intravenous amiodarone in 

patients with life-threatening ventricular tachyarrhythmias. 


204. Levine JH, Massumi A, Scheinman MM, et al: 

Intravenous amiodarone for recurrent sustained 

hypotensive ventricular tachyarrhythmias: Intravenous 

Amiodarone Multicenter Trial Group. J Am 


205. Kerin NZ, Faitel K, Naini M: The efficacy of intravenous 

amiodarone for the conversion of chronic 

atrial fibrillation: Amiodarone vs. quinidine for 

conversion of atrial fibrillation. Arch Intern Med 

156:49, 1996. 

206. Bogazzi F, Bartalena L, Gasperi M, et al: The various 

effects of amiodarone on thyroid function. 

Thyroid 11:511, 2001. 

207. Singh BN: Antiarrhythmic actions of amiodarone: 

A profile of a paradoxical agent. Am J Cardiol 78 

(4A):41, 1996. 

208. Kudenchuk PJ, Cob LA, Copass MK, et al: Amiodarone 

for resuscitation after out-of-hospital cardiac 

arrest due to ventricular fibrillation. N Engl J Med 

341(12):871, 1999. 

209. Dorian P, Cass D, Schwartz B, et al: Amiodarone as 

compared with lidocaine for shock-resistant ventricular 


210. Section 5: Pharmacology I: Agents for arrhythmias. 

Circulation 102(Suppl I):I–112, 2000. 

211. Strauss HC, Bigger JT Jr, Hoffman BF: Electrophysiological 

and beta-receptor blocking effects of 

MJ 1999 on dog and rabbit cardiac tissue. Circ Res 

26:661, 1970. 

212. Rowland E, Perrins EJ, Donaldson RM, Rickards 

AF: D-sotalol: The clinical electrophysiological 

effects of a new class III antiarrhythmic agent. Br 

Heart J 53:87, 1985. 

213. Nathan AW, Hellestrand KJ, Bexton RS, et al: Electrophysiological 

effects of sotalol—just another 

beta blocker? Br Heart J 47:515, 1982. 

214. Rizos I, Senges J, Jauernig R, et al: Differential effects 

of sotalol and metoprolol on induction of 

paroxysmal supraventricular tachycardia. Am J 

Cardiol 53:1022, 1984. 

215. Sundquist H: Basic review and comparison of betablocker 

pharmacokinetics. Curr Ther Res 28:388, 

1980. 

216. Parmley WW, Rabinowitz B, Chuck L, et al: Comparitive 

effects of sotalol and propranolol on contractility 

of papillary muscles and adenyl cyclase 

activity of myocardial extracts of cat. J Clin Pharmacol 

12:127, 1972. 

217. Simon A, Berman E: Long-term sotalol therapy in 

patients with atrial arrhythmias. J Clin Pharmacol 

19:547, 1979. 

218. Cavusoglu E, Frishman WH: Sotalol: A new b-adrenergic 

blocker for ventricular arrhythmias. Prog 

Cardiovasc Dis 37(6):423, 1995.

219. Gonzalez R, Scheinman MM, Herre JM, et al: Usefulness 

of sotalol for drug-refractory malignant 


1988. 

220. Singh SN, Cohen A, Chen YW, et al: Sotalol for 

refractory sustained ventricular tachycardia and 

nonfatal cardiac arrest. Am J Cardiol 62:399, 1988. 

221. Kienzle MG, Martins JB, Wendt DJ, et al: Enhanced 

efficacy of oral sotalol for sustained ventricular 

tachycardia refractory to type I antiarrhythmic 

drugs. Am J Cardiol 61:1012, 1988. 

222. Nademanee K, Feld G, Hendrickson JA, et al: Electrophysiologic 

and antiarrhythmic effects of sotalol 

in patients with life-threatening ventricular 

tachyarrhythmias. Circulation 72:555, 1985. 

223. Dorian P, Newman D: Effect of sotalol on ventricular 

fibrillation and defibrillation in humans. Am J 

Cardiol 72(4):72A, 1993. 

224. Pacifico A, Hohnloser SH, Williams JH, et al: Prevention 

of implantable–defibrillator shocks by 

treatment with sotalol. d, l-Sotalol Implantable 

Cardioverter–Defibrillator Study Group. N Engl J 

Med 340(24):1885, 1999. 

224a. Somberg JC, Preston RA, Ranade V, Molnar J: Developing 

a safe intravenous sotalol dosing regimen. 

Am J Therap 17: 365, 2010. 

225. Waldo AL, Camm AJ, deRuyter H, et al: Effect of 

d-sotalol on mortality in patients with left ventricular 

dysfunction after recent and remote myocardial 

infarction. The SWORD Investigators. Lancet 

10:348:416, 1996. 

226. DiMarco JP, VanderLugt JT, Lee KS, et al: Ibutilide. 

In: Singh BN, Wellens HJJ, Hiroka M, eds. Electropharmacological 

Control of Arrhythmias. Mount 

Kisco, NY: Futura, 1994:589. 

227. Wesley RC, Farkhani F, Bautista J: Ibutilide-induced 

reduction in defibrillation threshold: Enhanced 

countershock efficacy via slow inward 

sodium current activation. PACE 14:716, 1991. 

228. Glatter K, Yang Y, Chatterjee K, et al: Chemical 

cardioversion of atrial fibrillation or flutter with 

ibutilide in patients receiving amiodarone therapy. 


229. Zaqqa M, Afshar H, Rasekh A, et al: Predictors of 

conversion to sinus rhythm using ibutilide for atrial 

fibrillation or flutter. Am J Cardiol 85:112, 2000. 

230. Kumar Das M, Cheriparambil K, Bedi A, et al: Cardioversion 

of atrial fibrillation with ibutilide: When 

is it most effective? Clin Cardiol 25:411, 2002. 

231. Glatter KA, Dorostkar PC, Yang Y, et al: Electrophysiological 

effects of ibutilide in patients with 

accessory pathways. Circulation 104:1933, 2001. 

232. Dofetilide. Package insert and prescribing information. 

New York: Pfizer, 1999. 


233. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et 

al for the Danish Investigations of Arrhythmia and 

Mortality on Dofetilide Study Group: Dofetilide in 

patients with congestive heart failure and left ventricular 

dysfunction. N Engl J Med 341:857, 1999. 

234. Brendorp B, Elming H, Jun L, et al for the DIA- 

MOND Study Group: QTc interval as a guide to select 

those patients with congestive heart failure and 

reduced left ventricular systolic function who will 

benefit from antiarrhythmic treatment with dofetilide. 

Circulation 103:1422, 2001. 

235. Pedersen OD, Bagger H, Keller N, et al for the Danish 

Investigations of Arrhythmia and Mortality on 

Dofetilide Study Group: Efficacy of dofetilide in 

the treatment of atrial fibrillation-flutter in patients 

with reduced left ventricular function. A the Danish 

Investigations of Arrhythmia and Mortality 

on Dofetilide (DIAMOND) substudy. Circulation 

104:292, 2001. 

236. Køber L, Bloch Thomsen PE, Møller M, et al for the 

the Danish Investigations of Arrhythmia and Mortality 

on Dofetilide (DIAMOND) Study Group: Effect 

of dofetilide in patients with recent myocardial 

infarction and left ventricular dysfunction: a randomised 

trial. Lancet 356:2052, 2000. 

237. Nørgaard BJ, Wachtell K, Christensen PD, et al and 

the Danish Dofetilide in Atrial Fibrillation and 

Flutter Study Group: Efficacy and safety of intravenously 

administered dofetilide in acute termination 

of atrial fibrillation and flutter: A multicenter, 

randomized, double-blind, placebo-controlled 

trial. Am Heart J 137:1062, 1999. 

238. Singh S, Zoble RG, Yellen L, et al: Efficacy and 

safety of oral dofetilide in converting to and maintaining 

sinus rhythm in patients with chronic atrial 

fibrillation and atrial flutter. The Symptomatic 

Atrial Fibrilation Investigative Research on Dofetilide 

(SAFIRE-D) Study. Circulation 102:2385, 2000. 

239. Mounsey JP, DiMarco JP: Dofetilide. Circulation 

102:2665, 2000. 

240. Falk RH, Polak A, Singh SN, Friedrich T: Intravenous 

dofetilide, a class III antiarrhythmic agent for 

the termination of sustained atrial fibrillation or 

flutter. Intravenous Dofetilide Investigators. J Am 

Coll Cardiol 29(2):385, 1997. 

241. Zimetbaum PJ: Dronedarone for atrial fibrillation—an 

odyssey. N Engl J Med 360: 1811, 2009. 

242. Patel C, Yan G-X, Kowey PR: Dronedarone. Circulation 

120: 636, 2009. 

242a. Singh D, Cingolani E, Diamond GA, Kaul S: Dronedarone 

for atrial fibrillation. Have we expanded the 

antiarrhythmic armamentarium? J Am Coll Cardiol 

55: 1569, 2010. 

242b. Garcia D, Cheng-Lai A: Dronedarone: a new anti-


arrhythmic drug for the treatment of atrial fibrillation. 

Cardiol in Rev 17: 230, 2009. 

243. Manning AS, Thisse V, Hodeige D, et al: SR33589, 

a new amiodarone-like antiarrhythmic agent: Electrophysiological 

effects in anesthetized dogs. J Cardiovasc 

Pharmacol 25:252, 1995. 

244. Sun W, Wei S, Jonnalagedda S, Singh B: Electrophysiological 

effects of dronedarone (sr33589), a 

noniodinated benzofuran derivative, in the rabbit 

heart. Circulation 100(22):2276, 1999. 

245. Singh B, Connolly S, Crijns H, et al. Dronedarone 

for maintenance of sinus rhythm in atrial fibrillation 

or flutter N Engl J Med 2007;357:987-99. 

246. Djandjighian L, Planchenault J, Finance O, Pastor 

G: Hemodynamic and antiadrenergic effects 

of dronedarone and amiodarone in animals with 

a healed myocardial infarction. J Cardiovasc Pharmacol 

36(3):376, 2001. 

247. Le Heuzey JY, De Ferrari GM, Radzik D, et al: A 

short-term, randomized, double-blind, parallelgroup 

study to evaluate the efficacy and safety of 

dronedarone versus amiodarone in patients with 

persistent atrial fibrillation: the DIONYSOS study. 

J Cardiovasc Electrophysiol 21: 606, 2010. 

248. Kober L, Torp-Pederson C, McMurray J, et al: Increased 

mortality after dronedarone therapy for 

severe heart failure. N Eng J Med 358:2678, 2008. 

249. Hohnloser S, Crijns H, Van Eickels M, et al: Effect 

of dronedarone on cardiovascular events in atrial 


250. Connolly SJ, Crijns HJGM, Torp-Pedersen C, et al 

for the ATHENA Investigators: Analysis of stroke 

in ATHENA: a placebo-controlled, double-blind, 

parellel-arm trial to assess the efficacy of dronedarone 

400 mg BID for the prevention of cardiovascular 

hospitalization or death from any cause in 

patients with atrial fibrillation/atrial flutter. Circulation 

120: 1174, 2009. 

251. Davey J, Herold M, Hoglund C, et al. Dronedarone 

for the control of ventricular rate in permanent 

atrial fibrillation. The Efficacy and safety of dronedarone 

for the control of ventricular rate during 

atrial fibrillation study. Am Heart J 156:527, 2008. 

252. Gautier P, Guillemare E, Dhandhighian L, et al. In 

vivo and in vitro characterization of the novel antiarrhythmic 

agent SSR 149744C: electrophysiological, 

anti-adrenergic and anti-angiotensin 2 effects. 

J Cardiovasc Pharmacol. 44:244, 2004. 

253. Kowey P, Aliot E, Capucci , et al. Placebo-controlled 

double –blind dose ranging study of the efficacy 

and safety of SSR 149744C in patients with 

recent atrial fibrillation/ flutter. Heart Rhythm 

4:572, 2007. 

254. Arya A, Silberbauer J, Teichman SL, et al: A pre- 

liminary assessment of the effects of ATI-2042 in 

subjects with paroxysmal atrial fibrillation using 

implanted pacemaker methodology. Europace 11: 

458, 2009. 

255. Tian D, Frishman WH: Vernakalant: a new drug 

to treat patients with acute onset atrial fibrillation. 


256. Dorian P, Pintner A, Mangat I et al. The effect of 

vernakalant (RSD 1235), an investigational antiarrhythmic 

agent, on atrial electrophysiology in humans. 

J Cardiovasc Pharmacol. 50:35, 2007. 

257. Roy D, Pratt C, Juul-Moller S, et al. Vernakalant 

hydrochloride for rapid conversion of atrial fibrillation: 

A phase 3, randomized, placebo-controlled 


258. Kowey PR, Dorian P, Mitchell LB, et al: Vernakalant 

hydrochloride for the rapid conversion of 

atrial fibrillation after cardiac surgery: a randomized, 

double-blind, placebo-controlled trial. Circ 

Arrhythm Electrophysiol 2: 652, 2009. 

259. Wit AL, Cranefield PF: Verapamil inhibition of the 

slow response: A mechanism for its effectiveness 

against reentrant AV nodal tachycardia. Circulation 

50(III):146, 1974. 

260. Sung RJ, Shapiro WA, Shen EN, et al: Effects of 

verapamil on ventricular tachycardias possibly 

caused by reentry, automaticity, and triggered activity. 

J Clin Invest 72:350, 1983. 

261. Hoon TJ, Bauman JL, Rodvold KA, et al: The pharmacodynamic 

and pharmacokinetic differences 

of the d and l isomers of verapamil: Implications 

in the treatment of paroxysmal supraventricular 

tachycardia. Am Heart J 112:396, 1986. 

262. Abernethy DR, Schwartz JB, Todd EL, et al: Verapamil 

pharmacodynamics and disposition in 

young and elderly hypertensive patients: Altered 

electrocardiographic and hypotensive response. 


263 Waxman HL, Meyerburg RJ, Appel R, Sung: Verapamil 

for control of ventricular rate in paroxysmal 

supraventricular tachycardia and atrial fibrillation 

or flutter. Ann Intern Med 94:1, 1981. 

264. Haft JI, Habbab MA: Treatment of atrial arrhythmias, 

effectiveness of verapamil when preceded by 

calcium infusion. Arch Intern Med 146:1085, 1986. 

265. Klein HO, Kaplinsky E: Verapamil and digoxin: 

their respective effects on atrial fibrillation and 

their interaction. Am J Cardiol 50:894, 1982. 

266. Keech AC, Harper RW, Harrison PM, et al: Pharmacokinetic 

interaction between oral metoprolol 

and verapamil for angina pectoris. Am J Cardiol 

58:551, 1986. 

267. Stark G, Schulze-Bauer C, Stark U, et al: Comparison 

of the frequency-dependent effects on

the atrioventricular node of verapamil, amiodarone, 

digoxin, and diltiazem in isolated guinea pig 

hearts. J Cardiovasc Pharmacol 25:330, 1995. 

268. Talajic M, Lemery R, Roy D, et al: Rate-dependent 

effects of diltiazem on human atrioventricular nodal 

properties. Circulation 86:870, 1992. 

269. Dougherty AH, Jackman WM, Naccarelli GV, et al: 

Acute conversion of paroxysmal supraventricular 

tachycardia with intravenous diltiazem. Am J Cardiol 

70:587, 1992. 

270. Clair WK, Wilkinson WE, McCarthy EA, et al: 

Treatment of paroxysmal supraventricular tachycardia 

with oral diltiazem. Clin Pharmacol Ther 

51:562, 1992. 

271. Roy D: Efficacy of diltiazem in recurrent supraventricular 

tachyarrhythmias. Can J Cardiol 11:538, 

1995. 

272. Pelleg A: Cardiac cellular electrophysiologic actions 

of adenosine and adenosine triphosphate. Am 

Heart J 110:688, 1985. 

273. Belhassen B, Glick A, Laniado S: Comparative 

clinical and electrophysiologic effects of adenosine 

triphosphate and verapamil on paroxysmal reciprocating 

junctional tachycardia. Circulation 77:795, 

1988. 

274. Garratt C, Linker N, Griffith M, et al: Comparison 

of adenosine and verapamil for termination of 

paroxysmal junctional tachycardia. Am J Cardiol 

64:1310, 1989. 

275. DiMarco JP, Sellers TD, Lerman BB, et al: Diagnostic 

and therapeutic use of adenosine in patients 

with supraventricular tachyarrhythmias. J Am Coll 

Cardiol 6:417, 1985. 

276. Lerman BB, Belardinelli L, West GA, et al: Adenosine 

sensitive ventricular tachycardia: Evidence suggesting 

cyclic AMP–mediated triggered activity. 


277. Withering W: An account of the foxglove and some 

of its medical uses, with practical remarks on dropsy 

and other diseases. In: Willis FA, Keys TE, eds. 

Classics of Cardiology. New York: Henry Schuman, 

1941:231. 

278. Sellers TD, Bashore TM, Gallagher JJ: Digitalis in 

the preexcitation syndrome—analysis during atrial 

fibrillation. Circulation 56:260, 1977. 

279. Cotten M de V, Stopp PE: Action of digitalis on the 

nonfailing heart of the dog. Am J Physiol 192:114, 

1958. 

280. Sonnenblick EH, Williams JF Jr, Glick G, et al: 

Studies on digitalis: XV. Effects of cardiac glycosides 

on myocardial force velocity relations in the 

nonfailing human heart. Circulation 34:532, 1966. 

281. Mason DT, Braunwald E: Studies on digitalis: X. Effects 

of ouabain on forearm vascular resistance and 


venous tone in normal subjects and in patients in 

heart failure. J Clin Invest 43:532, 1964. 

282. DeMots H, Rahimtoola SH, McAnulty JH, Porter 

GA: Effects of ouabain on coronary and systemic 

vascular resistance and myocardial oxygen consumption 

in patients without heart failure. Am J 

Cardiol 41:88, 1978. 

283. Shanbour LL, Jacobson ED: Digitalis and the mesenteric 

Circulation. Am J Dig Dis 17:826, 1972. 

284. Murgatroyd FD, Gibson SM, Baiyan X, et al: Double-blind 

placebo-controlled trial of digoxin in 

symptomatic paroxysmal atrial fibrillation. Circulation 

99:2765, 1999. 

285. Smith TW, Butler VP, Haber E, et al: Treatment of 

life-threatening digitalis intoxication with digoxin-specific 

Fab antibody fragments. N Engl J Med 

307:1357, 1982. 

286. Nordrehaug JE, Johannessen K, Von der Lippe G: 

Serum potassium concentration as a risk factor of 

ventricular arrhythmias early in acute myocardial 

infarction. Circulation 71:645, 1985. 

287. Zwillinger L: Uber die Magnesiumwirkung auf das 

Hertz. Klin Wochenschr 14:1429, 1935. 

288. Watanabe Y, Dreifus LS: Electrophysiological effects 

of magnesium and its interactions with potassium. 

Cardiovasc Res 6:79, 1972. 

289. Chen H, Bando S, Nakaya Y: Alterations of cardiac 

conduction and refractoriness in humans following 

intravenous administration of magnesium sulfate. 

Tokushima J Exp Med 35:13, 1988. 

290. Iseri LT, French JH: Magnesium: nature’s physiologic 

calcium blocker. Am Heart J 108:188, 1984. 

291. Reinhart RA: Magnesium metabolism: A review 

with special reference to the relationship between 

intracellular content and serum levels. Arch Intern 

Med 148:2415, 1988. 

292. Specter MJ, Schweizer E, Goldman RH: Studies 

on magnesium’s mechanism of action in digitalisinduced 

arrhythmias. Circulation 52:1001, 1975. 

293. Tzivoni D, Banai S, Schuger C, et al: Treatment of 

torsades de pointes with magnesium sulfate. Circulation 

77:392, 1988. 

294. Scheinman MM, Sullivan RW, Hyatt KH: Magnesium 

metabolism in patients undergoing cardiopulmonary 

bypass. Circulation 39:I235, 1969. 

295. Billman GE, Hoskins RS: Prevention of ventricular 

fibrillation with magnesium sulfate. Eur J Pharm 

158:167, 1988. 

296. Allen BJ, Brodsky MA, Capparelli EV, et al: Magnesium 

sulfate therapy for sustained monomorphic 

ventricular tachycardia. Am J Cardiol 64:1202, 

1989. 

297. Dyckner T, Wester PO: Ventricular extrasystoles 

and intracellular electrolytes before and after po-


tassium and magnesium infusions in patients on 

diuretic treatment. Am Heart J 97:12, 1979. 

298. Smith LF, Heagerty RF, Bing RF, Barnett DB: Intravenous 

infusion of magnesium sulphate after acute 

myocardial infarction: Effects on arrhythmias and 

mortality. Int J Cardiol 12:175, 1986. 

299. Healy J, Baranchuk A, Crystal E. Prevention of 

atrial fibrillation with angiotensin-converting enzyme 

inhibitors and angiotensin receptor blockers: 

a meta-analysis. J Am Coll Cardiol 45:1832, 2005. 

300. Zhang Y, Zhang P, Mu Y, et al: The role of reninangiotensin 

system blockade therapy in the prevention 

of atrial fibrillation: a meta-analysis of 

randomized controlled trials. Clin Pharmacol Ther- 

ap 88: 521, 2010. 

301. Disertori M, Latini R, Barlera S. Valsartan for prevention 

of recurrent atrial fibrillation. N Engl J Med 

360:1606, 2009. 

302. Kulik A, Singh JP, Levin R, et al: Association between 

statin use and the incidence of atrial fibrillation 

following hospitalization for coronary artery 

disease. Am J Cardiol 105: 1655, 2010. 

303. Adabag AS, Mithani S, Al Aloul B, et al for the 

Veterans Affairs High-Density Lipoprotein Cholesterol 

Intervention Trial Study Group: Efficacy 

of gemfibrozil in the primary prevention of atrial 

fibrillation in a large randomized controlled trial. 

Am Heart J 157: 913, 2009.


Antiplatelet and Other 

Antithrombotic Drugs 


Robert G. Lerner, MD 

Harit Desai, MD 

1. Furie B, Furie BC: Mechanisms of thrombus formation. 

N Engl J Med 359: 938, 2008. 

2. Bennett JS: Mechanisms of platelet adhesion and aggregation: 

An update. Hosp Prac 15:70, 1992. 

3. Detwiler TC, Charo IP, Feinman RD: Evidence that 

calcium regulates platelet function. Thromb Haemost 

40:207, 1978. 

4. Smyth SS, Woulfe DS, Weitz JI, et al for the 2008 

Platelet Colloquium Participants. G-protein-coupled 

receptors as signaling targets for antiplatelet 

therapy. Arterioscler Thromb Vasc Biol 29: 449, 

2009. 

4a. Coller BS: Blood elements at surfaces: Platelets. 

Ann N Y Acad Sci 516:362, 1987. 

4b. Ma YQ, Qin J, Plow EF: Platelet integrin alpha(IIb) 

beta(3): activation mechanisms. J Thromb Haemost 

5: 1345, 2007. 

5. Hirsh J, Salzman EW, Marder VJ, Colman RW: 

Overview of the thrombotic process and its therapy. 

In: Colman RW, Hirsh J, Marder VJ, Salzman 

EW, eds. Hemostasis and Thrombosis: Basic Principles 

and Clinical Practice. 3d ed. Philadelphia: Lippincott, 

1994: 1151. 

6. Virmani R, Kolodgie FD, Burke AP, et al: Lessons 

from sudden coronary death. A comprehensive 

morphological classification scheme for atherosclerotic 

lesions. Arterioscler Thromb Vasc Biol 20: 

1262, 2000. 

7. Faggiotto A, Ross R, Harker L: Studies of hypercholesterolemia 

in the nonhuman primate. I. Changes 

that lead to fatty streak formation. Arteriosclerosis 

4:323, 1984. 

8. Mann JM, Davies MJ: Vulnerable plaque: Relation 

of characteristics to degree of stenosis in human 

coronary arteries. Circulation 94:928, 1996. 

9. Richardson PD, Davies MJ, Born GBR: Influence of 

plaque configuration and stress distribution of fissuring 

of coronary atherosclerotic plaques. Lancet 

2:941, 1989. 

9a. Gurbel PA, Tantry US: Acceptance of high platelet 

reactivity as a risk factor (editorial comment). J Am 

Coll Cardiol Cardiovasc Interv 3: 1008, 2010. 

9b. Frishman WH, Weksler B, Christodoulou JP, et 

al: Reversal of abnormal platelet aggregability and 

change in exercise tolerance in patients with angina 

pectoris following oral propranolol. Circulation 50: 

887, 1974. 

10. Steering Committee of the Physician’s Health Study 

Research Group: Final Report on the Aspirin Component 

of the Ongoing Physician’s Health Study. N 

Engl J Med 321:129, 1989. 

11. Lee G, Garcia JM, Corso PJ, et al: Correlation of 

coronary angioscopic to angiographic findings in 

coronary artery disease. Am J Cardiol 58:238, 1986. 

12. Virmani R, Burke AP, Kolodgie FD: Histopathology 

of atherosclerosis. In: Colman RW, Marder VJ, 

Clowes AW, et al (eds). Hemostasis and Thrombosis: 

Basic Principles and Clinical Practice. 5th ed. Philadelphia: 

Lippincott, 2006: 813. 

13. Ault KA, Cannon CP, Mitchell J, et al: Platelet activation 

in patients after an acute coronary syndrome: 

Results from the TIMI-12 trial. J Am Coll 

Cardiol 33:634, 1999. 

14. Miner J, Hoffhines A: The discovery of aspirin’s 

antithrombotic effects. Texas Heart Insti J 34: 179, 

2007. 

15. Patrono C, Garcia Rodriguez LA, Landolfi R, 

Baigent C: Low-dose aspirin for the prevention of 

atherothrombosis. N Engl J Med 353: 2373, 2005. 

16. Frishman WH, Cheng-Lai A, Nawarskas J, eds: 

Current Cardiovascular Drugs. 4th ed. Philadelphia: 

Current Medicine, 2005:98. 



18-1


17. Antiplatelet Trialist’s Collaboration: Secondary 

prevention of vascular disease by prolonged antiplatelet 

treatment. BMJ 296:320, 1988. 

18. Gross PL, Weitz JI: New antithrombotic drugs. Clin 

Pharmacol Ther 86: 139, 2009. 

19. Awtry EH, Loscalzo J: Aspirin. Circulation 

101:1206, 2000. 

20. Miller, KP, Frishman WH: Platelets and anti-platelet 

therapy in ischemic heart disease. Med Clin 

North Am 72:117, 1988. 

21. Patrono C, Coller B, Dalen JE, et al: Platelet-active 

drugs: The relationships among dose, effectiveness, 

and side effects. Chest 126(Suppl 1):243S, 2004. 

22. Moncada S, Vane JR: The role of prostacyclin in 

vascular tissue. Fed Proc 38:66, 1979. 

23. Preston FE, Whipps S, Jackson CA, et al: Inhibition 

of prostacyclin and platelet thromboxane A2 after 

low-dose aspirin. N Engl J Med 304:76, 1981. 

24. Clarke RJ, Mayo G, Price P, et al: Suppression of 

thromboxane A 2 but not of systemic prostacyclin by 

controlled-release aspirin. N Engl J Med 324:1137, 

1991. 

25. Taylor DW, Barnett HJ, Haynes RB, et al: Low-dose 

and high-dose acetylsalicylic acid for patients undergoing 

carotid endarterectomy: A randomised 

controlled trial. ASA and Carotid Endarterectomy 

(ACE) Trial Collaborators. Lancet 353:2179, 1999. 

25a. Rothwell PM, Wilson M, Elwin CE, et al: Long-term 

effect of aspirin on colorectal cancer incidence and 

mortality: 20 year follow-up of five randomised trials. 

Lancet 376: 1741, 2010. 

26. Cipollone F, Rocca B, Patrono C: Cyclooxygenase 

2 expression and inhibition in atherothrombosis. 

Arterioscler Thromb Vasc Biol 24: 246, 2004. 

27. Berger JS, Brown DL, Becker RC: Low-dose aspirin 

in patients with stable cardio-vascular disease: a 

meta-analysis. Am J Med 121: 43, 2008. 

28. Ridker PM, Manson JE, Graziano M, et al: Lowdose 

aspirin therapy for chronic stable angina: A 

randomized, placebo-controlled clinical trial. Ann 

Intern Med 114:835, 1991. 

29. Chesebro JH, Webster MWI, Smith HC, et al: Antiplatelet 

therapy in coronary disease progression: 

Reduced infarction and new lesion formation. Circulation 

80 (Suppl 11):266, 1989. 

30. Juul-Moller S, Edvardsson N, Jahnmatz B, et al: 

Double-blind trial of aspirin in primary prevention 

of myocardial infarction in patients with 

stable chronic angina pectoris. The Swedish Angina 

Pectoris Aspirin Trial (SAPAT) Group. Lancet 

340:1421, 1992. 

30a. O’Connor RE, Brady W, Brooks SC, et al: Part 10: 

acute coronary syndromes. 2010 American Heart 

Association Guidelines for Cardiopulmonary Re- 

suscitation and Emergency Cardiovascular Care. 

Circulation 122 Suppl 3: S787, 2010. 

31. Lewis HD, Davis JW, Archibald DG, et al: Protective 

effects of aspirin against myocardial infarction 

and death in men with unstable angina. N Engl J 

Med 309:396, 1983. 

32. Cairns JA, Gent M, Singer J, et al: Aspirin, sulfinpyrazone, 

or both in unstable angina. N Engl J Med 

313:1369, 1985. 

33. Theroux P, Quimet H, McCans J, et al: Aspirin, 

heparin, or both to treat acute unstable angina. N 

Engl J Med 320:1014, 1989. 

34. The RISC Group: Risk of myocardial infarction and 

death during treatment with low-dose aspirin and 

intravenous heparin in men with unstable coronary 

artery disease. Lancet 336:827, 1990. 

35. Manson JE, Grobbee DE, Stampfer MJ, et al: Aspirin 

in the primary prevention of angina pectoris in 

a randomized trial of United States physicians. Am 

J Med 89:772, 1990. 

36. Steering Committee of the Physicians’ Health Study 

Research Group: Final report on the aspirin component 

of the ongoing Physicians’ Health Study. N 

Engl J Med 321:129, 1989. 

37. Peto R, Gray R, Collins R, et al: Randomized trial of 

prophylactic daily aspirin in British male doctors. 

BMJ 296:313, 1988. 

38. Fowkes FGR, Price JF, Stewart MCW, et al for the 

Aspirin for Asymptomatic Atherosclerosis Trialists: 

Aspirin for the prevention of cardiovascular 

events in a general population screened for a low 

ankle brachial index: a randomized controlled trial. 

JAMA 303: 841, 2010. 

39. Manson JE, Stampfer MJ, Colditz GA, et al: A prospective 

study of aspirin use and primary prevention 

of cardiovascular disease in women. JAMA 

266:521, 1991. 

40. Ridker PM, Cook NR, Lee IM, et al: A randomized 

trial of low-dose aspirin in the primary prevention 

of cardiovascular disease in women. N Engl J Med 

352: 1293, 2005. 

41. Wolff T, Miller T, Ko S: Aspirin for the primary 

prevention of cardiovascular events: an update of 

the evidence for the U.S. Preventive Services Task 

Force. Ann Intern Med 150: 405, 2009. 

42. U.S. Preventive Services Task Force: Aspirin for the 

prevention of cardiovascular disease: U.S. Preventive 

Services Task Force recommendation statement. 

Ann Intern Med 150: 396, 2009. 

43. Greving JP, Buskens E, Koffjberg H, Algra A: Costeffectiveness 

of aspirin treatment in the primary 

prevention of cardiovascular disease events in subgroups 

based on age, gender and varying cardiovascular 

risk. Circulation 117: 2875, 2008.

44. Berger JS, Roncaglioni MC, Avanzini F, et al: Aspirin 

for the primary prevention of cardiovascular 

events in women and men. A sex-specific 

meta-analysis of randomized controlled trials. 

JAMA 295: 306, 2006. 

45. de Gaetano G: Collaborative Group of the Primary 

Prevention Project (PPP): Low-dose aspirin and 

vitamin E in people at cardiovascular risk: A randomised 

trial in general practice. Lancet 357:89, 

2001. 

46. Antithrombotic Trialists’ (ATT) Collaboration: 

Aspirin in the primary and secondary prevention 

of vascular disease: collaborative meta-analysis of 

individual participant data from randomized trials. 

Lancet 373: 1849, 2009. 

47. Berger JS: Aspirin for preventive therapy in patients 

with asymptomatic vascular disease (editorial). 

JAMA 303: 880, 2010. 

48. Jackson EA, Sivasubramian R, Spencer FA, et al: 

Changes over time in the use of aspirin in patients 

hospitalized with acute myocardial infarction 

(1975-1977): A population-based prospective. Am 

Heart J 144:259, 2002. 

49. The Persantine-Aspirin Reinfarction Study Research 

Group: Persantine and aspirin in coronary 

artery disease. Circulation 62:449, 1980. 

50. The Aspirin Myocardial Infarction Study Research 

Group: The aspirin myocardial infarction study: final 

results. Circulation 62 (Suppl V):V79, 1980. 

51. Breddin K, Loew D, Lechner K, et al: The German- 

Austrian Aspirin Trial: A comparison of acetylsalicylic 

acid, placebo and phenprocoumon in 

secondary prevention of myocardial infarction. 

Circulation 62(Suppl V):V63, 1980. 

52. Elwood PC, Cochrane AL, Burr ML, et al: A randomized 

controlled trial of acetylsalicylic acid in 

the secondary prevention of mortality from myocardial 

infarction. Br Med J 1:436, 1974. 

53. Elwood PC, Sweetnam PM: Aspirin and secondary 

mortality after myocardial infarction. Circulation 

62(Suppl V):V53, 1980. 

54. The Coronary Drug Project Research Group: Aspirin 

in coronary heart disease. Circulation 62(Suppl 

V):V59, 1980. 

55. Climt CR, Knatterud GL, Stamler J: Persantine- 

Aspirin Reinfarction Study II. Secondary coronary 

prevention with persantine and aspirin. J Am Coll 

Cardiol 7:251, 1986. 

56. Aspirin after myocardial infarction. Lancet 1:1172, 

1980. 

57. Goldstein RE, Andrews M, Hall W, et al: Marked 

reduction in long-term cardiac deaths with aspirin 

after a coronary event. J Am Coll Cardiol 28:326, 

1996. 


58. ACC/AHA Guidelines for the Management of Patients 

with ST Elevation Myocardial Infarction. A 

Report of the American College of Cardiology/ 

American Heart Association Task Force on Practice 

Guidelines (Committee to Revise the 1999 

Guidelines for the Management of Patients with 

Acute Myocardial Infarction). Circulation 110:3- 

82, 2004. 

59. Hart RG, Halperin JL, McBride R, et al: Aspirin for 

the primary prevention of stroke and other major 

vascular events: Meta-analysis and hypotheses. 

Arch Neurol 57:306, 2000. 

60. De Wood MA, Spores J, Notske R, et al: Prevalence 

of total coronary occlusion during the early hours 

of transmural infarction. N Engl J Med 303:897, 

1980. 

61. Fitzgerald DJ, Catella R, Roy L, et al: Marked platelet 

activation in vivo after intravenous streptokinase 

in patients with acute myocardial infarction. 


62. ISIS-2 (Second International Study of Infarct Survival) 

Collaborative Group: Randomized trial of 

intravenous streptokinase, oral aspirin, both, or 

neither among 17,187 cases of suspected acute 

myocardial infarction: ISIS-2. Lancet 2:349, 1988. 

63. Patrono C, Baigent C, Hirsh J, Roth G: Antiplatelet 

drugs. ACCP evidence-based clinical practice 

guidelines 8th ed. Chest 133 (Suppl): 199S, 2008. 

64. Frishman WH, Chiu R, Landzberg BR, Weiss M: 

Medical therapies for the prevention of restenosis 

after percutaneous coronary interventions. Curr 

Probl Cardiol 23:533, 1998. 

65. Lam JYT, Chesebro JH, Steel PM, et al: Is vasopressin 

related to platelet deposition? Relationship in a 

porcine preparation of arterial injury in vivo. Circulation 

75:243, 1987. 

66. White CW, Chaitman B, Ticlopidine Study Group: 

Antiplatelet agents are effective in reducing the immediate 

complications of PTCA: Results from the 

ticlopidine multicenter trial (abstr.). Circulation 

76(Suppl IV):IV-400, 1987. 

67. Schwartz L, Bourassa MG, Lesperance J, et al: Aspirin 

and dipyridamole in the prevention of restenosis 

after percutaneous transluminal coronary 

angioplasty. N Engl J Med 318:1714, 1988. 

68. Barnathan ES, Schwartz JS, Taylor L, et al: Aspirin 

and dipyridamole in the prevention of acute coronary 

thrombosis complicating coronary angioplasty. 


69. Muller C, Buttner HJ, Petersen J, Roskamm H: A 

randomized comparison of clopidogrel and aspirin 

versus ticlopidine and aspirin after the placement 

of coronary-artery stents. Circulation 101(6):590, 

2000.


70. Lytle W, Loop FD, Cosgrove DM, et al: Long-term 

(5 to 12 years) serial studies of internal mammary 

artery and saphenous vein coronary bypass grafts. J 


71. Spray TL, Roberts WC: Changes in saphenous 

veins used as aortocoronary bypass grafts. Am 

Heart J 94:500, 1977. 

72. Brown BG, Cukingnan RA, DeRouen T, et al: 

Improved graft patency in patients treated with 

platelet-inhibiting therapy after coronary bypass 

surgery. Circulation 72:138, 1985. 

73. Chesebro JH, Fuster V, Elveback LR, et al: Effect of 

dipyridamole and aspirin on late vein-graft patency 

after coronary artery bypass operations. N Engl J 

Med 310:209, 1984. 

74. Goldman S, Copeland J, Moritz T, et al: Improvement 

in early saphenous vein graft patency after 

coronary artery bypass surgery with antiplatelet 

therapy: Results of a Veterans Administration Cooperative 


75. Goldman S, Copeland J, Moritz T, et al: Saphenous 

vein graft patency 1 year after coronary artery bypass 

surgery and effects of antiplatelet therapy: 

Results of a Veterans Administration Cooperative 


76. Goldman S, Zadina K, Krasnicka B, et al: Predictors 

of graft patency 3 years after coronary artery 

bypass graft surgery. Department of Veterans Affairs 

Cooperative Study Group No. 297. J Am Coll 

Cardiol 29:1563, 1997. 

77. Yli-Mayry S, Huikuri HV, Korhonen UR, et al: Efficacy 

and safety of anticoagulant therapy started 

pre-operatively in preventing coronary vein graft 

occlusion. Eur Heart J 14(5):723, 1993. 

78. Gavaghan TP, Gebski V, Baron DW: Immediate 

postoperative aspirin improves vein graft patency 

early and late after coronary artery bypass graft 

surgery. A placebo-controlled, randomized study. 

Circulation 83(5):1526, 1991. 

79. Antiplatelet Trialist’s Collaboration: Collaborative 

overview of randomized trials of antiplatelet 

therapy-I: Prevention of death, myocardial infarction, 

and stroke by prolonged antiplatelet therapy 

in various categories of patients. BMJ 308:81, 1994. 

80. The UK-TIA Study Group: United Kingdom Transient 

Ischemic Attack aspirin trial: Final results. J 

Neurol Neurosurg Psychiatry 54:1044, 1991. 

81. Fed Reg 63:56802, 66015, 1998. 

82. CAPRIE Steering Committee: A randomised, 

blinded, trial of clopidogrel versus aspirin in patients 

at risk of ischaemic events (CAPRIE). Lancet 

348:1329, 1996. 

83. Diener HC, Cunha L, Forbes C, et al: European 

Stroke Prevention Study. 2. Dipyridamole and 

acetylsalicylic acid in the secondary prevention of 

stroke. J Neurol Sci 143(1-2):1, 1996. 

84. Wahl DG, Bounameaux H, de Moerloose P, Sarasin 

FP: Prophylactic antithrombotic therapy for patients 

with systemic lupus erythematosus with or 

without antiphospholipid antibodies. Do the benefits 

outweigh the risks? A decision analysis. Arch 

Intern Med 160:2042, 2000. 

85. Pulmonary Embolism Prevention (PEP) Trial Collaborative 

Group: Prevention of pulmonary embolism 

and deep venous thrombosis with low-dose 

aspirin: Pulmonary Embolism Prevention (PEP) 

Trial. Lancet 355:1295, 2000. 

86. Peterson P, Boysen G, Godfredsen J, et al: Placebocontrolled 

randomized trial of warfarin and aspirin 

for prevention of thromboembolic complications 

in chronic atrial fibrillation: The Copenhagen 

AFASAK Study. Lancet 1:175, 1989. 

87. The Stroke Prevention in Atrial Fibrillation Investigators: 

A comparison of warfarin with aspirin for 

prevention of thromboembolism in atrial fibrillation: 

Results of the SPAFII Study. Lancet 343:687, 

1994. 

88. Golzari H, Cebul RD, Bahler RC: Atrial fibrillation 

restoration and maintenance of sinus rhythm and 

indications for anticoagulation therapy. Ann Intern 

Med 125:311, 1996. 

89. Yasaka M, Yamaguchi T: Secondary prevention of 

stroke in patients with nonvalvular atrial fibrillation: 

optimal intensity of anticoagulation. CNS 

Drugs 15: 623, 2001. 

90. Warfarin Antiplatelet Vascular Evaluation Trial 

Investigators: Oral anticoagulant and anti-platelet 

therapy and peripheral arterial disease. N Engl J 

Med 357: 217, 2007. 

91. Mohler ER III: Atherothrombosis – wave goodbye 

to combined anticoagulation and anti-platelet therapy? 

N Engl J Med 357: 293, 2007. 

92. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR: Aspirin 

for the prevention of cardio-vascular events 

in patients with peripheral artery disease. A metaanalysis 

of randomized trials. JAMA 301: 1909, 

2009. 

93. Catella-Lawson F, Crofford LJ: Cyclooxygenase inhibition 

and thrombogenicity. Am J Med 110(Suppl 

3A):28S, 2001. 

93a. Fosslien E: Cardiovascular complications of nonsteroidal 

anti-inflammatory drugs. Ann Clin Lab 

Sci 35: 347, 2005. 

94. Jhund PS, Davie AP, McMurray JJV: Aspirin inhibits 

the acute venodilator response to furosemide in 

patients with chronic heart failure. J Am Coll Cardiol 

37:1234, 2001. 

95. Hanjis C, Frishman WH, Lerner RG: Aspirin resis-

tance. Mechanisms and clinical implications. Cardiol 

in Rev 14: 18, 2006. 

96. Gurbel PA, Bliden KP, DiChiara J, et al: Evaluation 

of dose-related effects of aspirin on platelet function. 

Results from the Aspirin-Induced Platelet Effect 

(ASPECT) study. Circulation 115: 3156, 2007. 

97. Cuisset T, Frere C, Quilici J, et al: Aspirin noncompliance 

is the major cause of “aspirin resistance” in 

patients undergoing coronary stenting. Am Heart J 

157: 889, 2009. 

98. Braunwald E, Angiolillo D, Bates E, et al: Investigating 

the mechanisms of hyporesponse to antiplatelet 

approaches. Clin Cardiol 31 (suppl 1): I-21, 

2008. 

99. Gladding P, Webster M, Ormiston J, et al: Antiplatelet 

drug nonresponsiveness. Am Heart J 155: 

591, 2008. 

100. Braunwald E, Angiolillo D, Bates E, et al: Assessing 

the current role of platelet function testing. Clin 

Cardiol 31 (Suppl 1): I-10, 2008. 

101. Gurbel PA, Becker RC, Mann KG, et al: Platelet 

function monitoring in patients with coronary artery 

disease. J Am Coll Cardiol 50: 1822, 2007. 

102. Fusitani RM, Merdestgaard AG, Marcus CS, et al: 

Perioperative suppression of platelet adherence to 

small diameter polytetrafluoroethylene grafts. J 

Surg Res 44:455, 1998. 

103. Best LC, McGuire MB, Jones PBB, et al: Mode of 

action of dipyridamole on human platelets. Thromb 

Res 16:367, 1979. 

104. Mehta J, Mehta P, Pepine CJ, et al: Platelet function 

studies in coronary artery disease. Effect of dipyridamole. 

Am J Cardiol 47:1111, 1981. 

105. Cructhley DJ, Ryan JW: Effects of aspirin and dipyridamole 

on the degradation of adenosine diphosphate 

by cultured cells derived from bovine 

pulmonary artery. J Clin Invest 66:29, 1989. 

106. Salem DN, O’Gara PT, Madias C, Pauker SG: Valvular 

and structural heart disease. ACCP evidencebased 

clinical practice guidelines 8th ed. Chest 

133(Suppl):593S, 2008. 

107. Pumphrey CW, Chesebro JH, Dewanjee MK: In 

vivo quantitation of platelet deposition on human 

peripheral arterial bypass grafts using indium-111labeled 

platelets. Am J Cardiol 51:796, 1983. 

108. Dixon BS, Beck GJ, Vazquez MA, et al for the DAC 

study group: Effect of dipyridamolde plus aspirin 

on hemodialysis graft patency. N Engl J Med 360: 

2191, 2009. 

109. Diener HC, Cunha L, Forbes C, et al: European 

Stroke Prevention Study. Dipyridamole and acetylsalicylic 

acid in the secondary prevention of stroke. 

J Neurol Sci 143: 1, 1996. 

110. Schwartz L, Bourassa MG, Lesperance J, et al: As- 


pirin and dipyridamole in the prevention of restenosis 

after percutaneous transluminal coronary 

angioplasty. N Engl J Med 318:1714, 1988. 

111. DiMinno G, Cerbone Am, Mattioli PM, et al: Functionally 

thromboasthenic state in normal platelets 

following the administration of ticlopidine. J Clin 

Invest 75:328, 1985. 

112. Gent M, Blakely JA, Easton JD, et al: The Canadian 

American Ticlopidine Study in thromboembolic 

stroke. Lancet I:1215, 1989. 

113. Hass WK, Easton JD, Adams HP, et al:. A randomized 

trial comparing ticlopidine hydrochloride 

with aspirin for the prevention of stroke in high 

risk patients. N Engl J Med 321:501, 1989. 

114. Janzon L, Bergqvist D, Boberg J, et al: Prevention of 

myocardial infarction and stroke in patients with 

intermittent claudication: Effects of ticlopidine: 

Results from STIMS, the Swedish Ticlopidine Multicenter 

Study. J Intern Med 227:301, 1990. 

115. Limet R, David JL, Magotteau P, et al: Prevention 

of aorta-coronary bypass graft occlusion. Beneficial 

effect of ticlopidine on early and late patency rates 

of venous coronary bypass surgery grafts: A double-blind 

study. J Thorac Cardiovasc Surg 94:773, 

1987. 

116. Balsano F, Rizzon P, Violi F, et al: Antiplatelet treatment 

with ticlopidine in unstable angina: a controlled 

multicenter trial. Circulation 82:17, 1990. 

117. Schomig A, Neumann FJ, Kastrati A, et al: A randomized 

comparison of antiplatelet and anticoagulant 

therapy after the placement of coronary artery 

stents. N Engl J Med 334:1084, 1996. 

118. Steinhubl SR, Ellis SG, Wolski K, et al, for the 

EPISTENT Investigators: Ticlopidine pretreatment 

before coronary stenting is associated with 

sustained decrease in adverse cardiac events. Data 

from the Evaluation of Platelet IIb/IIIa inhibitor for 

Stenting (EPISTENT) Trial. Circulation 103:1403, 

2001. 

119. Scrutinio D, Cimminiello C, Marubini E, et al, on 

behalf of the STAMI Group: Ticlopidine versus aspirin 

after myocardial infarction (STAMI) trial. J 


120. Marco J, Ariens RAS, Fajadet J, et al: Effect of aspirin 

and ticlopidine on plasma tissue factor levels in 

stable and unstable angina pectoris. Am J Cardiol 

85:527, 2000. 

121. Steinhubl SR, Tan WA, Foody JM, Topol EJ: Incidence 

and clinical course of thrombotic thrombocytopenic 

purpura due to ticlopidine following 

coronary stenting. EPISTENT Investigators. Evaluation 

of Platelet IIb/IIIa Inhibitor for Stenting. 

JAMA 281:806, 1999. 

122 Taniuchi M, Kurz HI, Lasala JM: Randomized


comparison of ticlopidine and clopidogrel after intracoronary 

stent implantation in a broad patient 

population. Circulation 104:539, 2001. 

123. Jarvis B, Simpson K: Clopidogrel. A review of its 

use in the prevention of atherosclerosis. Drugs 

60:347, 2000. 

124. Lerner RG, Frishman WH, Mohan KT: Clopidogrel. 

A new antiplatelet drug. Heart Dis 2:168, 2000. 

125 Saw J, Madsen EH, Chan S, Maurer-Spurej E: The 

ELAPSE (Evaluation of Long-Term Clopidogrel 

Antiplatelet and Systemic Anti-Inflammatory Effects) 

study. J Am Coll Cardiol 52: 1826, 2008. 

126. Moshfegh K, Redondo M, Julmy F, et al: Antiplatelet 

effects of clopidogrel compared with aspirin 

after myocardial infarction: Enhanced inhibitory 

effects of combination therapy. J Am Coll Cardiol 

36:699, 2000. 

127. Mehta SR, Yusuf S, Peters RJG, et al, for the Clopidogrel 

in Unstable angina to prevent Recurrent 

Events trial (CURE) Investigators. Effects of pretreatment 

with clopidogrel and aspirin followed 

by long-term therapy in patients undergoing percutaneous 

coronary intervention: The PCI-CURE 

study. Lancet 358:527, 2001. 

128. The Clopidogrel in Unstable Angina to Prevent Recurrent 

Events Trial Investigators. Effects of clopidogrel 

in addition to aspirin in patients with acute 

coronary syndromes without ST-segment elevation. 

N Engl J Med 345:494, 2001. 

129. Sabatine MS, Cannon CP, Gibson CM, et al for 

the CLARITY-TIMI 28 Investigators: Addition of 

clopidogrel to aspirin and fibrinolytic therapy for 

myocardial infarction with ST-segment elevation. 

N Engl J Med 352: 1179, 2005. 

130. Hughes S: COMMIT trial confirms clopidogrel 

benefit in MI. Available at http:///www.theheart. 

org/printarticle.do?primarykey-401761. Accessed 

March 10, 2005. 

131. Berger PB, Bell MR, Rihal CS, et al: Clopidogrel 

versus ticlopidine after intracoronary stent placement. 


132. Bertrand ME, Rupprecht H-J, Urban P, et al, for 

the CLASSICS Investigators: Double-blind study of 

the safety of clopidogrel with and without a loading 

dose in combination with aspirin compared 

with ticlopidine in combination with aspirin after 

coronary stenting. The Clopidogrel Aspirin Stent 

International Cooperative Study (CLASSICS). Circulation 

102:624, 2000. 

133. Banerjee S, Varghese C, Samuel J, et al: Comparison 

of the impact of short (1 year) clopidogrel use following percutaneous 

coronary intervention on mortality. Am J Cardiol 

102: 1159, 2008. 

133a. Park SJ, Park DW, Kim YH, et al: Duration of dual 

antiplatelet therapy after implantation of drugeluting 

stents. N Engl J Med 362: 1374, 2010. 

133b. Berger PB: Optimal duration of clopidogrel use 

after implantation of drug-eluting stents – still in 

doubt. N Engl J Med 362: 1441, 2010. 

134. Ho PM, Peterson ED, Wang L, et al: Incidence of 

death and acute myocardial infarction associated 

with stopping clopidogrel after acute coronary syndrome. 

JAMA 299: 532, 2008. 

135. Patel JH, Stoner JA, Owora A, et al: Evidence for 

using clopidogrel alone or in addition to aspirin in 

post coronary artery bypass surgery patients. Am J 

Cardiol 103: 1687, 2009. 

136. The ACUITY Trial: Outcomes following pre-operative 

clopidogrel administration in patients with 

acute coronary syndromes undergoing coronary 

artery bypass surgery. J Am Coll Cardiol 53: 1965, 

2009. 

137. Bhatt DL, Fox KAA, Werner-Hacke ChB, et al for 

the CHARISMA Investigators: Clopidogrel and 

aspirin versus aspirin alone for the prevention of 

atherothrombotic events. N Engl J Med 354: 1706, 

2006. 

138. Sacco RL, Diener H-C, Yusuf S, et al for the PRo- 

FESS Study Group: Aspirin and extended-release 

dipyridamole versus clopidogrel for recurrent 

stroke. N Engl J Med 359: 1238, 2008. 

139. The ACTIVE Investigators: Effect of clopidogrel 

added to aspirin in patients with atrial fibrillation. 

N Engl J Med 360: 2066, 2009. 

140. The ACTIVE Writing Group on behalf of the AC- 

TIVE Investigators: Clopidogrel plus aspirin versus 

oral anticoagulation for atrial fibrillation in the 

Atrial Fibrillation Clopidogrel Trial with Irbesartan 

for Prevention of Vascular Events (ACTIVE 

W): a randomised controlled trial. Lancet 367: 

1903, 2006. 

140a. Paikin JS, Wright DS, Crowther MA, et al: Triple 

antithrombotic therapy in patients with atrial fibrillation 

and coronary artery stents. Circulation 

121: 2067, 2010. 

141. Nguyen T, Frishman WH, Nawarskas J, Lerner 

RG: Variability of response to clopidogrel. Possible 

mechanisms and clinical implications. Cardiol in 

Rev 14: 136, 2006. 

142. Yong G, Rankin J, Ferguson L, et al: Randomized 

trial comparing 600 with 300 mg loading dose of 

clopidogrel in patients with non-ST elevation acute 

coronary syndrome undergoing percutaneous coronary 

intervention: results of the Platelet Responsiveness 

to Aspirin and Clopidogrel and Troponin 

Increment after Coronary Intervention in Acute 

Coronary Lesions (PRACTICAL) trial. Am Heart

J 157: e1, 2009. 

143. Bonello L, Camoin-Jau L, Armero S, et al: Tailored 

clopidogrel loading dose according to platelet reactivity 

monitoring to prevent acute and subacute 

stent thrombosis. Am J Cardiol 103; 5, 2009. 

144. Bonello L, Lemesle G, De Labriolle A, et al: Impact 

of a 600 mg loading dose of clopidogrel on 30 day 

outcome in unselected patients undergoing percutaneous 

coronary intervention. Am J Cardiol 102: 

1318, 2008. 

145. Gladding P, Webster M, Zeng I, et al: The antiplatelet 

effect of higher loading and maintenance dose 

regimens of clopidogrel. The PRINC (Plavix Response 

in Coronary Intervention) trial. J Am Coll 

Cardiol Intervent 1: 612, 2008. 

146. Aleil B, Jacquemin L, DePoli F, et al: Clopidogrel 

150 mg/day to overcome low responsiveness in patients 

undergoing elective percutaneous coronary 

intervention. J Am Coll Cardiol Intervent 1: 631, 

2008. 

147. von Beckerath N, Kastrati A, Wieczorek A, et al: A 

double-blind, randomized study on platelet aggregation 

in patients treated with a daily dose of 150 

or 75 mg of clopidogrel for 30 days. Eur Heart J 28: 

1814, 2007. 

148. Cuisset T, Frere C, Quilici J: Benefit of a 600 mg 

loading dose of clopidogrel on platelet reactivity 

and clinical outcomes in patients with non-ST segment 

elevation acute coronary syndrome undergoing 

coronary stenting. J Am Coll Cardiol 48: 1339, 

2006. 

149. Patti G, Colonna G, Pasceri V, et al: Randomized 

trial of high loading dose of clopidogrel for reduction 

of periprocedural myocardial infarction in 

patients undergoing coronary intervention. Results 

from the ARMYDA-2 (Antiplatelet therapy for reduction 

of myocardial damage during angioplasty) 

study. Circulation 111: 2099, 2005. 

150. Dangas G, Mehran R, Guagliumi G, et al for the 

HORIZONS-AMI Trial Investigators: role of clopidogrel 

loading dose in patients with ST-segment elevation 

myocardial infarction undergoing primary 

angioplasty. J Am Coll Cardiol 54: 1438, 2009. 

150a. Mehta SR, Bassand JP, Chrolavicius S, et al: Dose 

comparisons of clopidogrel and aspirin in acute 

coronary syndromes. N Engl J Med 363: 930, 2010. 

150b. Mehta SR, Tanguay J-F, Eikelboom JW, e tal: Double-dose 

versus standard-dose clopidogrel and 

high-dose versus low-dose aspirin in individuals 

undergoing percutaneous coronary intervention 

for acute coronary syndromes (CURRENT-OA- 

SIS7): a randomised factorial trial. Lancet 376: 

1233, 2010. 

151. Saw J, Steinhubl SR, Berger PB, et al: Lack of ad- 


verse clopidogrel-atorvastatin clinical interaction 

from secondary analysis of a randomized, placebocontrolled 

clopidogrel trial. Circulation 108: 921, 

2003. 

152. Gilard M, Arnaud B, Cornily J-C, et al: Influence 

of omeprazole on the antiplatelet action of clopidogrel 

associated with aspirin. J Am Coll Cardiol 51: 

256, 2008. 

153. PPI interactions with clopidogrel revisited. The 

Medical Letter 51: 13, 2009. 

154. Khalique SC, Cheng-Lai A: Drug interaction between 

clopidogrel and proton pump inhibitors. 


154a. Gaglia MA, Waksman R: Proton pump inhibitors 

and clopidogrel. Cardiovasc Therap epub March 25, 

2010. 

154b. Ray WA, Murray KT, Griffin MR, et al: Outcomes 

with concurrent use of clopidogrel and protonpump 

inhibitors: a cohort study. Ann Intern Med 

152: 337, 2010. 

155. O’Donoghue ML, Braunwald E, Antman EM, et 

al: Phamacodynamic effect and clinical efficacy of 

clopidogrel and prasugrel with or without a proton 

pump inhibitor: an analysis of two randomised trials. 

Lancet 374: 989, 2009. 

155a. Bhatt DP, Cryer BL, Contant CF, et al: Clopidogrel 

with or without omeprazole in coronary artery disease. 

N Engl J Med 363: 1909, 2010. 

155b. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S: 

Cardiovascular outcomes and mortality in patients 

using clopidogrel with proton pump inhibitors after 

percutaneous coronary intervention or acute 

coronary syndrome. Circulation 120: 2322, 2009. 

156. Simon T, Verstuyft C, Mary-Krause M, et al: Genetic 

determinants of response to clopidogrel and 

cardiovascular events. N Engl J Med 360: 363, 2009. 

157. Mega JL, Close SL, Wiviott SD, et al: Cytochrome 

P450 polymorphisms and response to clopidogrel. 

N Engl J Med 360: 354, 2009. 

158. Shuldiner AR, O’Connell JR, Bliden KP, et al: Association 

of cytochrome P450 2C19 genotype with 

the antiplatelet effect and clinical efficacy of clopidogrel 

therapy. JAMA 302: 849, 2009. 

159. Roden DM, Stein CM: Clopidogrel and the concept 

of high-risk pharmacokinetics. Circulation 119: 

2127, 2009. 

160. Freedman JE, Hylek EM: Clopidogrel, genetics and 

drug responsiveness. N Engl J Med; 360: 411, 2009. 

160a. Mega JL, Close SL, Wiviott SD, et al: Genetic variants 

in ABCB1 and CYP2C19 and cardiovascular 

outcomes after treatment with clopidogrel and prasugrel 

in the TRITON-TIMI38 trial: a pharmacogenetic 

analysis. Lancet 376: 1312, 2010. 

160b. Wiviott SD, Mega JL: Another step on the road to


tailored antiplatelet therapy (editorial comment): J 


160c. Mega JL, Simon T, Collet J-P, et al: Reduced function 

CYP2C19 genotype and risk of adverse clinical 

outcomes among patients treated with clopidogrel 

predominantly for PCI. JAMA 304: 1821, 2010. 

161. Duggan ST, Keating GM: Prasugrel: a review of 

its use in patients with acute coronary syndromes 

undergoing percutaneous coronary intervention. 

Drugs 69: 1707, 2009. 

162. Koo MH, Nawarskas JJ, Frishman WH: Prasugrel. 

A new antiplatelet drug for the prevention and 

treatment of cardiovascular disease. Cardiol in Rev 

16: 314, 2008. 

162a. Wiviott SD, Antman EM, Braunwald E: Prasugrel. 

Circulation 122: 394, 2010. 

163. Jakubowski J, Payne C, Brandt J, et al. The platelet 

inhibitory effects and pharmacokinetics of prasugrel 

after administration of loading and maintenance 

doses in healthy subjects. J Cardiovasc 

Pharmacol 47:377, 2006. 

164. Farid NA, Payne CD, Ernest II CS, et al: Prasugrel, 

a new thienopyridine antiplatelet drug, weakly 

inhibits cytochrome P450 2B6 in humans. J Clin 

Pharmacol 48: 53. 2008. 

165. Weerakkody GJ, Jakubowski JA, Brandt JT, et al. 

Comparison of speed of onset of platelet inhibition 

after loading doses of clopidogrel versus prasugrel 

in healthy volunteers and correlation with responder 

status. Am J Cardiol 100: 331, 2007. 

166. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel 

achieves greater inhibition of platelet aggregation 

and a lower rate of non-responders compared with 

clopidogrel in aspirin-treated patients with stable 

coronary artery disease. Eur Heart J 27:1166, 2006. 

167. Brandt JT, Payne CD, Wiviott SD, et al. A comparison 

of prasugrel and clopidogrel loading doses on 

platelet function: magnitude of platelet inhibition 

is related to active metabolite formation. Am Heart 

J 153:66-e9, 2007. 

168. Payne CD, Li YG, Small DS, et al: Increased active 

metabolite formation explains the greater platelet 

inhibition with prasugrel compared to high-dose 

clopidogrel. J Cardiovasc Pharmacol 50: 555, 2007. 

169. Wiviott SD, Antman EM, Winters KJ, et al. Randomized 

comparison of prasugrel, a novel thienopyridine 

P2Y12 antagonist, with clopidogrel in 

percutaneous coronary intervention. Results of the 

Joint Utilization of Medications to Block Platelets 

Optimally (JUMBO) TIMI-26 trial. Circulation 

111:3366, 2005. 

170. Wiviott SD, Antman EM, Gibson M, et al. Evaluation 

of prasugrel compared with clopidogrel in patients 

with acute coronary syndromes: design and 

rationale for the Trial to Assess Improvement in 

Therapeutic Outcomes by Optimizing Platelet Inhibition 

with Prasugrel- Thrombolysis in Myocardial 

Infarction 38 (TRITON-TIMI 38). Am Heart J 

152:627, 2006. 

171. Wiviott SD, Braunwald E, McCabe, CH, et al. Prasugrel 

versus clopidogrel in patients with acute 


172 Wiviott SD, Braunwald E, Angiolillo DJ, et al for 

the TRITON-TIMI 38 Investigators: Greater clinical 

benefit of more intensive oral antiplatelet therapy 

with prasugrel in patients with diabetes mellitus 

in the trial to assess improvement in therapeutic 

outcomes by optimizing platelet inhibition with 

prasugrel-thrombolysis in myocardial infarction 

38. Circulation 118: 1626, 2008. 

173. Montalescot G, Wiviott SD, Braunwald E, et al 

for the TRITON-TIMI 38 Investigators: Prasugrel 

compared with clopidogrel in patients undergoing 

percutaneous coronary intervention for ST-elevation 

myocardial infarction TRITON-TIMI 38): 

double-blind randomised controlled trial. Lancet 

373: 723, 2009. 

174. Wiviott SD, Braunwald E, McCabe C, et al for the 

TRITON-TIMI 38 Investigators: Intensive oral antiplatelet 

therapy for reduction of ischaemic events 

including stent thrombosis in patients with acute 

coronary syndromes treated with percutaneous 

coronary intervention and stenting in the TRI- 

TON-TIMI 38 trial: a subanalysis of a randomised 

trial. Lancet 372: 1353, 2008. 

175. Unger EF: Weighing benefits and risks – the FDA’s 

review of prasugrel. N Engl J Med 361: 942, 2009. 

176. Wiviott SD, Trenk D, Frelinger AL, et al for the 

PRINCIPLE-TIMI 44 Investigators: Prasugrel 

compared with high loading- and maintenancedose 

clopidogrel in patients with planned percutaneous 

coronary intervention. The Prasugrel 

in Comparison to Clopidogrel for Inhibition of 

Platelet Activation and Aggregation-Thrombolysis 

in Myocardial Infarction 44 Trial. Circulation 116: 

2923, 2007. 

177. Gurbel PA, Becker RC, Mann KG, et al: Platelet 

function monitoring in patients with coronary artery 

disease. J Am Coll Cardiol 50: 1822, 2007. 

178. Bhatt DL: Prasugrel in clinical practice. N Engl J 

Med 361, 940, 2009. 

179. Antman EM, Wiviott SD, Murphy SA, et al: Early 

and late benefits of prasugrel in patients with acute 

coronary syndromes undergoing percutaneous 

coronary intervention. J Am Coll Cardiol 51: 2028, 

2008. 

180. O’Donoghue M, Antman EM, Braunwald E, et al: 

The efficacy and safety of prasugrel with and with-

out a glycoprotein IIb/IIIa inhibitor in patients 

with acute coronary syndromes undergoing percutaneous 

intervention. J Am Coll Cardiol 54: 678, 

2009. 

181. Mega JL, Close SL, Wiviott SD, et al: Cytochrome 

P450 genetic polymorphisms and the response to 

prasugrel. Circulation 199: 2553, 2009. 

182. Phillips DR, Charo IF, Scarborough RM: GPIIb- 

IIIa: The responsive integrin. Cell 65:359, 1991. 

183. Coller BS: Platelets and thrombolytic therapy. N 

Engl J Med 322:33, 1990. 

184. D’Souza SE, Ginsberg MH, Burke TA, Plow EF: Localization 

of an arg-gly-asp recognition site within 

an integrin adhesion receptor. Science 242:91, 1988. 

185. Frishman WH, Burns B, Atac B, et al: Novel antiplatelet 

therapies for treatment of patients with 

ischemic heart disease: Inhibitors of the platelet 

glycoprotein IIb/IIIa integrin receptor Am Heart J 

130:877, 1995. 

186. Lefkowitz J, Plow EF, Topol EJ: Platelet glycoprotein 

IIb/IIIa receptors in cardiovascular medicine. 

N Engl J Med 332:1553, 1995. 

187. Shebuski RJ, Stabilito IJ, Sitko GR, Polokoff MH: 

Acceleration of a recombinant tissue-type plasminogen 

activator-induced thrombolysis and prevention 

of reocclusion by the combination of heparin 

and the arg-gly-asp-containing peptide bitistatin in 

a canine model of coronary thrombosis. Circulation 

82:169, 1990. 

188. Yasuda T, Gold HF, Leinbach RC, Y et al: Kistrin, 

a polypeptide GPIIb/IIIa receptor antagonist, enhances 

and sustains coronary arterial thrombolysis 

with recombinant tissue-type plasminogen activator 

in a canine preparation. Circulation 83:1038, 

1991. 

189. Scarborough RM, Rose JW, Hsu MA, et al: Barbourin: 

A GPIIb/IIIa-specific integrin antagonist 

from the venom of Sistrurus M. barbouri. J Biol 

Chem 266:9359, 1991. 

190. Coller BS, Peerschke EI, Scudder LE, Sullivan CA: 

A murine monoclonal antibody that completely 

blocks the binding of fibrinogen to platelets produces 

a thrombasthenic-like state in normal platelets 

and binds to glycoproteins IIb and/or IIIa. J 

Clin Invest 72:325, 1983. 

191. Coller BS: A new murine monoclonal antibody 

reports an activation dependent change in the 

conformation and/or microenvironment of the 

glycoprotein IIb/IIIa complex. J Clin Invest 76:101, 

1985. 

192. Coller BS, Anderson K, Weisman HF: New antiplatelet 

agents: platelet GPIIb/IIIa antagonists. 

Thromb Haemost 74(1):302, 1995. 

193. Kohler G, Milstein C: Continuous cultures of fused 


cells secreting antibody of predefined specificity. 

Nature 2567:495, 1975. 

194. Faulds D, Sorkin EM. Abciximab (c7E3 Fab): A review 

of its pharmacology and therapeutic potential 

in ischemic heart disease. Drugs 48:583, 1994. 

195. Hanson SR, Pareti FI, Ruggeri ZM, et al: Effects of 

monoclonal antibodies against the platelet glycoprotein 

IIb/IIIa complex on thrombosis and hemostasis 

in the baboon. J Clin Invest 81:149, 1988. 

196. Gold HK, Gimple LW, Yasuda T, Coller BS: Pharmacodynamic 

study of F(ab’)2 fragments of murine 

monoclonal antibody 7E3 directed against 

human platelet glycoprotein IIb/IIIa in patients 

with unstable angina pectoris. J Clin Invest 86:651, 

1990. 

197. Bhattacharya S, Jordan R, Machin S, et al: Blockade 

of human platelet GP IIb/IIIa receptor by a murine 

monoclonal antibody Fab fragment (7E3): Potent 

dose-dependent inhibition of platelet function. 

Cardiovasc Drug Ther 9:665, 1995. 

198. Christopoulos C, Mackie I, Lahiri A, et al: Flow 

cytometric observations on the in vivo use of Fab 

fragments of a chimeric monoclonal antibody to 

platelet glycoprotein IIb-IIIa. Blood Coag Fibrinolysis 

4:729, 1993. 

199. Sweeney J, Holme S, Heaton A, et al: Infusion of a 

chimeric monoclonal Fab fragment (c7E3) against 

platelet glycoprotein IIb-IIIa potently inhibits 

platelet aggregation but does not affect in vivo 

platelet survival (abstr). J Am Coll Cardiol 21:253A, 

1993. 

200. Simoons ML, deBoer MJ, van den Brand MJBM, 

et al, and the European Cooperative Study Group: 

Randomized trial of GPIIb/IIIa platelet receptor 

blocker in refractory unstable angina. Circulation 

89:596, 1994. 

201. Kaplan AV, Leung LL-K, Leung W-H, et al: Roles 

of thrombin and platelet membrane glycoprotein 

IIb/IIIa in platelet-subendothelial deposition after 

angioplasty in an ex vivo whole artery model. Circulation 

84:1279, 1991. 

202. Tcheng JE, Ellis SG, George BS, et al: Pharmacodynamics 

of chimeric glycoprotein IIb/IIIa integrin 

antiplatelet antibody Fab 7E3 in high-risk coronary 

angioplasty. Circulation 90:1757, 1994. 

203. EPIC Investigators: Use of a monoclonal antibody 

directed against the platelet glycoprotein IIb/IIIa 

receptor in high-risk coronary angioplasty. N Engl 

J Med 330:956, 1994. 

204. Topol EJ, Califf RM, Weissman HF, et al, on behalf 

of EPIC Investigations. Randomized trial of coronary 

intervention with antibody against platelet 

IIb/IIIa integrin for reduction of clinical restenosis; 

results at six months. Lancet 343:881, 1994.


205. Coller BS: Anti-GPIIb/IIIa drugs: Current strategies 

and future directions. Thromb Haemost 86:427, 

2000. 

206. Dasgupta H, Blankenship JC, Wood GC, et al: 

Thrombocytopenia complicating treatment with 

intravenous glycoprotein IIb/IIIa receptor inhibitors: 

a pooled analysis. Am Heart J 140:206, 2000. 

207. Fredrickson BJ, Turner NA, Kleiman NS, et al: 

Effects of abciximab, ticlopidine, and combined 

abciximab/ticlopidine therapy on platelet and leukocyte 

function in patients undergoing coronary 

angioplasty. Circulation 101:1122, 2000. 

208. Lincoff AM: Results of the interim analysis of the 

EPILOG Trial. J Am Coll Cardiol 27(Suppl A):XXI, 

1996. 

209. Ferguson JJ: EPILOG and CAPTURE trials halted 

because of positive interim results. Circulation 

93:637, 1996. 

210. GUSTO IV-ACS Investigators: Effect of glycoprotein 

IIb/IIIa receptor blocker abciximab on outcome 

in patients with acute coronary syndromes 

without early coronary revascularisation. Lancet 

357:1915, 2001. 

211. Stone GW, Grines CL, Cox DA, et al: Comparison 

of angioplasty with stenting, with or without abciximab 

in acute myocardial infarction. N Engl J Med 

346:957, 2002. 

212. Gibson CM, deLemos J, Murphy SA et al, for the 

TIMI Study Group: Combination therapy with abciximab 

reduces angiographically evident thrombus 

in acute myocardial infarction. A TIMI 14 

substudy. Circulation 103:2550, 2001. 

213. The GUSTO V Investigators: Reperfusion therapy 

for acute myocardial infarction with fibrinolytic 

therapy or combination reduced fibrinolytic therapy 

and platelet glycoprotein IIb/IIIa inhibition: 

The GUSTO V randomised trial. Lancet 357:1905, 

2001. 

214. Cantor WJ, Kaplan AL, Velianou JL, et al: Effectiveness 

and safety of abciximab after failed thrombolytic 

therapy. Am J Cardiol 87:439, 2001. 

215. Montalescot G, Barragan P, Wittenberg O, et al, 

ADMIRAL Investigators: Platelet glycoprotein IIb/ 

IIIa inhibition with coronary stenting for acute 

myocardial infarction. N Engl J Med 344(25):1895, 

2001. 

216. Boden WE, McKay RG: Optimal treatment of acute 

coronary syndromes–-an evolving strategy. N Engl 

J Med 344(25):1939, 2001. 

217. Throckmorton DC: Future trials of antiplatelet 

agents in cardiac ischemia. N Engl J Med 344:1937, 

2001. 

218. Kastrati A, Mehilli J, Neumann F-J, et al: Abciximab 


undergoing percutaneous coronary intervention 

after clopidogrel pretreatment. The ISAR-REACT 

2 randomized trial. JAMA 295: 1531, 2006. 

219. Kastrati MJ, Schulz S, Früngel S, et al for the 

BRAVE-3 Study Investigators: Abciximab in patients 

with acute ST-segment elevation myocardial 

infarction undergoing primary percutaneous coronary 

intervention after clopidogrel loading: a randomized 

double-blind trial. Circulation 119: 1933, 

2009. 

220. Kouns WC, Kirchhofer D, Hadvary P, et al: Reversible 

conformational changes induced in 

glycoprotein IIb/IIIa by a potent and selective peptidomimetric 

inhibitor. Blood 80:2539, 1992. 

221. Nichols AJ, Ruffolo RR, Huffman WF, et al: Development 

of GP IIb/IIIa antagonists as antithrombotic 

drugs. Trends Pharmacol Sci 13:413, 1992. 

222. Goa KL, Noble S: Eptifibatide. A review of its use 

in patients with acute coronary syndromes and/or 


Drugs 57:439, 1999. 

222a. Akerblom A, James SK, Koutouzis M, et al: Eptifibatide 

is noninferior to abciximab in primary percutaneous 

coronary intervention. J Am Coll Cardiol 

56: 470, 2010. 

222b. Zeymer U, Margenet A, Haude M, et al: Randomized 

comparison of eptifibatide versus abciximab 

in primary percutaneous coronary intervention in 

patients with acute ST-segment elevation myocardial 

infarction. Results of the EVA-AMI Trial. J Am 

Coll Cardiol 56: 463, 2010. 

223. Schulman SP, Goldschmidt-Clermont PJ, Topol 

EJ, et al: Effects of integrelin, a platelet glycoprotein 

IIb/IIIa receptor antagonist, in unstable angina. 

A randomized multicenter trial. Circulation 

94(9):2083, 1996. 

224. Randomised placebo-controlled trial of effect 

of eptifibatide on complications of percutaneous 

coronary intervention: IMPACT-II. Integrilin 

to Minimise Platelet Aggregation and Coronary 

Thrombosis-II. Lancet 349(9063):1422, 1997. 

225. The ESPRIT Investigators: Novel dosing regimen of 

eptifibatide in planned coronary stent implantation 

(ESPRIT): A randomised, placebo-controlled trial. 

Lancet 356(9247):2037, 2000. 

226. O’Shea JC, Hafley GE, Greenberg S, et al, ESPRIT 

Investigators: Platelet glycoprotein IIb/IIIa integrin 

blockade with eptifibatide in coronary stent intervention: 

The ESPRIT trial: A randomized controlled 

trial. JAMA 285(19):2468, 2001. 

227. Kirtane AJ, Piazza G, Murphy SA, et al: Correlates 

of bleeding events among moderate-to high-risk 

patients undergoing percutaneous coronary intervention 

and treated with eptifibatide. Observations

from the PROTECT-TIMI-30 trial. J Am Coll Cardiol 

57: 2374, 2006. 

228. Fung AY, Saw J, Starovoytov A, et al: Abbreviated 

infusion of eptifibatide after successful coronary 

intervention. The BRIEF-PCI (Brief Infusion of 

Eptifibatide Following Percutaneous Coronary Intervention) 

randomized trial. J Am Coll Cardiol 53: 

837, 2009. 

229. Anderson JL, Adams CD, Antman EM, et al:ACC/ 


with unstable angina/non-ST-elevation 

myocardial infarction. A report of the ACC/AHA 

Task Force on Practice Guidelines, developed in 

collaboration with the American College of Emergency 

Physicians, Society for Cardiovascular Angiography 

and Interventions, Society of Thoracic 

Surgeons, endorced by the American Association 

of Cardiovascular and Pulmonary Rehabilitation 

and Society for Academic Emergency Medicine. J 

Am Coll Cardiol 50: e1, 2007. 

230. Montalescot G, Borentain M, Payot L, et al: Early 

vs late administration of glycoprotein IIb/IIIa inhibitors 

in primary percutaneous coronary intervention 

of acute ST-segment elevation myocardial 

infarction. A meta-analysis. JAMA 292: 362, 2004. 

231. Giugliano RP, White JA, Bode C, et al for the EAR- 

LY ACS Investigators: Early versus delayed, provisional 

eptifibatide in acute coronary syndromes. N 

Engl J Med 360: 2176, 2009. 

232. Stone GW, Bertrand ME, Moses JW, et al for the 

ACUITY Investigators: Routine upstream initiation 

vs deferred selective use of glycoprotein IIb/ 

IIIa inhibitors in acute coronary syndromes. The 

ACUITY Timing trial. JAMA 297: 591, 2007. 

233. Gurm HS, Smith DE, Collins JS, et al: The relative 

safety and efficacy of abciximab and eptifibatide in 

patients undergoing primary percutaneous coronary 

intervention. J Am Coll Cardiol 51: 529, 2008. 

234. The RESTORE Investigators: Effects of platelet 

glycoprotein IIb/IIIa blockade with tirofiban on 

adverse cardiac events in patients with unstable 

angina or acute myocardial infarction undergoing 

coronary angioplasty. Circulation 96(5):1445, 1997. 

235. PRISM-PLUS Study Investigators: Inhibition of 

the platelet glycoprotein IIb/IIIa receptor with tirofiban 

in unstable angina and non-Q-wave myocardial 

infarction. Platelet Receptor Inhibition in 

Ischemic Syndrome Management in Patients Limited 

by Unstable Signs and Symptoms. N Engl J Med 

339(16):1163, 1998. 

236. van’t Hof AWJ, Valgimigli M: Defining the role of 

platelet glycoprotein receptor inhibitors in STEMI. 

Focus on tirofiban. Drugs 69; 85, 2009. 

237. Cannon CP, Weintraub WS, Demopoulos LA, et al, 


for the TACTICS–-Thrombolysis in Myocardial Infarction 

18 Investigators: Comparison of early invasive 

and conservative strategies in patients with 

unstable coronary syndromes treated with the glycoprotein 

IIb/IIIa inhibitor tirofiban. N Engl J Med 

344:1879, 2001. 

238 Topol EJ, Moliterno DJ, Herrmann HC, et al: Comparison 

of two platelet glycoprotein IIb/IIIa inhibitors, 

tirofiban and abciximab, for the prevention of 

ischemic events with percutaneous coronary revascularization. 

N Engl J Med 344(25):1888, 2001. 

239. Valgimigli M, Camp G, Percoco G, et al: Comparison 

of angioplasty with infusion of tirofiban or abciximab 

and with implantation of sirolimus-eluting 

or uncoated stents for acute myocardial infarction. 

The MULTISTRATEGY randomized trial. JAMA 

299; 1788, 2008. 

240. Kereiakes DJ, Runyon JP, Kleinman NS, et al: Differential 

dose response to oral xemilofiban after 

antecedent intravenous abciximab. Circulation 94: 

906, 1996. 

241. O’Neill WW, Serruys P, Knudtson M, et al: Longterm 

treatment with a platelet glycoprotein-receptor 

antagonist after percutaneous coronary 

revascularization. EXCITE Trial Investigators. 

Evaluation of Oral Xemilofiban in Controlling 

Thrombotic Events. N Engl J Med 342(18):1316, 

2000. 

242. Cannon CP, McCabe CH, Wilcox RG, et al: Oral 

glycoprotein IIb/IIIa inhibition with orbofiban 

in patients with unstable coronary syndromes 

(OPUS-TIMI 16) trial. Circulation 102(2):149, 

2000. 

243. The SYMPHONY Investigators: Comparison of 

sibrafiban with aspirin for prevention of cardiovascular 

events after acute coronary syndromes: A 

randomised trial. Lancet 355(9201):337, 2000. 

244. Second SYMPHONY Investigators: Randomized 

trial of aspirin, sibrafiban, or both for secondary 

prevention after acute coronary syndromes. Circulation 

103(13):1727, 2001. 

245. Sorelle R: SmithKline Beecham halts tests of Lotrafiban, 

an oral glycoprotein IIb/IIIa inhibitor. 

Circulation 103:e9001, 2001. 

246. Chew DP, Bhatt DL, Sapp S, Topol EJ: Increased 

mortality with oral platelet glycoprotein IIb/IIIa 

antagonists: A meta-analysis of phase III multicenter 

randomized trials. Circulation 103(2):201, 

2001. 

247. Rosenberg RD, Bauer KA: The heparin-antithrombin 

system: A natural anticoagulant mechanism. 

In: Coleman RW, Hirsh J, Marder VJ, et al, eds. 

Hemostasis and Thrombosis: Basic Principles and 

Clinical Practice. 3rd ed. Philadelphia: JB Lippin-


cott, 1992:837. 

248. Bjork I, Lindahl U: Mechanism of the anticoagulant 

action of heparin. Mol Cell Biochem 48:161, 

1982. 

249. Hirsh J, Raschke R: Heparin and low-molecularweight 

heparin. Chest 126(Suppl):188S, 2004. 

250. Loscalzo J: Thrombin inhibitors in fibrinolysis: A 

Hobson’s choice of alternatives. Circulation 94:863, 

1996. 

251. Hull RD, Raskob GE, Hirsh J, et al: Continuous 

intravenous heparin compared with intermittent 

subcutaneous heparin in the initial treatment of 

proximal-vein thrombosis. N Engl J Med 315:1098, 

1996. 

251a. Uprichard J, Manning RA, Laffan MA: Monitoring 

heparin anticoagulation in the acute phase response. 

Br J Haematol March 11, 2010 epub ahead 

of print. 

252. Levine M, Hirsh J, Gent M, et al: A randomized trial 

comparing activated thromboplastin time with 

heparin assay in patients with acute venous thromboembolism 

requiring large daily doses of heparin. 


253. Geerts WH, Bergqvist D, Pineo GF, et al: Prevention 

of venous thromboembolism. Chest 

133(Suppl):381S, 2008. 

254. Nurmohamed Mt, Rosendaal FR, Buller HR, et al: 

Low-molecular-weight heparin versus standard 

heparin in general and orthopedic surgery: A meta-analysis. 

Lancet 340:152, 1992. 

255. Iorio A, Agnelli G: Low-molecular-weight and 

unfractionated heparin for prevention of venous 

thromboembolism in neurosurgery. A meta-analysis. 


256. Liem A, Zijlstra F, Ottervanger JP, et al: High-dose 

heparin as pretreatment for primary angioplasty in 

acute myocardial infarction: The Heparin in Early 

Patency (HEAP) Randomized Trial. J Am Coll Cardiol 

35:600, 2000. 

257. Mahaffey KW, Granger CB, Collins R, et al: Overview 

of randomized trials of intravenous heparin 

in patients with acute myocardial infarction treated 

with thrombolytic therapy. Am J Cardiol 77:551, 

1996. 

258. Eisenberg PR, Sherman LA, Jaffe AS: Paradoxic 

elevation of fibrinopeptide A after streptokinase: 

Evidence for continued thrombosis despite intense 

thrombolysis. J Am Coll Cardiol 10:527, 1987. 

259. Eisenberg PR, Sobel BE, Jaffe AS: Activation of 

prothrombin accompanying thrombolysis with recombinant 

tissue-type plasminogen activator. J Am 

Coll Cardiol 19:1065, 1992. 

260. The SCATI (Studio sulla Caliparina nell’Angina e 

nella Thrombosi Ventriculare nell’Infarto) Group: 

Randomized controlled trial of subcutaneous calcium-heparin 

in acute myocardial infarction. Lancet 

2:182, 1989. 

261. Gruppo Italiano per lo Studio della Streptochinase 

Nell’Infarcto Miocardico: GISSI 2: A factor randomized 

trial of alteplase and heparin versus no 

heparin among 12,490 patients with acute myocardial 


262. The International Study Group: In-hospital mortality 

and clinical course of 20,891 patients with 

suspected acute myocardial infarction randomized 

between alteplase and streptokinase with or without 

heparin. Lancet 336:71, 1990. 

263. ISIS-3 Collaborative Group. ISIS-3: A randomised 

comparison of streptokinase vs tissue plasminogen 

activator vs anistreplase and of aspirin plus heparin 

vs aspirin alone among 41,299 cases of suspected 

acute myocardial infarction. Lancet 339:753, 1991. 

264. Yusuf S, Collins R, Peto R, et al: Intravenous and 

intracoronary fibrinolytic therapy in acute myocardial 

infarction: Overview of results on mortality, 

reinfarction and side effects from 33 randomized 

controlled trials. Eur Heart J 6:556, 1985. 

265. Hsia J, Hamilton WP, Kleiman N, et al: A comparison 

between heparin and low-dose aspirin as adjunctive 

therapy with tissue plasminogen activator 

for acute myocardial infarction: Heparin-Aspirin 

Reperfusion Trial (HART) Investigators. N Engl J 

Med 323: 1433, 1990. 

266. Topol EJ, George BS, Kereiakes DJ, et al: A randomized 

controlled trial of intravenous tissue plasminogen 

activator and early intravenous heparin 

in acute myocardial infarction. Circulation 79:281, 

1989. 

267. The GUSTO Investigators: An international randomized 

trial comparing four thrombolytic strategies 

for acute myocardial infarction. N Engl J Med 

329:673, 1993. 

268. Harjai KJ, Stone GW, Grines CL, et al: Usefulness of 

routine unfractionated heparin infusion following 

primary percutaneous coronary intervention for 

acute myocardial infarction in patients not receiving 

glycoprotein IIb/IIIa inhibitors. Am J Cardiol 

99: 202, 2007. 

269. Antman EM for the TIMI 9B Investigators: Hirudin 

in acute myocardial infarction. Thrombolysis 

and thrombin inhibition in myocardial infarction 

(TIMI) 9B trial. Circulation 94:911, 1996. 

270. Mungall DR, Anbe D, Forrester PL, et al: A prospective 

randomized comparison of the accuracy 

of computer-assisted versus GUSTO nomogramdirected 

heparin therapy. Clin Pharmacol Ther 

55:591, 1994. 

271. Braunwald E, Antman EM, Beasley JW, et al: ACC/

AHA guidelines for the management of patients 

with unstable angina and non-ST-segment elevation 

myocardial infarction: executive summary 

and recommendations. A report of the American 

College of Cardiology/American Heart Association 

Task Force on Practice Guidelines (Committee 

on the Management of Patients with Unstable 

Angina). Circulation 102:1193, 2000. 

272. Zidane M, Schram MT, Planken EW, et al: Frequency 

of major hemorrhage in patients treated 

with unfractionated intravenous heparin for deep 

venous thrombosis or pulmonary embolism. A 

study in routine clinical practice. Arch Intern Med 

160:2369, 2000. 

273. Engelberg H: Actions of heparin in the atherosclerotic 

process. Pharmacol Rev 48:327, 1996. 

274. Nelson JC, Lerner RG, Goldstein R, Cagin NA: 

Heparin-induced thrombocytopenia. Arch Intern 

Med 138: 548, 1978. 

274a. Napolitano LM, Warkentin TE, AlMahameed A, 

Nasraway SA: Heparin-induced thrombocytopenia 

in the critical care setting: diagnosis and management. 

Crit Care Med 34: 2898, 2006. 

275. Das P, Ziada K, Steinhubl SR, et al: Heparin-induced 

thrombocytopenia and cardio-vascular diseases. 

Am Heart J 152: 19, 2006. 

276. Crespo EM, Oliveira GBF, Honeycutt EF, et al: 

Evaluation and management of thrombocytopenia 

and suspected heparin-induced thrombocytopenia 

in hospitalized patients: The Complications After 

Thrombocytopenia Caused by Heparin (CATCH) 

registry. Am Heart J 157: 651, 2009. 

277. Oliveira GBF, Crespo EM, Becker RC, et al: Incidence 

and prognostic significance of thrombocytopenia 

in patients treated with prolonged heparin 

therapy. Arch Intern Med 168: 94, 2008. 

278. Warkentin TE, Kelton JG: Temporal aspects of 

heparin-induced thrombocytopenia. N Engl J Med 

344:1286, 2001. 

279. Warkentin TE, Levine MN, Hirsh J, et al: Heparininduced 

thrombocytopenia in patients treated 

with low-molecular-weight heparin. N Engl J Med 

332:1330, 1995. 

279a. FDA drug safety communication: update: follow 

up to the Public Health Alert about changes to the 

heparin sodium USP monography, April 7, 2010. 

http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ 

ucm207506.htm. 

280. Hirsh J: Heparin. N Engl J Med 324:1565, 1991. 

281. Hogg PJ, Jackson CM: Fibrin monomer protects 

thrombin from inactivation by heparin-antithrombin 

III: Implications for heparin efficacy. Proc Natl 

Acad Sci USA 86:3619, 1989. 


282. Weitz JI, Huboda M, Massel D, et al: Clot-bound 

thrombin is protected from inhibition by heparinantithrombin 

but is susceptible to inactivation by 

antithrombin III-independent inhibitors. J Clin Invest 

86:385, 1990. 

283. Loscalzo J, Melinick B, Handin R: The interaction 

of platelet factor 4 and glycosaminoglycans. Arch 

Biochem Biophys 240:446, 1985. 

284. Hirsh J, Levine MN: Low-molecular-weight heparin. 

Blood 79:1, 1992. 

285. Lane DA, Denton J, Flynn AM, et al: Anticoagulant 

activities of heparin oligosaccharides and their 

neutralization by platelet factor IV. Biochem J 

218:725, 1984. 

286. Anderrson LO, Barrowcliffe TW, Holmer E, et al: 

Molecular weight dependency of the heparin potentiated 

inhibition of thrombin and activated factor 

X: Effect of heparin neutralization in plasma. 

Thromb Res 115:531, 1979. 

287. Kakkar VV: Effectiveness and safety of low-molecular-weight 

heparins (LMWH) in the prevention 

of venous thromboembolism. Thromb Haemost 

74:364, 1995. 

288. Hirsh J, Siragusa S, Ginsberg JS: Low-molecularweight 

heparins (LMWH) in the treatment of 

patients with acute venous thromboembolism. 

Thromb Haemost 74:360, 1995. 

289. Kakkar VV, Cohen AT, Edmundson RA, et al: Lowmolecular-weight 

heparins versus standard heparin 

for patients of venous thromboembolism after 

major abdominal surgery. Lancet 341:259, 1993. 

290. Albers GW, Amarenco P, Easton JD, et al: Antithrombotic 

and thrombolytic therapy for ischemic 

stroke. Chest 119:300s, 2001. 

291. International Stroke Trial Collaborative Group: 

The International Stroke Trial (IST): A randomised 

trial of aspirin, subcutaneous heparin, both, or neither 

among 19435 patients with acute ischaemic 

stroke. Lancet 349(9065):1569, 1997. 

292. Kay R, Wong KS, Yu YL, et al: Low-molecularweight 

heparin for the treatment of acute ischemic 

stroke. N Engl J Med 333:1588, 1995. 

293. Carter NJ, McCormack PL, Plosker GL: Enoxaparin. 

A review of its use in ST-segment elevation 

myocardial infarction. Drugs 68: 691, 2008. 

294. The Assessment of the Safety and Efficacy of a new 

Thrombolytic Regimen (ASSENT)-3 Investigators: 

Efficacy and safety of tenecteplase in combination 

with enoxaparin, abciximab, or unfractionated 

heparin in acute myocardial infarction: ASSENT-3. 

Lancet 358:605, 2001. 

295. Llevadot J, Giugliano RP, Antman EM: Bolus fibrinolytic 

therapy in acute myocardial infarction. 

JAMA 286:442, 2001.


296. Antman EM, Morrow DA, McCabe CH, et al for 

the EXTRACT-TIMI 25 Investigators: Enoxaparin 

versus unfractionated heparin with fibrinolysis for 

ST-elevation myocardial infarction. N Engl J Med 

354: 1477, 2006. 

297. Gibson CM, Murphy SA, Montalescot G, et al for 

the EXTRACT-TIMI 25 Investigators: Percutaneous 

coronary intervention in patients receiving 

enoxaparin or unfractionated heparin after fibrinolytic 

therapy for ST-segment elevation myocardial 

infarction in the ExTRACT-TIMI 25 trial. J Am 

Coll Cardiol 49: 2238, 2007. 

298. Eikelboom JW, Quinlan DJ, Mehta SR, et al: Unfractionated 

and low-molecular-weight heparin as 

adjuncts to thrombolysis in aspirin-treated patients 

with ST-elevation acute myocardial infarction. A 

meta-analysis of the randomized trials. Circulation 

112: 3855, 2005. 

299. Gurfinkel EP, Manos EJ, Mejail RI, et al: Low-molecular-weight 

heparin versus regular heparin or 

aspirin in treatment of unstable angina and silent 

ischemia. J Am Coll Cardiol 26:313, 1995. 

300. Low-molecular-weight heparin during instability 

in coronary artery disease, Fragmin during Instability 

in Coronary Artery Disease (FRISC) study 

group. Lancet 347:561, 1996. 

301. Cohen M, Demers C, Gurfinkel EP, et al: A comparison 

of low-molecular-weight heparin with 

unfractionated heparin for unstable coronary artery 

disease. Efficacy and Safety of Subcutaneous 

Enoxaparin in Non-Q-Wave Coronary Events 

Study Group. N Engl J Med 337(7):447, 1997. 

302. Goodman SG, Cohen M, Bigonzi F, et al: Randomized 

trial of low-molecular-weight heparin (enoxaparin) 

versus unfractionated heparin for unstable 

coronary artery disease: One-year results of the 

ESSENCE Study. Efficacy and Safety of Subcutaneous 

Enoxaparin in Non-Q Wave Coronary Events. 


303. Elkelboom JW, Anand SS, Malmberg K, et al: Unfractionated 

heparin and low-molecular-weight 

heparin in acute coronary syndrome without ST 

elevation: A meta-analysis. Lancet 355:1936, 2000. 

304. Becker RC, Meade TW, Berger PB: The primary 

and secondary prevention of coronary artery disease. 

ACCP evidence based clinical practice guidelines 

8th ed.. Chest 133(Suppl): 776s, 2008. 

305. The SYNERGY Trial Investigators: Enoxaparin vs 

unfractionated heparin in high-risk patients with 

non-ST segment elevation acute coronary syndromes 

managed with an intended early invasive 

strategy. Primary results of the SYNERGY randomized 

trial. JAMA 292: 45, 2004. 

306. Mahaffey KW, Cohen M, Garg J, et al for the SYN- 

ERGY Trial Investigators: High-risk patients with 

acute coronary syndromes treated with low molecular 

weight or unfractionated heparin. Outcomes 

at 6 months and 1 year in the SYNERGY trial. 

JAMA 294: 2594, 2005. 

307. Levine M, Gent M, Hirsh J, et al: Ardeparin (lowmolecular-weight 

heparin) vs. graduated compression 

stockings for the prevention of venous 

thromboembolism. Arch Intern Med 156:851, 1996. 

308. Leclerc JR, Goerts WH, Desjardins L, et al: Prevention 

of venous thromboembolism after knee 

arthroplasty–-a randomized, double-blind trial 

comparing enoxaparin with warfarin. Ann Intern 

Med 124:619, 1996. 

309. Hull R, Raskob G, Pineo G, et al: A comparison of 

subcutaneous low-molecular-weight heparin with 

Warfarin sodium for prophylaxis against deep-vein 

thrombosis after hip or knee implantation. N Engl J 

Med 329:1370, 1993. 

310. Heit JA, Berkowitz SD, Bona R, et al: Efficacy and 

safety of low-molecular-weight heparin (ardeparin 

sodium) compared to warfarin for the prevention 

of VTE after total knee replacement surgery: A 

double-blind, dose-ranging study. Thromb Haemost 

77:32, 1997. 

311. Hull RD, Raskob GE, Pineo GF, et al: Subcutaneous 

low-molecular-weight heparin compared with 

continuous intravenous heparin in the treatment of 

proximal-vein thrombosis. N Engl J Med 326:975, 

1992. 

312. Levine M, Gent M, Hirsh J, et al: A comparison of 

low-molecular-weight heparin administered primarily 

at home with unfractionated heparin. Administered 

in the hospital for proximal deep-vein 

thrombosis. N Engl J Med 334:677, 1996. 

313. Koopman M, Prandoni P, Piovella F, et al: Treatment 

of venous thrombosis with intravenous unfractionated 

heparin administered in the hospital 

as compared with subcutaneous low-molecularweight 

heparin administered at home. N Engl J 

Med 334:682, 1996. 

314. Gould MK, Dembitzer AD, Doyle RL, et al: Lowmolecular-weight 

heparins compared with unfractionated 

heparin for treatment of acute deep 

venous thrombosis. A meta-analysis of randomized, 

controlled trials. Ann Intern Med 130:800, 

1999. 

315. Faxon DP, Spiro TE, Minor S, et al: Low-molecular-weight 

heparin in prevention of restenosis after 

angioplasty. Results of Enoxaparin Restenosis Trial 

(ERA). Circulation; 90:908, 1994. 

316. Cairns JA, Gill J, Morton B, et al: Fish oils and 

low-molecular-weight heparin for the reduction 

of restenosis after percutaneous transluminal coro-

nary angioplasty. The EMPAR Study. Circulation 

94:1553, 1996. 

317. Lablanche JM, McFadden EP, Meneveau N, et al: 

Effect of nadroparin, a low-molecular-weight heparin, 

on clinical and angiographic restenosis after 

coronary balloon angioplasty: The FACT study. 

Fraxiparine Angioplastic Coronaire Transluminate. 


318. Kiesz RS, Buszman P, Martin JL, et al: Local delivery 

of enoxaparin to decrease restenosis after 

stenting: Results of initial multicenter trial: Polish- 

American Local Lovenox NIR Assessment study 

(The POLONIA study). Circulation 103:26, 2001. 

319. Montalescot G, White HD, Gallo R, et al for the 

STEEPLE Investigators: Enoxaparin versus unfractionated 

heparin in elective percutaneous coronary 

intervention. N Engl J Med 355: 1006, 2006. 

320. White HD, Gallo R, Cohen M, et al: The use of 

intravenous enoxaparin in elective percutaneous 

coronary intervention in patients with renal impairment: 

results from the Safety and Efficacy of 

Enoxaparin in PCI patients, an international randomized 

evaluation (STEEPLE) trial. Am Heart J 

157: 125: 2009. 

321. Belch JJF: Pharmacotherapy of Raynaud’s phenomenon. 

Drugs 52:682, 1996. 

322. Mannarino E, Pasqualini L, Innocente S, et al: Efficacy 

of low-molecular-weight heparin in the management 

of intermittent claudication. Angiology 

42:1, 1991. 

323. Calabro A, Piarulli F, Milan D, et al: Clinical assessment 

of low-molecular-weight heparin effects 

in peripheral vascular disease. Angiology 44:188, 

1993. 

324. Edmondson RA, Cohen AT, Das SK, et al: Lowmolecular-weight 

heparin versus aspirin and dipyridamole 

after femoropopliteal bypass grafting. 

Lancet 344:914, 1994. 

325. Boston Area Anticoagulation Trial: The effect of 

low-dose warfarin on the risk of stroke in patients 

with non-rheumatic atrial fibrillation: The Boston 

Area Anticoagulation Trial for Atrial Fibrillation 

Investigators. N Engl J Med 323:1505, 1990. 

326. Harenberg J, Weuster B, Pfitzer M, et al: Prophylaxis 

of embolic events in patients with atrial fibrillation 

using low-molecular-weight heparin. Semin 

Thromb Hemost 19(Suppl 1):116, 1993. 

327. Berge E, Abdelnoor M, Nakstad PH, et al: Lowmolecular-weight 

heparin versus aspirin in 

patients with acute ischaemic stroke and atrial fibrillation: 

A double-blind randomised study. Lancet 

355:1205, 2000. 

328. Murray RD, Deitcher SR, Shah A, et al: Potential 

clinical efficacy and cost benefit of a 


transesophageal echocardiography-guided lowmolecular-weight 

heparin (enoxaparin) approach 

to antithrombotic therapy in patients undergoing 

immediate cardioversion from atrial fibrillation. J 

Am Soc Echocardiogr 14:200, 2001. 

329. Jeffrey RF, Khan AA, Douglas, JT, et al: Anticoagulation 

with low-molecular-weight heparin 

(Fragmin) during continuous hemodialysis in the 

intensive care unit. Artif Organs 17(8):717, 1993. 

330. Schmitt Y, Schneider H: Low-molecular-weight 

heparin (LMWH): Influence on blood lipids in patients 

on chronic hemodialysis. Nephrol Dial Transplant 

8(5):438, 1993. 

331. Saltissi D, Morgan C, Westhuyzen J, Healy H: 

Comparison of low-molecular-weight heparin 

(enoxaparin sodium) and standard unfractionated 

heparin for haemodialysis anticoagulation. Nephrol 

Dial Transplant 11:2698, 1999. 

332. Melandri G, Semprini F, Cervi V, et al: Benefit of 

adding low-molecular-weight heparin to the conventional 

treatment of stable angina pectoris. A 

double-blind, randomized, placebo-controlled 

trial. Circulation 88(6):2517, 1993. 

333. Lee AY, Levine MN, Baker RI, et al: Low-molecular-weight-heparin 

versus a coumarin for the prevention 

of recurrent venous thromboembolism in 

patients with cancer. N Engl J Med 349: 146, 2003. 

334. Estrada CA, Mansfield CJ, Heudebert GR: Costeffectiveness 

of low-molecular-weight heparin in 

the treatment of proximal deep vein thrombosis. J 

Gen Intern Med 15:108, 2000. 

335. Marcoff L, Zhang Z, Zhang W, et al: Cost effectiveness 

of enoxaparin in acute ST-segment elevation 

myocardial infarction. The ExTRACT-TIMI 25 


336 Hull RD, Raskob GE, Rosenbloom D, et al: Treatment 

of proximal vein thrombosis with subcutaneous 

low-molecular-weight heparin vs intravenous 

heparin. An economic perspective. Arch Intern 

Med 157:289, 1997. 

337. Wilde MI, Markham A: Danaparoid: A review of 

its pharmacology and clinical use in the management 

of heparin induced thrombocytopenia. Drugs 

54:903, 1997. 

338. Chesebro J, Fuster V: Thrombosis in unstable angina. 

N Engl J Med 327:192, 1992. 

338a. Rupprecht HJ, Blank R: Clinical pharmacology of 

direct and indirect factor Xa inhibitors. Drugs 70: 

2153, 2010. 

339. Graham DJ, Alexander JJ: The effect of thrombin 

on bovine aortic endothelial and smooth muscle 

cells. J Vasc Surg 11:307, 1990. 

340. Jones A, Geczy CL: Thrombin and factor Xa enhance 

the production of interleukin-1. Immunol-


ogy 71:236, 1990. 

340a. Greinacher A, Lubenow N: Recombinant hirudin 

in clinical practice. Circulation 103:1479, 2001. 

341. Rydel TJ, Ravichandran KG, Tulinsky A, et al: The 

structure of a complex of recombinant hirudin and 

human alpha-thrombin. Science 249:277, 1990. 

342. Greinacher A, VÖlpel H, Janssens U, et al: Recombinant 

hirudin (lepirudin) provides safe and 

effective anticoagulation in patients with the immunologic 

type of heparin-induced thrombocytopenia: 

A prospective study. Circulation 99:73, 1999. 

343. Greinacher A, Janssens U, Berg G, et al: Lepirudin 

(recombinant hirudin) for parenteral anticoagulation 

in patients with heparin-induced thrombocytopenia. 


343a. Desirudin (Iprivask) for DVT prevention. The 

Medical Ltr 52: 85, 2010. 

343b. Eriksson BI, Ekman S, Lindbratt S, et al: Prevention 

of thromboembolism with use of recombinant 

hirudin. Results of a double-blind, multicenter trial 

comparing the efficacy of desirudin (Revasc) with 

that of unfractionated heparin in patients having a 

total hip replacement. J Bone Joint Surg Am 79: 326, 

1997. 

344. Cannon CP, McCabe CH, Henry TD, et al: A pilot 

trial of recombinant desulfatohirudin compared 

with heparin in conjunction with tissue-type plasminogen 

activator and aspirin for acute myocardial 

infarction: Results of the Thrombolysis in Myocardial 

Infarction (TIMI) 5 Trial. J Am Coll Cardiol 

23:993, 1994. 

345. Neuhaus KL, Niederer W, Wagner J, et al: HIT (Hirudin 

for the Improvement of Thrombolysis) results 

of a dose escalation study (abstr.). Circulation 

88:I–292, 1993. 

346. Lee LV, for the TIMI 6 Investigators: Initial experience 

with hirudin and streptokinase in acute myocardial 

infarction: Results of the TIMI 6 trial. Am J 

Cardiol 75:7, 1995. 

347. Antman EM, for the TIMI 9A Investigators: Hirudin 

in acute myocardial infarction: Safety report 

from the Thrombolysis and Thrombin Inhibition 

in Myocardial (TIMI) 9A trial. Circulation 90:1624, 

1994. 

348. The Global Use of Strategies to Open Occluded 

Coronary Arteries (GUSTO) IIa Investigators: A 

randomized trial of intravenous heparin versus recombinant 

hirudin for acute coronary syndromes. 


349. Antman EM for the TIMI 9B Investigators: Hirudin 

in acute myocardial infarction: thrombolysis 

and thrombin inhibition in myocardial infarction: 

Thrombolysis and thrombin inhibition in myocardial 

infarction (TIMI) 9B trial. Circulation 94:911, 

1996. 

350. van den Boss AA, Deckers JW, Heyndricks GR, 

et al: Safety and efficacy of recombinant hirudin 

(CGP 39393) versus heparin in patients with stable 

angina undergoing coronary angioplasty. Circulation 

88:2058, 1993. 

351. OASIS-2 Investigators: Effects of recombinant 

hirudin (Lepirudin) compared with heparin on 

death, myocardial infarction, refractory angina, 

and revascularisation in patients with acute myocardial 

ischaemia without ST elevation. A randomised 

trial. Lancet 353: 429, 1999. 

352. Serruys PW, Deckers JW, Close P, on behalf of the 

HELVETICA study group: A double-blind, randomized 

heparin controlled trial evaluating acute 

and long-term efficacy of r-hirudin (CGP 39393) in 

patients undergoing coronary angioplasty (abstr). 

Circulation 90(Suppl I) [pt 2]:I-394, 1994. 

353. Bittl JA, Strony J, Brinker JA, et al: Treatment with 

bivalirudin (hirulog) as compared with heparin 

during coronary angioplasty for unstable and postinfarction 

angina. Hirulog Angioplasty Study Investigators. 

N Engl J Med 333:764, 1995. 

354 Zoldhelyi P, Webster MWI, Fuster V, et al: Recombinant 

hirudin in patients with chronic, stable coronary 

artery disease: Safety, half-life, and effect on 

coagulation parameters. Circulation 88:2015, 1993. 

355 Walenga JM, Hoppensteadt D, Koza MM, et al: 

Comparative studies on various essays for the laboratory 

evaluation of hirudin. Semin Thromb Hemost 

17:103, 1991. 

356 Lefkovits J, Topol EJ: Direct thrombin inhibitors 

in cardiovascular medicine. Circulation 90:1522, 

1994. 

357. Porta R, Pescador M, Mantovani M, Prino G: 

Quantitative comparison of recombinant hirudin’s 

antithrombotic and anticoagulant activities with 

those of heparin. Thromb Res 57:639, 1990. 

358. Global Use of Strategies to Open Occluded Coronary 

Arteries (GUSTO) IIb Investigators: A comparison 

of recombinant hirudin with heparin for 

the treatment of acute coronary syndrome. N Engl J 

Med 335:775, 1996. 

358a. Gajra A, Husain J, Smith A: Lepirudin in the management 

of heparin-induced thrombo-cytopenia. 

Expert Opin Drug Metab Toxicol 4: 1131, 2008. 

358b. Petros S: Lepirudin in the management of patients 

with heparin-induced thrombocytopenia. Biologics 

2: 481, 2008. 

359. Fareed J, Walenga J, Hoppensteadt D, et al: Neutralization 

of recombinant hirudin: Some practical 

considerations. Semin Thromb Hemost 17:137, 

1991. 

360 Theroux P, Perez-Villa F, Waters D, et al: A ran-

domized double-blind comparison of two doses 

of Hirulog or heparin as adjunctive therapy to 

streptokinase to promote early patency of the infarct-related 

artery in acute myocardial infarction. 


361 Maraganore JM, Bourdon P, Jablonski J, et al: Design 

and characterization of Hirulog: A novel class 

of bivalent peptide inhibitors of thrombin. Biochemistry 

29:7095, 1990. 

362. Fuchs J, Cannon CP: Hirulog in the treatment of 

unstable angina: Results of the Thrombin Inhibition 

in Myocardial Ischemia (TIMI) 7 trial. Circulation 

92:727, 1995. 

363. Nawarskas JJ, Anderson JR: Bivalirudin: A new approach 

to anticoagulation. Heart Dis 3:131, 2001. 

364. Dogne JM, de Leval X, Delarge J, et al: New trends 

in thromboxane and prostacyclin modulators. Curr 

Med Chem 7(6):609, 2000. 

365. Lincoff AM, Bittl JA, Kleiman NS, et al for the RE- 

PLACE-1 Investigators: Comparison of bivalirudin 

versus heparin during percutaneous coronary 

intervention (the Randomized Evaluation of PCi 

Linking Angiomax to Reduced Clinical Events 

[REPLACE]-1- Trial). Am J Cardiol 93: 1092, 2004. 

366. Lincoff AM, Bittl JA, Harrington RA, et al for the 

REPLACE-2 Investigators: Bivalirudin and provisional 

glycoprotein IIb/IIIa blockade compared 

with heparin and planned glycoprotein IIb/IIIa 

blockade during percutaneous coronary intervention. 

REPLACE-2 randomized trial. JAMA 289: 

853, 2003. 

367. Chew DP, Lincoff AM, Gurm H, et al for the RE- 

PLACE-2 Investigators: Bivalirudin versus heparin 

and glycoprotein IIb/IIIa inhibition among patients 

with renal impairment undergoing percutaneous 

coronary intervention (a subanalysis of the 

REPLACE-2 trial). Am J Cardiol 95: 581, 2005. 

368. Gibson CM, Morrow DA, Murphy SA, for the 

TIMI study group: A randomized trial to evaluate 

the relative protection against post-percutaneous 

coronary intervention microvascular dysfunction, 

ischemia and inflammation among antiplatelet and 

anti-thrombotic agents. The PROTECT-TIMI 30 

trial. J Am Coll Cardiol 47: 2364, 2006. 

369. Stone GW, McLaurin BT, Cox DA, et al for the 

ACUITY Investigators: Bivalirudin for patients 

with acute coronary syndromes. N Engl J Med 355: 

2203, 2006. 

370. Stone GW, White HD, Ohman EM, et al: Bivalirudin 


undergoing percutaneous coronary intervention: a 

subgroup analysis from the Acute Catheterization 

and Urgent Intervention Triage strategy (ACU- 

ITY) trial. Lancet 369: 907, 2007. 


371. Kastrati A, Neumann FJ, Mehilli J, et al for the 

ISAR-REACT 3 trial investigators: Bivalirudin 

versus unfractionated heparin during percutaneous 

coronary intervention. N Engl J Med 359: 688, 

2008. 

372. Stone GW, Witzenbichler B, Guagliumi G, et al for 

the HORIZONS-AMI Trial Investigators: Bivalirudin 

during primary PCI in acute myocardial infarction. 

N Engl J Med 358: 2218, 2008. 

373. Mehran R, Lansky AJ, Witzenbichler B, et al for the 

HORIZONS-AMI Trial Investigators: Bivalirudin 

in patients undergoing primary angioplasty for 

acute myocardial infarction (HORIZONS-AMI): 1 

year results of a randomised controlled trial. Lancet 

374: 1149, 2009. 

374. Feldman DN, Wong SC, Gade CL, et al: Impact of 

bivalirudin on outcomes after percutaneous coronary 

revascularization with drug-eluting stents. 

Am Heart J 154: 695, 2007. 

374a. Parodi G, Antoniucci D, Nikolsky E, et al: Impact 

of bivalirudin therapy in high-risk patients with 

acute myocardial infarction. 1-year results from 

the HORIZONS-AMI (Harmonizing Outcomes 

with Revascularization and Stents in Acute Myocardial 

Infarction) trial. J Am Coll Cardiol Intv 3: 

796, 2010. 

374b. Grubb KJ, Salehi P, Chedrawy EG: Bivalirudin: alternative 

anticoagulation during cardiopulmonary 

bypass in patients with heparin-induced thrombocytopenia. 

Recent Pat Cardiovasc Drug Discov 5: 20, 

2010. 

375. Yeh RW, Jang IK: Argatroban: update. Am Heart J 

151: 1131, 2006. 

376. Lewis BE, Wallis DE, Berkowitz SD, et al for the 

ARG-911 Study Investigators: Argatroban anticoagulant 

therapy in patients with heparin-induced 

thrombocytopenia. Circulation 103: 1838, 2001. 

377. Hursting MJ, Verme-Gibboney CN: Risk factors 

for major bleeding in patients with heparin-induced 

thrombocytopenia treated with argatroban: 

a retrospective study. J Cardiovasc Pharmacol 52: 

561, 2008. 

378. Lewis BE, Wallis DE, Hursting MJ, et al: Effects of 

argatroban therapy, demographic variables, and 

platelet count on thrombotic risks in heparin-induced 

thrombocytopenia. Chest 129: 407, 2006. 

379. Cruz-Gonzalez I, Sanchez-Ledesma M, Osakabe 

M, et al: What is the optimal anti-coagulation level 

with argatroban during percutaneous coronary intervention? 

Blood Coagul Fibrinolysis 19: 401, 2008. 

380. SPORTIF Executive Steering Committee for the 

SPORTIF V Investigators: Ximelagatran vs warfarin 

for stroke prevention in patients with nonvalvular 

atrial fibrillation. A randomized trial. JAMA


293: 690, 2005. 

381. Colwell C, Mouret P: Ximelagatran for the prevention 

of venous thromboembolism following elective 

hip or knee replacement surgery. Semin Vasc 

Med 5: 266, 2005. 

382. Francis CW, Berkowitz SD, Comp PC, et al for the 

EXULT A Study Group: Comparison of ximelagatran 

with warfarin for the prevention of venous 

thromboembolism after total knee replacement. N 

Engl J Med 349: 1703, 2003. 

383 Turpie AGG, Bauer KA, Eriksson BI, et al: 

Fondaparinux vs enoxparin for the prevention of 

venous thromboembolism in major orthopedic 

surgery. A meta-analysis of 4 randomized doubleblind 

studies. Arch Intern Med 162: 1833, 2002. 

384. Cohen AT, Davidson BL, Gallus AS, et al: Efficacy 

and safety of fondaparinux for the prevention of 

venous thromboembolism in older acute medical 

patients: randomised placebo controlled trial. BMJ 

332: 325, 2006. 

385. Buller HR, Davidson BL, Decousus H, et al: 

Fondaparinux or enoxaparin for the initial treatment 

of symptomatic deep venous thrombosis. A 

randomized trial. Ann Intern Med 140: 867, 2004. 

385a. Decousus H, Prandoni P, Mismetti P, et al for the 

CALISTO Study Group: Fondaparinux for the 

treatment of superficial-vein thrombosis in the 

legs. N Engl J Med 363: 1222, 2010. 

386. The Matisse Investigators: Subcutaneous 

fondaparinux versus intravenous unfractionated 

heparin in the initial treatment of pulmonary embolism. 

N Engl J Med 349: 1695, 2003. 

387. Mehta SR, Steg PG, Granger CB, et al for the AS- 

PIRE Investigators: Randomized, blinded trial 

comparing fondaparinux with unfractionated 

heparin in patients undergoing contemporary percutaneous 

coronary intervention. Arixtra Study in 

Percutaneous Coronary Intervention: A randomized 

evaluated (ASPIRE) pilot trial. Circulation 

111: 1390, 2005. 

387a. FUTURA-OASIS 8 Trial Group, Steg PG, Jolly SS, 

Mehta SR, et al: Low-dose vs standard-dose unfractionated 

heparin for percutaneous coronary intervention 

in acute coronary syndromes treated with 

fondaparinux: the FUTURA-OASIS 8 randomized 

trial. JAMA 304: 1339, 2010. 

388. The Fifth Organization to Assess Strategies in 

Acute Ischemic Syndromes Investigators: Comparison 

of fondaparinux and enoxaparin in acute 


389. Mehta SR, Granger CB, Eikelboom JW, et al: Efficacy 

and safety of fondaparinux versus enoxaparin 

in patients with acute coronary syndromes undergoing 

percutaneous coronary intervention. Results 

from the OASIS-5 Trial. J Am Coll Cardiol 50: 1742, 

2007. 

390. Sculpher MJ, Lozano-Ortega G, Sambrook J, et al: 

Fondaparinux versus enoxaparin in non-ST-elevation 

acute coronary syndromes: short-term cost 

and long-term cost-effectiveness using data from 

the Fifth Organization to Assess Strategies in Acute 

Ischemic Syndromes Investigators (OASIS-5) Trial. 

Am Heart J 157: 845, 2009. 

391 Jolly SS, Faxon DP, Fox KAA, et al: Efficacy and 

safety of fondaparinux versus enoxaparin in patients 

with acute coronary syndromes treated with 

glycoprotein IIb/IIIA inhibitors or thienopyridines. 

Results from the OASIS-5 Trial. J Am Coll 

Cardiol 54: 468, 2009. 

392. The OASIS-6 Trial Group: Effects of fondaparinux 

on mortality and reinfarction in patients with 

acute ST-segment elevation myocardial infarction. 

The OASIS-6 Randomized Trial. JAMA 295: 1519, 

2006. 

393. Turpie AGG: Fondaparinux in the management of 

patients with ST-elevation acute myocardial infarction. 

Vasc Health Risk Mgmt 2: 371, 2006. 

394. Mehta SR, Boden WE, Eikelboom JW, et al: Antithrombotic 

therapy with fondaparinux in relation 

to interventional management strategy in patients 

with ST-segment and non-ST-segment elevation 

acute coronary syndromes. An individual patientlevel 

combined analysis of the Fifth and Sixth 

Organization to Assess Strategies in Ischemic Syndromes 

(OASIS 5 & 6) Randomized Trials. Circulation 

118: 2038, 2008. 

395. The van Gogh Investigators: Idraparinux versus 

standard therapy for venous thrombo-embolic disease. 

N Engl J Med 357: 1084, 2007. 

395a. Harenberg J: Development of idraparinux and idrabiotaparinux 

for anticoagulant therapy. Thromb 

Haemost 102: 811, 2009. 

396. Hirsh J: Oral anticoagulant drugs. N Engl J Med 

324:1865, 1991. 

396a. Ansell J, Hirsh J, Hylek E, et al: Pharmacology and 

management of the vitamin K antagonists: American 

College of Chest Physicians evidence-based 

clinical practice guidelines (8th ed). Chest 133: 

160S, 2008. 

397. Koch-Weser J, Sellers EM: Drug interactions with 

coumarin anticoagulants. N Engl J Med 285:487– 

498, 547, 1971. 

398. Wells PS, Holbrook AM, Crowther NR, et al: Interactions 

of warfarin with drugs and food. Ann 

Intern Med 121:676, 1994. 

398a. Ozer N, Cam N, Tangurek B, et al: The impact of 

CYP2C9 and VKORC1 genetic poly-morphism 

and patient characteristics upon warfarin dose re-

quirements in an adult Turkish population. Heart 

Vessels 25: 155, 2010. 

399. Raskob GE, Pineo GE, Hull RD: The technique of 

administering oral anticoagulant therapy. J Crit Illness 

6:923, 1991. 

400. Hirsh J: Substandard monitoring of warfarin in 

North America. Time for change. Arch Intern Med 

152:257, 1992. 

401. Guyatt GH, Cook DJ, Jaeschke R, et al: Grades of 

recommendation for antithrombotic agents. ACCP 

evidence-based practice guidelines 8th ed. Chest 

133:123S, 2008. 

402. Hirsh J, Dalen JE, Deykin D, et al: Oral anticoagulants. 

Mechanism of action, clinical effectiveness 

and optimal therapeutic range. Chest 108:231S, 

1995. 

403. Warkentin TE: Venous thromboembolism in heparin-induced 

thrombocytopenia. Curr Opin Pulm 

Med 6:343, 2000. 

404. Moriarty HT, Lam-PO-Tang PR, Anastas N: Comparison 

of the thromboplastins using the ISI and 

INR system. Pathology 22:71, 1990. 

405. Van den Bessellar AMHP, Lewis SM, Mannucci 

PM: Status of present and candidate international 

reference preparations (IRP) of thromboplastins 

for the prothrombin time: A report of the subcommittee 

for the control of anticoagulation. Thromb 

Haemost 69:85, 1993. 

406. Cannegeiter SC, Rosendaal FR: Optimal oral anticoagulation 

for patients with mechanical heart 

valves. N Engl J Med 333:11, 1995. 

407. Cortelazzo S. Finazzi G, Viero P, et al: Thrombotic 

and hemorrhagic complications in patients with 

mechanical heart valve prosthesis attending an anticoagulation 

clinic. Thromb Haemost 69:316, 1993. 

408. Rosendaal FR: The Scylla and Charybdis of oral anticoagulant 

treatment. N Engl J Med 335:587, 1996. 

409. Turpie AG, Gent M, Laupacis A, et al: Comparison 

of aspirin with placebo in patients treated with 

warfarin after heart valve replacement. N Engl J 

Med 329:524, 1993. 

410. Fihn SD: Aiming for safe anticoagulation. N Engl J 

Med 333:54, 1995. 

411. Stein PD, Alpert JS, Bussey HI, et al: Antithrombotic 

therapy in patients with mechanical and 

biological prosthetic heart valves. Chest 119(Suppl 

1):220S, 2001. 

412. Salem DN, Daudelin HD, Levine HJ, et al: Antithrombotic 

therapy in valvular heart disease. Chest 

119(Suppl 1):207S, 2001. 

413. Singer DE, Albers GW, Dalen JE, et al: Antithrombotic 

therapy in atrial fibrillation. Chest 133(Suppl 

1):546S, 2008. 

414. Hylek EM, Skates SJ, Sheehan MA, et al: An analy- 


sis of the lowest effective intensity of prophylactic 

anticoagulation for patients with non-rheumatic 

atrial fibrillation. N Engl J Med 335:540, 1996. 

415. The European Atrial Fibrillation Trial Study Group: 

Optimal oral anticoagulant therapy in patients 

with non-rheumatic atrial fibrillation and recent 

cerebral ischemia. N Engl J Med 333:5, 1995. 

416. Yamaguchi T, for Japanese Nonvalvular Atrial 

Fibrillation-Embolism Secondary Prevention Cooperative 

Study Group: Optimal intensity of warfarin 

therapy for secondary prevention of stroke 

in patients with nonvalvular atrial fibrillation. A 

multicenter, prospective, randomized trial. Stroke 

31:817, 2000. 

417. Veterans Administration Cooperative Study: Anticoagulants 

in acute myocardial infarction: results 

of a cooperative clinical trial. JAMA 225:724, 1973. 

418. International Anticoagulant Review Group: Collaborative 

analysis of long-term anticoagulant 

administration after acute myocardial infarction. 

Lancet 1:203, 1970. 

419. ASPECT Research Group: Effect of long-term oral 

anticoagulant treatment on mortality and cardiovascular 

morbidity after myocardial infarction. 

Lancet 343:400, 1994. 

420. Smith P, Arnesen H, Holme I: The effect of warfarin 

on mortality and reinfarction after myocardial 


421. Azar AJ, Cannegieter SC, Deckers JW, et al: Optimal 

intensity of oral anticoagulant therapy after 

myocardial infarction. J Am Coll Cardiol 27:1349, 

1996. 

422. Cohen M, Adams PC, Parry G, et al, and the Antithrombotic 

Therapy in Acute Coronary Syndromes 

Research Group: Combination antithrombotic 

therapy in unstable rest angina and non-Q-wave 

infarction in nonprior aspirin users. Primary end 

points analysis from the ATACS trial. Circulation 

89:81, 1994. 

423. Cannegieter SC, Rosendaal FR, Wintzen AR, et 

al: Optimal oral anticoagulant therapy in patients 

with mechanical heart valves. N Engl J Med 333:11, 

1995. 

424. Chesebro JH, Fuster V: Optimal antithrombotic 

therapy for mechanical prosthetic heart valves. Circulation 

94:2055, 1996. 

425 Altman R, Rouvier J, Gurfinkel E, et al: Comparison 

of high-dose with low-dose aspirin in patients 

with mechanical heart valve replacement treated 

with oral anticoagulant. Circulation 94:2113, 1996. 

426. Massel D, Little SH: Risks and benefits of adding 

anti-platelet therapy to warfarin among patients 

with prosthetic heart valves: A meta-analysis. J Am 

Coll Cardiol 37:569, 2001.


427. Collaborative Group of the Primary Prevention 

Project (PPP): Low-dose aspirin and vitamin E in 

people at cardiovascular risk: A randomised trial in 

general practice. Lancet 357:89, 2001. 

428. Ezekowitz MD, Bridgers SL, James KE, et al, for the 

Veterans Affairs Stroke Prevention in Nonrheumatic 

Atrial Fibrillation Investigators: Warfarin in 

the prevention of stroke associated with nonrheumatic 

atrial fibrillation. N Engl J Med 327:1406, 

1992. 

429 Atrial Fibrillation Investigators: Risk factors for 

stroke and efficacy of anti-thrombotic therapy in 

atrial fibrillation: Analysis of pooled data from 

five randomized controlled trials. Arch Intern Med 

154:1449, 1994. 

430. The Stroke Prevention in Atrial Fibrillation Investigators: 

Predictors of thromboembolism in atrial 

fibrillation: I. Clinical features of patients at risk. 


431. Singer DE, Chang Y, Fang MC, et al: The net clinical 

benefit of warfarin anticoagulation in atrial fibrillation. 

Ann Intern Med 151: 297, 2009. 

432. Mant J, Hobbs R, Fletcher K, et al: Warfarin versus 

aspirin for stroke prevention in an elderly community 

population with atrial fibrillation (the Birmingham 

Atrial Fibrillation Treatment of the Aged 

Study, BAFTA): a randomised controlled trial. Lancet 

370: 493, 2007. 

433. Mungall D, White R: Aging and warfarin therapy. 


434. Choudhry NK, Soumerai SB, Normand SLT, et al: 

Warfarin prescribing in atrial fibrillation: the impact 

of physician, patient, and hospital characteristics. 

Am J Med 119: 607, 2006. 

435. Verheugt FWA: Good old warfarin for stroke prevention 

in atrial fibrillation (commentary). Lancet 

367: 1877, 2006. 

435a. Hansen ML, Sorensen R, Clausen MT, et al: Risk 

of bleeding with single, dual, or triple therapy with 

warfarin, aspirin and clopidogrel in patients with 

atrial fibrillation. Arch Intern Med 170: 1433, 2010. 

436. Presti CF, Hart RG: Thyrotoxicosis, atrial fibrillation 

and embolism revisited. Am Heart J 117:976, 

1989. 

437. ten Berg JM, Kelder JC, Suttorp MJ, et al: Effect of 

coumarins started before coronary angioplasty on 

acute complications and long-term follow up. A 

randomized trial. Circulation 102:386, 2000. 

438. Aguilar MI, Hart RG, Kase CS, et al: Treatment of 

warfarin-associated intracerebral hemorrhage: literature 

review and expert opinion. Mayo Clin Proc 

82: 82, 2007. 

439. Garcia DA, Regan S, Crowther M, Hylek EM: The 

risk of hemorrhage among patients with warfarin- 

associated coagulopathy. J Am Coll Cardiol 47: 804, 

2006. 

440. DeZee KJ, Shimeall WT, Douglas KM, et al: Treatment 

of excessive anticoagulation with phytonadione 

(vitamin K). Arch Intern Med 166: 391, 2006. 

441. Sun DK, Frishman WH, Grossman M: Adverse 

dermatologic effects of cardiovascular drug therapy. 

In Frishman WH, Sonnenblick EH (eds): Cardiovascular 

Pharmacotherapeutics. NY: McGraw 

Hill 1997; 1005. 

442. Gage BF, Birman-Deych E, Radford MJ, et al: Risk 

of osteoporotic fracture in elderly patients taking 

warfarin. Arch Intern Med 166: 241, 2006. 

443. Lerner RG, Aronow WS, Sekhri A, et al: Warfarin 

use and the risk of valvular calcification. J Thromb 

Haemost 7: 2023, 2009. 

444. Hall JAG, Pauli RM, Wilson KM: Maternal and fetal 

sequelae of anticoagulation during pregnancy. 

Am J Med 68:122, 1980. 

445. Anderson JL, Horne BD, Stevens SM, et al: Randomized 

trial of genotype-guided versus standard 

warfarin dosing in patients initiating oral anticoagulation. 

Circulation 116: 2563, 2007. 

446. Rosove MH, Grody WW: Should we be applying 

warfarin pharmacogenetics to clinical practice? 

No, not now. Ann Intern Med 151: 270, 2009. 

447. Smith WL: Prostanoid biosynthesis and mechanisms 

of action. Am J Physiol 263:F181, 1992. 

448. Gresele P, Deckmyn H, Giuseppe G, et al: Thromboxane 

synthase inhibitors, thromboxane receptor 

antagonists and dual blockers in thrombotic disorders. 

Trends Pharmacol Sci 12:158, 1991. 

449. Zeidner JF, Frishman WH, Lerner RG: Investigational 

antiplatelet drugs for the treatment and prevention 

of coronary artery disease. Cardiol in Rev 

16: 250, 2008. 

450. Fiddler GI, Lumley P: Preliminary studies with 

thromboxane synthase inhibitors and thromboxane 

receptor blockers: A review. Circulation 

81(Suppl I):I69, 1990. 

451. Reilly, IA, Doran JB, Smith B, Fitzgerald GA: Increased 

thromboxane biosynthesis in a human 

preparation of platelet activation. Biochemical and 

functional consequences of selective inhibition of 

thromboxane synthase. Circulation 73:1300, 1986. 

452. Terres W, Kupper W, Hamm CW: Resting myocardial 

ischemia after intravenous infusion of 

BM 13.177, a thromboxane receptor antagonist. 

Thromb Res 48:577, 1987. 

453. Lane IF, Irwin JTC, Jennings SA, et al: A specific 

thromboxane receptor antagonist evaluated in vascular 

graft patients. Br J Surg 71:903, 1984. 

454. Meadows TA, Bhatt DL: Clinical aspects of platelet 

inhibitors and thrombus formation. Circ Res 100:

1261, 2007. 

455. Gresele P, Deckymyn H, Arnout J, et al: Characterization 

of N,N`-bis(3-picolyl)-4-Methoxy-Isophtalamide 

(picotamide) as a dual 

thromboxane synthase inhibitor/thromboxane A 2 

receptor antagonist in human platelets. Thromb 

Haemost 61(3):479, 1989. 

456. DeClerk F, Beetens J, deChaffoy D, et al: R 68070: 

Thromboxane A 2 /prostaglandin endoperoxide receptor 

blockade combined in one molecule. Biochemical 

profile in vitro. Thromb Haemost 61(1):35, 

1989. 

457. Hoet B, Falcon C, De Reys S, et al: R68070, a combined 

thromboxane/endoperoxide receptor antagonist 

and thromboxane synthase inhibitor, inhibits 

human platelet activation in vitro and in vivo: A 

comparison with aspirin. Blood 75(3):646, 1990. 

458. Timmermans C, Vrolix M, VanHaecke J, et al: 

Ridogrel in the setting of percutaneous transluminal 

coronary angioplasty. Am J Cardiol 68:463, 

1991. 

459. The RAPT Investigators: The Ridgorel vs. Aspirin 

Patency Trial. Randomized trial of ridogrel, 

a combined thromboxane A 2 synthase inhibitor 

and thromboxane A 2 /prostaglandin endoperoxide 

receptor antagonist vs. aspirin as adjunct to 

thrombolysis in patients with acute myocardial infarction. 


460. Hirsh J, Salzman EW, Harker L, et al: Aspirin and 

other platelet active drugs: Relationship among 

dose, effectiveness and side effects. Chest 95(2):12S, 

1989. 

461. Tranchesi B, Pileggi F, Vercammen E, et al: Ridogrel 

does not increase the speed and rate of coronary 

recanalization in patients with myocardial 

infarction treated with alteplase and heparin. Eur 

Heart J 15(5):660, 1994. 

462. Ritter JM, Barrow SE, Doktor HS, et al: Thromboxane 

A 2 receptor antagonism and synthase inhibition 

in essential hypertension. Hypertension 

22:197, 1993. 

463. Kudo K, Abe K, Chiba S, et al: Role of thromboxane 

A 2 in the hypotensive effect of captopril in essential 


464. Patel JP, Beck LD, Briglia FA, et al: Beneficial effects 

of combined thromboxane and leukotriene receptor 

antagonism in hemorrhagic shock. Crit Care 

Med 23:231, 1995. 

465. Berndt MC, Shen Y, Dopheide SM, et al: The vascular 

biology of the glycoprotein Ib-IX-V complex. 

Thromb Haemost 86(1):178, 2001. 

466. Krupski WC, Bass A, Cadroy Y, et al: Antihemostatic 

and antithrombotic effects of monoclonal 

antibodies against von Willebrand factor in non- 


human primates. Surgery 112:433, 1992. 

467. Furie B, Furie BC, Flaumenhaft R: A journey with 

platelet P-selectin: The molecular basis of granule 

secretion, signalling and cell adhesion. Thromb 

Haemost 86(1):214, 2001. 

468. Ray KK, Morrow DA, Gibson CM, et al: Predictors 

of the rise in vWF after ST elevation myocardial infarction: 

implications for treatment strategies and 

clinical outcome: an ENTIRE-TIMI 23 substudy. 

Eur Heart J 26: 440,2005. 

469. Montalescot G, Philippe F, Ankri A, et al: Early 

increase of von Willebrand factor predicts adverse 

outcome in unstable coronary artery disease: beneficial 

effects of enoxaparin. French Investigators of 

the ESSENCE trial. Circulation 98: 294, 1998. 

470. Spiel AO, Gilbert JC, Jilma B: von Willebrand factor 

in cardiovascular disease. Focus on acute coronary 

syndromes. Circulation 117: 1449, 2008. 

471 Becker RC: The investigation of biomarkers in cardiovascular 

disease: time for a coordinated, international 

effort. Eur Heart J 26: 421, 2005. 

471a. Kiefer TL, Becker RC: Inhibitors of platelet adhesion. 

Circulation 120: 2488, 2009. 

472. Lee JF, Stovall GM, Ellington AD: Aptamer therapeutics 

advance. Curr Opin Chem Biol 10: 282, 

2006. 

473. Gilbert JC, DeFeo-Fraulini T, Hutabarat RM, et al: 

First-in-human evaluation of anti-von Willebrand 

factor therapeutic aptamer ARC1779 in healthy 

volunteers. Circulation 116: 2678, 2007. 

474. Blann AD: Plasma von Willebrand factor, thrombosis, 

and the endothelium: the first 30 years. 

Thromb Haemost 95: 49, 2006. 

475. Reininger AJ, Heijnen HF, Schumann H, et al: 

Mechanism of platelet adhesion to von Willebrand 

factor and microparticle formation under high 

shear stress. Blood 107: 3537, 2006. 

476. Husted S, Emanuelsson H, Heptinstall S, et al. 

Pharmacodynamics, pharmacokinetics, and safety 

of the oral reversible P2Y12 antagonist AZD6140 

with aspirin in patients with atherosclerosis: A 

double-blind comparison to clopidogrel with aspirin. 

Eur Heart J 27:1038, 2006. 

476a. Gaglia MA Jr., Manoukian SV, Waksman R: Novel 

antiplatelet therapy. Am Heart J 160: 595, 2010. 

476b. Nawarskas JJ, Clark SM: Ticagrelor: a novel reversible 

oral antiplatelet agent. Cardiol in Rev 19: 2011 

in press. 

477. Schömig A: Ticagrelor – is there need for a new 

player in the antiplatelet-therapy field? (editorial). 

New Engl J Med 361: 1108, 2009. 

477a. Storey RF, Angiolillo DJ, Patil SB, et al: Inhibitory 

effects of ticagrelor compared with clopidogrel on 

platetlet function in patients with acute coronary


syndromes. The PLATO (PLATelet inhibition and 

patient Outcomes) PLATELET Substudy. J Am Coll 

Cardiol 56: 1456, 2010. 

478. Cannon CP, Husted S, Harrington RA, et al for the 

DISPERSE-2 Investigators: Safety, tolerability, and 

initial efficacy of AZD6140, the first reversible oral 

adenosine diphosphate receptor antagonist, compared 

with clopidogrel, in patients with non-ST 

segment elevation acute coronary syndromes. Primary 

results of the DISPERSE-2 Trial. J Am Coll 

Cardiol 50: 1844, 2007. 

479. Storey RF, Husted S, Harrington RA, et al: Inhibition 

of platelet aggregation by AZD6140, a reversible 

oral P2N 12 receptor antagonist, compared with 

clopidogrel in patients with acute coronary syndromes. 


480. Wallentin L, Becker RC, Budaj A, et al for the PLA- 

TO Investigators: Ticagrelor versus clopidogrel in 

patients with acute coronary syndromes. N Engl J 

Med 361: 1045, 2009. 

481. James S, Akerblom A, Cannon CP, et al: Comparison 

of ticagrelor, the first reversible oral P2Y 12 receptor 

antagonist, with clopidogrel in patients with 

acute coronary syndromes: rationale, design and 

basline characteristics of the PLATelet inhibition 

and patient Outcomes (PLATO) trial. Am Heart J 

157: 599, 2009. 

481a. Wallentin L, James S, Storey RF, et al for the PLA- 

TO Investigators: Effect of CYP2C19 and ABCB1 

single nucleotide polymorphisms on outcomes of 

treatment with ticagrelor versus clopidogrel for 

acute coronary syndromes: a genetic substudy of 

the PLATO trial. Lancet August 27, 2010 (epub 

ahead of print). 

481b. Gurbel PA, Bliden KP, Butler K, et al: Response to 

ticagrelor in clopidogrel nonresponders and responders 

and effect of switching therapies. The RE- 

SPOND study. Circulation 121: 1188, 2010. 

482. Antoniades C, Tousoulis D, Stefanadis C. Nitric 

oxide-releasing aspirin: Will it say NO to atherothrombosis? 

Intl J Cardiol 118:170, 2007. 

483. Fiorucci S, Mencarelli A, Mannucci R, et al. NCX- 

4016, a nitric oxide-releasing aspirin, protects endothelial 

cells against apoptosis by modulating 

mitochondrial function. FASEB J 16:1645, 2002. 

484. Gresele P, Momi S. Pharmacologic profile and 

therapeutic potential of NCX 4016, a nitric oxidereleasing 

aspirin, for cardiovascular disorders. Cardiovasc 

Drug Rev 24:148, 2006. 

485. Fu Y, Wang Z, Chen W, et al. Cardioprotective 

effects of nitric oxide-aspirin in myocardial 

ischemia-reperfused rats. Am J Physiol Heart Circ 

Physiol 293: H1545, 2007. 

486. Napoli C, Aldini G, Wallace JL, et al. Efficacy and 

age-related effects of nitric oxide-releasing aspirin 

on experimental restenosis. Proc Natl Acad Sci USA 

99:1689, 2002. 

487. Muscara MN, Lovren F, McKnight W, et al. Vasorelaxant 

effects of a nitric oxide-releasing aspirin 

derivative in normotensive and hypertensive rats. 

Br J Pharmacol 133:1314, 2001. 

488. Lorusso R, De Cicco G, Beghi C, et al. Functional 

effects of nitric oxide-releasing aspirin on vein conduits 

of diabetic patients undergoing CABG. Intl J 

Cardiol 118: 164, 2007. 

489. Jayet PY, Thalmann S, Sartori C, et al. Nitro-Aspirin 

improves insulin sensitivity in obese subjects 

(abst). Circulation 110 Suppl III: III-820, 2004. 

490. Gresele P, Migliacci R, Bonizzoni E, et al. Nitroaspirin 

prevents effort-induced endothelial dysfunction 

in intermittent claudication (abst). Circulation 

110(Suppl III): III-520, 2004. 

491. Wu CC, Teng CM. Comparison of the effects of 

PAR1 antagonists, PAR4 antagonists, and their 

combinations of thrombin-induced human platelet 

activation. Eur J Pharmacol 546: 142, 2006. 

491a. Leonardi S, Tricoci P, Becker RC: Thrombin receptor 

antagonists for the treat-ment of atherothrombosis. 

Therapeutic potential of vorapaxar and 

E-5555. Drugs 70: 1771, 2010. 

492. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, et al. 

Protease-activated receptors 1 and 4 mediate activation 

of human platelets by thrombin. J Clin Invest 

103:879, 1999. 

493. Xu Y, Huo Y, Toufektsian MC. Activated platelets 

contribute importantly to myocardial reperfusion 

injury. Am J Physiol Heart Circ Physiol 290:H692, 

2006. 

494. Becker RC, Moliterno DJ, Jennings LK, et al for 

the TRA-PCI Investigators: Safety and tolerability 

of SCH530348 in patients undergoing non-urgent 

percutaneous coronary intervention: a randomised, 

double-blind, placebo-controlled phase II study. 

Lancet 373: 919, 2009. 

495. Tanigawa T, Nishikawa M, Kitai T, et al: Increased 

platelet aggregability in response to shear stress in 

acute myocardial infarction and its inhibition by 

combined therapy with aspirin and cilostazol after 

coronary intervention. Am J Cardiol 85:1054, 2000. 

496. Park S-W, Lee CW, Kim H-S, et al: Comparison of 

cilostazol versus ticlopidine therapy after stent implantation. 

Am J Cardiol 84:511, 1999. 

497. Han Y, Li Y, Wang S, et al: Cilostazol in addition 

to aspirin and clopidogrel improves long-term 

outcomes after percutaneous coronary intervention 

in patients with acute coronary syndromes: a 

randomized, controlled study. Am Heart J 157: 733, 

2009.

498. Jeong YH, Lee SW, Choi BR, et al: Randomized 

comparison of adjunctive cilostazol versus high 

maintenance dose clopidogrel in patients with high 

post-treatment platelet reactivity. Results of the 

ACCEL-RESISTANCE (Adjunctive Cilostazol vs 

High Maintenance Dose Clopidogrel in Patients 

with Clopidogrel Resistance) randomized study. J 


499. Yasue H, Ogawa H, Tanaka H, et al, on behalf of the 

Japanese Antiplatelets Myocardial Infarction Study 

(JAMIS) Investigators: Effects of aspirin and trapidil 

on cardiovascular events after acute myocardial 

infarction. Am J Cardiol 83:1308, 1999. 

500. Cruz-Fernandez JM, Lopez-Bescos L, Garcia-Dorado 

D, et al, and Triflusal in Myocardial Infarction 

(TIM) Investigators: Randomized comparative 

trial of Triflusal and aspirin following acute myocardial 

infarction. Eur Heart J 21:457, 2000. 

501. Hirsh J, O’Donnell M, Eikelboom JW: Beyond unfractionated 

heparin and wafarin. Current and future 

advances. Circulation 116: 552, 2007. 

502. Turpie AGG: New oral anticoagulants in atrial fibrillation. 

Eur Heart J 29: 155, 2007. 

503. Lohrmann J, Becker RC: New anticoagulants – the 

path from discovery to clinical practice. N Engl J 

Med 358: 2827, 2008. 

504. Fiessiner JN, Huisman MV, Davidson BL, et al 

for the THRIVE Treatment Study Investigators: 

Ximelagatran vs low molecular weight heparin and 

warfarin for the treatment of deep vein thrombosis. 

A randomized trial. JAMA 293: 681, 2005. 

505. Executive Steering Committee on behalf of the 

SPORTIF III Investigators: Stroke prevention with 

the oral direct thrombin inhibitor ximelagatran 

compared with warfarin in patients with non-valvular 

atrial fibrillation (SPORTIF III): randomised 

controlled trial. Lancet 362: 1691, 2003. 

506. Ford GA, Choy AM, Deedwania P, et al: Direct 

thrombin inhibition and stroke prevention in elderly 

patients with atrial fibrillation. Experience 

from SPORTIF III and V Trials. Stroke 38: 2965, 

2007. 

507. Wallentin L, Wilcox RG, Weaver WD, et al for the 

ESTEEM Investigators: Oral ximelagatran for secondary 

prophylaxis after myocardial infarction: the 

ESTEEM randomised controlled trial. Lancet 362: 

789, 2003. 

508. Sanford M, Plosker GL: Dabigatran etexilate. Drugs 

68: 1699, 2008. 

509. Eriksson BI, Dahl OE, Rosencher N, et al for the 

RE-NOVATE Study Group: Dabigatran etexilate 

versus enoxaparin for prevention of venous 

thromboembolism after total hip replacement: a 

randomised, double-blind, non-inferiority trial. 


Lancet 370: 949, 2007. 

510. Eriksson BI, Dahl OE, Rosencher N, et al: Oral 

dabigatran etexilate vs subcutaneous enoxparin for 

the prevention of venous thromboembolism after 

total knee replacement: the RE-MODEL randomized 

trial. J Thromb Haemost 5: 2178, 2007. 

511. Eriksson BI, Dahl OE, Buller R, et al: A new oral 

direct thrombin inhibitor, dabigatran etexilate, 

compared with enoxaparin for prevention of 

thromboembolic events following total hip or knee 

replacement. The BISTRO II randomized trial. J 


512. Connolly SJ, Ezekowitz MD, Yusuf S, et al for the 

RE-LY Steering Committee and Investigators: Dabigatran 

versus warfarin in patients with atrial fibrillation. 

N Engl J Med 361: 1139, 2009. 

512a. Wallentin L, Yusuf S, Ezekowitz MD, et al: Efficacy 

and safety of dabigatran compared with warfarin 

at different levels of international normalised ratio 

control for stroke prevention in atrial fibrillation: 

an analysis of the RE-LY trial. Lancet 376: 975, 

2010. 

513. Lip GYH, Rasmussen LH, Olsson SB, et al: Oral direct 

thrombin inhibitor AZD0837 for the prevention 

of stroke and systemic embolism in patients 

with non-valvular atrial fibrillation: a randomized 

dose-guiding, safety and tolerability study of four 

doses of AZD0837 vs vitamin K antagonists. Eur 

Heart J 30: 2897, 2009. 

514. Toomey JR, Abboud MA, Valocik RE, et al: A comparison 

of B-D-xyloside, odiparcil, to warfarin in 

a rate model of venous thrombosis. J Thromb Haemost 

4: 1989, 2006. 

515. Chen T, Lam S: Rivaroxaban. An oral direct factor 

Xa inhibitor for the prevention of thromboembolism. 


516. Duggan ST, Scott LJ, Plosker GL: Rivaroxaban: a review 

of its use for the prevention of venous thromboembolism 

after total hip or knee replacement 

surgery. Drugs 69: 1829, 2009. 

516a. Morell J, Sullivan B, Khalabuda M, McBride BF: 

Role of orally available antagonists of factor Xa in 

the treatment and prevention of thromboembolic 

disease: focus on rivaroxaban. J Clin Pharmacol 50: 

986, 2010. 

517. Eriksson BI, Borris LC, Friedman RJ, et al for the 

RECORD1 Study Group: Rivaroxaban versus 

enoxaparin for thromboprophylaxis after hip arthroplasty. 

N Engl J Med 358: 2765, 2008. 

518. Kakkar AK, Brenner B, Dahl OE, et al for the 

RECORD2 Investigators: Extended duration 

rivaroxaban versus short-term enoxaparin for 

the prevention of venous thrombo-embolism 

after total hip arthroplasty: a double-blind, ran-


domised controlled trial. Lancet 372: 32, 2008. 

519. Lassen MR, Ageno W, Borris LC, et al for the RE- 

CORD3 Investigators: Rivaroxaban versus enoxaparin 

for thromboprophylaxis after total knee 

arthroplasty. N Engl J Med 358: 2776, 2008. 

520. Turpie AGG, Lassen MR, Davidson BL, et al for 

the RECORD4 Investigators: Rivaroxaban versus 

enoxaparin for thromboprophylaxis after total 

knee arthroplasty (RECORD4): a randomised trial. 

Lancet 373: 1673, 2009. 

521. Buller HR, Lensing AWA, Prins MH, et al on behalf 

of the Einstein-DVT Dose Ranging Study Investigators: 

A dose-ranging study evaluating once 

daily oral administration of the factor Xa inhibitor 

rivaroxaban in the treatment of patients with acute 

symptomatic deep vein thrombisL the Einstein- 

DVT dose ranging study. Blood 112: 2242, 2008. 

522. Agnelli G, Gallus A, Goldhaber SZ, et al for the 

ODIXa-DVT Study Investigators: Treatment of proximal 

deep vein thrombosis with the oral direct factor 

Xa inhibitor rivaroxaban (BAY59-7939): the ODIXa- 

DVT (oral direct factor Xa inhibitor BAY59-7939 in 

patients with acute symptomatic deep vein thrombosis) 


522a. The Executive Steering Committee on behalf of 

the ROCKET AF Study Investigators: Rivaroxaban 

– once daily, oral, direct factor Xa inhibition compared 

with vitamin K antagonism for prevention 

of stroke and embolism trial in atrial fibrillation: 

rationale and design of the ROCKET AF study. Am 

Heart J 159: 340, 2010. 

522b. Patel MR, Mahaffey KW, Garg J, Rivaroxaban 

versus warfarin in nonvalvular atrial fibrillation. 

N Engl J Med August 10, 2011 epub. 

523. Mega JL, Braunwald E, Mohanavelu S, et al on behalf 

of the ATLA ACS-TIMI 46 study group: Rivaroxaban 

versus placebo in patients with acute 

coronary syndromes (ATLAS ACS-TIMI 46): a 

randomised, double-blind, phase II trial. Lancet 

374: 29, 2009. 

523a. The EINSTEIN Investigators: Oral rivaroxaban for 

symptomatic venous thrombo-embolism. N Engl J 

Med 363: 2499, 2010. 

523b. Cohen AT, Spiro TE, Büller HR, et al: Extended- 

duration rivaroxaban thromboprophylaxis in 

acutely ill medical patients: MAGELLAN study 

protocol. J Thromb Thrombolysis 31: 407, 2011 

524. Tyberg A, Dias S, Lerner RG, Frishman WH: Oral 

anticoagulant medications in clinical development. 

Cardiol in Rev in press. 

525. Lassen MR, Raskob GE, Gallus A, et al: Apixaban 

or enoxaparin for thromboprophylaxis after knee 

replacement. N Engl J Med 361: 594, 2009. 

526. Lassen MR, Raskob GE, Gallus A, et al for the AD- 

VANCE-2 Investigators: Apixaban versus enoxaparin 

for thromboprophylaxis after knee replacement 

(ADVANCE-2): a randomised double-blind trial. 

Lancet 375: 807, 2010. 

526a. Lassen MR, Gallus A, Raskob GE, et al: Apixaban 

versus enoxaparin for thrombo-prophylaxis after 

hip replacement. N Engl J Med 363: 2487, 2010. 

527. APPRAISE Steering Committeee and Investigators: 

Apixaban, an oral, direct, selective factor Xa inhibitor, 

in combination with antiplatelet therapy after 

acute coronary syndrome. Results of the Apixaban for 

Prevention of Acute Ischemic and Safety Events (AP- 

PRAISE) trial. Circulation 119: 2877, 2009. 

527a. Granger CB, Alexander JH, McMurray JJV, et al 

for the ARISTOTLE Committee and Investigators: 

Apixaban versus warfarin in patients with 

atrial fibrillation. N Engl J Med August 28, 2011 

epub. 

527b. Eikelboom JW, O’Donnell M, Yusuf S, et al: Rationale 

and design of AVERROES: Apixaban versus 

acetylsalicylic acid to prevent stroke in atrial fibrillation 

patients who have failed or are unsuitable for 

vitamin K antagonist treatment. Am Heart J 159: 

348, 2010. 

527c. Connolly SJ, Eikelboom J, Joyner C, et al for the 

AVERROES Steering Committee and Investigators: 

Apixaban in patients with atrial fibrillation. N Engl 

J Med 364: 806, 2011. 

527d. APPRAISE-2 study with investigational compound 

apixaban in acute coronary syndrome discontinued. 

BusinessWire November 18, 2010. www. 

businesswire.com/news/bms/20101118007161/en/ 

APPRAISE-2-study-investigational-compoundapixaban-acute-coronary. 

528. Agnelli G, Haas G, Ginsberg JS, et al: A phase II 

study of the oral factor Xa inhibitor LY517717 for 

the prevention of venous thromboembolism after 

hip or knee replacement. J Thromb Haemost 5: 746, 

2007. 

528a. Ogata K, Mendell-Harary J, Tachibana M, et al: 

Clinical safety, tolerability, pharm-acokinetics, and 

pharmacodynamics of the novel factor Xa inhibitor 

edoxaban in healthy volunteers. J Clin Pharmacol 

50: 743, 2010. 

528b. Schirmer SH, Baumhakel M, Neuberger H-R, et al: 

Novel anticoagulants for stroke prevention in atrial 

fibrillation: current clinical evidence and future development. 


529. Turpie AGG, Bauer KA, Davidson BL, et al for the 

EXPERT Study Group: A randomized evaluation 

of betrixaban, an oral factor Xa inhibitor, for prevention 

of thromboembolic events after total knee 

replacement (EXPERT). Thromb Haemost 101: 68, 

2009.

530. Konishi N, Hiroe K, Sinozawa E, et al: Antithrombotic 

profiles of TAK-442, a novel oral factor Xa 

inhibitor, in venous and aterial thrombosis models. 

J Thromb Haemost 7 Suppl 2: PP-WE-400 abstract, 

2009. 

530a. Hylek EM: Therapeutic potential of oral factor Xa 

inhibitors. N Engl J Med 363: 2559, 2010. 

531. Baughman RA, Kapoor SC, Agarwal RK, et al: 

Oral delivery of anticoagulant doses of heparin. A 

randomized, double-blind, controlled study in humans. 


532. Eriksson BI, Dahl OE, Lassen DP, et al Partial factor 

IXa inhibition with TTP889 for prevention of 

venous thromboembolism: an exploratory study. J 


532a. Cohen MG, Purdy DA, Rossi JS, et al: First clinical 

application of an actively reversile direct factor IXa 

inhibitor as an anticoagulation strategy in patients 


Circulation 122: 614, 2010. 

533. Steffel J, Luscher TF: Novel anticoagulants in clinical 

development: focus on factor Xa and direct thrombin 

inhibitors. J Cardiovasc Med 10: 616, 2009. 

534. Hinder M, Frick A, Jordaan P, et al: Direct and rapid 

inhibition of factor Xa by otamixaban: a pharmacokinetic 

and pharmacodynamic investigation 

in patients with coronary artery disease. Clin Pharmacol 

Ther 80: 691, 2006. 

535. Sabatine MS, Antman EM, Widimsky P, et al: Otamixaban 

for the treatment of patients with non-STelevation 

acute coronary syndromes (SEPIA-ACS1 

TIMI 42): a randomised, double-blind, active-controlled, 

phase 2 trial. Lancet 374:787, 2009. 

536. Cohen M, Bhatt DL, Alexander JH, et al on behalf 

of the SEPIA-PCI Trial Investigators: Randomized, 

double-blind, dose-ranging study of otamixaban, 

a novel, parenteral, short-acting direct factor Xa 

inhibitor, in percutaneous coronary intervention. 

The SEPIA-PCI trial. Circulation 115: 2642, 2007. 

537. Hirsh J, O’Donnell M, Weitz JI: New anticoagulants. 

Blood 105: 453, 2005. 

538. Chesebro JH, Rauch U, Fuster V, Badimon JJ: 

Pathogenesis of thrombosis in coronary artery disease. 

Haemostasis 27(Suppl 1):12, 1997. 

539. Toschi V, Gallo R, Lettino M, et al: Tissue factor 

modulates the thrombogenicity of human atherosclerotic 

plaques. Circulation 95:594, 1997. 

540. Banai S, Gertz SD: Tissue factor as a therapeutic 

target in coronary syndromes. Am J Cardiol 763:87, 

2001. 

541. Friederich PW, Levi M, Bauer KA, et al: Ability of 

recombinant factor VIIa to generate thrombin during 

inhibition of tissue factor in human subjects. 

Circulation 103:2555, 2001. 


542. Giugliano RP, Wiviott SD, Stone PH, et al for the 

ANTHEM-TIMI-32 Investigators: Recombinant 

nematode anticoagulant protein c2 in patients with 

non-ST-segment elevation acute coronary syndrome. 


543. Shibata M, Kumar SR, Amar A, et al: Anti-inflammatory, 

antithrombotic, and neuroprotective effects 

of activated protein C in a murine model of 

focal ischemic stroke. Circulation 103:1799, 2001. 

544. Dalhbäck B: Protein S and C4b-binding protein: 

Components involved in the regulation of the 

protein C anticoagulant system. Thromb Haemost 

66:49, 1991. 

545 Arljots B, Bergqvist D, Dahlbäck B: Inhibition of 

microarterial thrombosis by activated protein C in 

a rabbit model. Thromb Haemost 72:415, 1994. 

546. Esmon CT: Inflammation and thrombosis: Mutual 

regulation by protein C. Immunologist 6:84, 1998. 

547. Bernard GR, Vincent JL, Laterre PF, et al: Recombinant 

human protein C Worldwide Evaluation in 

Severe Sepsis (PROWESS) study group. Efficacy 

and safety of recombinant human activated protein 

C for severe sepsis. N Engl J Med 344(10):699, 2001. 

548. Esmon CT: The roles of protein C and thrombomodulin 

in the regulation of blood coagulation. J 

Biol Chem 258:12238, 1983. 

549. Ireland H, Kunz G, Kyriakoulis K, et al: Thrombomodulin 

gene mutations associated with myocardial 

infarction. Circulation 96:15, 1997. 

550. Nakashima M, Uematsu T, Umemura K et al: A 

novel recombinant soluble human thrombomodulin, 

ART-123, activates the protein C pathway in 

healthy male volunteers. J Clin Pharmacol 38:540, 

1998. 

551. Eikelboom JW, Weitz JI: update on antithrombotic 

therapy. New anticoagulants. Circulation 121: 1523, 

2010. 

552. RD Heparin Arthroplasty Group: RD heparin 

compared with warfarin for prevention of venous 

thromboembolic disease following total hip or 

knee arthroplasty. J Bone Joint Surg 76: 1174, 1994. 

553. Spiro TE, Fitzgerald RH, Trowbridge AA, et al: 

Enoxaparin low molecular weight heparin for the 

prevention of venous thromboembolic disease after 

knee replacement surgery. Blood 83: 246a, 1994. 

554. Heit JA, Berkowitz Sd, Bona R, et al: Efficacy and 

safety of low molecular weight heparin (ardeparin 

sodium) compared to warfarin for the prevention 

of venous thromboembolism after total knee replacement: 

a double-blind, dose-ranging study: 

Ardeparin Arthroplasty Study Group: Thromb 

Haemost 77: 32, 1997.


Thrombolytic Agents 

Robert Forman, MD 


1. Collen D: Fibrin-selective thrombolytic therapy 

for acute myocardial infarction. Circulation 93:857, 

1996. 

2. Robbins KC, Summaira L., Hsieh B, Shah RJ: The 

peptide chains of human plasmin. Mechanism of 

activation of human plasminogen to plasmin. J Biol 

Chem 242:2333, 1967. 

3. Granger CB, Califf RM, Topol EJ: Thrombolytic 

therapy for acute myocardial infarction. Drugs 

44:293, 1992. 

4. Collen D, Verstrate M: Pharmacology of thrombolytic 

drugs. In: Schlant RC, Alexander RW, eds. 

Hurst’s The Heart, 8th ed. New York: McGraw Hill, 

1994:1327. 

5. Kamat SG, Michelson AD, Benoit SE, et al: Fibrinolysis 

inhibits shear stress-induced platelet aggregation. 


6. Collen D: On the regulation of control of fibrinolysis. 

Thromb Haemost 43:77, 1980. 

7. Anderson HV, Willerson JT: Thrombolysis in acute 

myocardial infarction. N Engl J Med 329:703, 1993. 

8. Modi NB, Fox NL, Clow F-W, et al: Pharmacokinetics 

and pharmacodynamics of tenecteplase: Results 

from a phase II study in patients with acute 

myocardial infarction. J Clin Pharmacol 40:508, 

2000. 

9. van de Werf F, Cannon CP, Luyten A, et al for the 

ASSENT-1 investigators: Safety assessment of single-bolus 

administration of TNK tissue-plasminogen 

activator in acute myocardial infarction: The 

ASSENT-1 trial. Am Heart J 137:786, 1999. 

10. Torr SR, Nachowiak DA, Fujui S, Sobel BE: Plasminogen 

steal and clot lysis. J Am Coll Cardiol 

19:1085, 1992. 

11. Davies, MJ, Thomas, AC: Plaque fissuring—the 

cause of acute myocardial infarction, sudden 

ischemic death and crescendo angina. Br Heart J 

53:363, 1985. 

12. DeWood MA, Spokes J, Notske R, et al: Prevalence 

of total coronary occlusion during early hours of 

transmural myocardial infarction. N Engl J Med 

303:897, 1980. 

13. Reimer KA, Lowe JE, Rasmussen MM, Jennings 

RB: The wake-front phenomenon of ischemic cell 

death l. Myocardial infarct size versus duration 

of coronary occlusion in dogs. Circulation 56:786, 

1977. 

14. Rentrop P, Blanke H, Karsch KR, et al: Acute myocardial 

infarction. Intracoronary application of nitroglycerin 

and streptokinase. Clin Cardiol 2:354, 

1979. 

15. Rentrop P, Blanke H, Karsch KR, et al: Selective 

intracoronary thrombolysis in acute myocardial 

infarction and unstable angina. Circulation 63:307, 

1981. 

16. Kennedy JW, Ritchie JL, Davis KB, et al: The Western 

Washington randomized trial of intracoronary 

streptokinase in acute myocardial infarction. N 

Engl J Med 309:1477, 1983. 

17. Kennedy JW, Ritchie JL, Davis KB, et al: The Western 

Washington randomized trial of intracoronary 

streptokinase in acute myocardial infarction. N 

Engl J Med 312:1073, 1985. 

18. van Domburg RT, Sonnenschein K, Nieuwlaat R, 

et al: Sustained benefit 20 years after reperfusion 

therapy in acute myocardial infarction. J Am Coll 

Cardiol 46: 15, 2005. 

19. Gruppo Italiano per lo Studio della streptochinasi 

nell’infarto miocardico (GISSI): Effective intravenous 

thrombolytic treatment in acute myocardial 


20 ISIS-2 (Second International Study of Infarct Sur- 



19-1


vival) Collaborative Group:Randomized trial of 

intravenous streptokinase, oral aspirin, both or 

neither among 17,187 cases of suspected acute 

myocardial infarction: ISIS-2. Lancet 2:349, 1988. 

21. The ISAM Study Group: A prospective trial of intravenous 

streptokinase in acute myocardial infarction 

(ISAM) mortality, morbidity, and infarct 

size at 21 days. N Engl J Med 314:1465, 1986. 

22. AIMS Trial Study Group: Effect of intravenous 

APSAC on mortality after acute myocardial infarction: 

Preliminary report of a placebo-controlled 

clinical trial. Lancet 1:842, 1988. 

23. AIMS Trial Study Group: Long-term effects of 

intravenous anistreplase in acute myocardial infarction: 

Final report of the AIMS study. Lancet 

335:427, 1990. 

24. Wilcox RG, Von der Lippe G., Olson G, et al: Trial 

of tissue plasminogen activator for mortality reduction 

in acute myocardial infarction: Anglo-Scandinavian 

Study of Early Thrombolysis (ASSET). 

Lancet 2:525, 1988. 

25. Gruppo Italiano per lo Studio Della sopravvivenza 

nell’infarcto miocardico. GISSI-2: A factorial randomized 

trial of alteplase versus streptokinase and 

heparin versus no heparin among 12,490 patients 

with acute myocardial infarction. Lancet 336:65, 

1990. 

26. Third International Study of Infarct Survival Collaborative 

Group. ISIS-3: A randomized comparison 

of streptokinase versus tissue plasminogen 

activator versus anistreplase and of aspirin plus 

heparin nobreak versus aspirin alone among 

41,299 cases of suspected acute myocardial infarction. 

Lancet 339:753, 1992. 

27. The GUSTO Investigators: An international randomized 

trial comparing four thrombolytic strategies 


329:673, 1993. 

28. Califf RM, White HD, Van de Werf F, et al: Oneyear 

results from the Global Utilization of Streptokinase 

and tPA for Occluded Coronary Arteries 

(GUSTO-1) trial. Circulation 94:1233, 1996. 

29. Mueller HS, Rao AK, Forman SA: The TIMI Investigators 

thrombolysis in myocardial infarction 

(TIMI): Comparative studies of coronary reperfusion 

and systemic fibrinogenolysis with two forms 

of recombinant tissue-type plasminogen activator. 


30. The Continuous Infusion versus Double-Bolus Administration 

of Alteplase (COBOLT) Investigators: 

A comparison of continuous infusion of alteplase 

with double-bolus administration for acute myocardial 


31. Bode C, Smalling RW, Berg G, et al for RAPID II 

Investigators; Randomized comparison of coronary 

thrombolysis achieved with double-bolus reteplase 

(recombinant plasminogen activators) and 

front-loaded, accelerated alteplase (recombinant 

tissue plasminogen activator) in patients with acute 


32. International Joint Efficacy Comparison of thrombolytics: 

Randomized, double-blind comparison of 

reteplase double-bolus administration with streptokinase 

in acute myocardial infarction (INJECT): 

Trial to investigate equivalence Lancet 346:329, 

1995. 

33. Global Use of Strategies to Open Coronary Arteries 

(GUSTO III) Investigation: Comparison of 

reteplase with alteplase for acute myocardial infarction. 

N Engl J Med 337:1118, 1997. 

34. Assessment of the Safety and Efficacy of a New 

Thrombolytic (ASSENT-2) Investigators: Single 

bolus tenecteplase compared with front-loaded 

alteplase in acute myocardial infarction: The AS- 

SENT-2 double-blind trial. Lancet 354:716, 1999. 

35. EMERAS (Estudio Multicentrico Estreptoquinasa 

Republicas de America del Sur) Collaborative 

Group: Randomized trial of late thrombolysis in 

patients with suspected acute myocardial infarction. 

Lancet 342:767, 1993. 

36. LATE Study Group: Late assessment of thrombolysis 

efficacy (LATE). Study with alteplase after onset 

of acute myocardial infarction. Lancet 342:759, 

1993. 

36a. Lambert L, Brown K, Segal I, et al: Association 

between timeliness of reperfusion therapy and 

clinical outcomes in ST-elevation myocardial infarction. 

JAMA 303: 2148, 2010. 

37. Morrison LJ,Verbeek PR, McDonald AC,et al. Mortality 

and prehospital thrombolysis for acute myocardial 

infraction: a meta-analysis - JAMA 283:2686, 

2000. 

38. Steg PG, Bonnefoy E, Chbaud S et al. Impact of 

time to treatment on mortality after prehospital fibrinolysis 

or primary angioplasty: data from CAP- 

TIM randomized clinical trial. Circulation 108: 

2851, 2003. 

39. Bottiger BW, Arntz H-R, Chamberlain DA, et al for 

the TROICA Trial Investigators and the European 

Resuscitation Council Study Group: Thrombolysis 

during resuscitation for out-of-hospital cardiac arrest. 

N Engl J Med 359: 2651, 2008. 

40. Stadlbauer KH, Krismer AC, Arntz HR, et al: Effects 

of thrombolysis during out-of-hospital cardiopulmonary 

resuscitation. Am J Cardiol 97: 305, 

2006. 

41. Stenestrand U, Lindback J, Wallentin L for the 

RIKS-HIA Registry: Long-term outcome of pri-

mary percutaneous coronary intervention vs prehospital 

and in-hospital thrombolysis for patients 

with ST-elevation myocardial infarction. JAMA 

296: 1749, 2006. 

42. Chesboro JH, Knatterud G, Roberts R, et al: 

Thrombolysis in myocardial infarction (TIMI) 

trial, phase 1: A comparison between intravenous 

and tissue plasminogen activator and intravenous 

streptokinase. Circulation 76:142, 1987. 

43. Dalen JE: Six and twelve month follow-up of phase 

1 thrombolysis in myocardial infarction (TIMI) 

trial. Am J Cardiol 62:179, 1988. 

44. The GUSTO angiographic investigators: The effects 

of tissue plasminogen activator, streptokinase, or 

both on coronary artery patency, ventricular function 

and survival after acute myocardial infarction. 

N Engl J Med 329:1615, 1993. 

45. Gillis JC, Wagstaff AJ, Goa KL: Alteplase. Reapproval 

of its pharmacolgic properties and therapeutic 

uses in acute myocardial infarction. Drugs 

50:101, 1995. 

46. Rurors JA, McNeil AJ, Siddiqui RT, et al: Efficacy 

of 100-mg of double-bolus alteplase in achieving 

complete perfusion in the treatment of acute myocardial 

infarction. J Am Coll Cardiol 23:6, 1944. 

47. Smalling RW, Bode C, Kalbfleisch J, et al and RAP- 

ID investigators: More rapid, complete, and stable 

coronary thrombolysis with bolus administration 

of reteplase compared with alteplase infusion in 

acute myocardial infarction. Circulation 91:2725, 

1995. 

48. Cannon CP, McCable CH, Gibson CM, et al and 

TIMI 10A investigators. TNK-tissue plasminogen 

activator in acute myocardial infarction. Results of 

thrombolysis in myocardial infarction (TIMI) 10A 

dose ranging trial. Circulation 95:351, 1997. 

49. Cannon CP, Gibson CM, McCabe CH, et al for 

TIMI 10B investigators. TNK-tissue plasminogen 

activator compared with front loaded alteplase in 

acute myocardial infarction. Circulation 98:2805, 

1998. 

50. Gibson CM, Murphy SA, Kirtane AJ et al. Association 

of duration of symptoms at presentation with 

angiographic and clinical outcomes after fibrinolytic 

therapy in patients with ST-segment elevation 

myocardial infarction. J Am Coll Cardiol 44:980, 

2004. 

51. Goldman LE, Eisenberg MJ: Identification and 

management of patients with failed thrombolysis 

after acute myocardial infarction. Ann Intern Med 

132:556, 2000. 

52. Ohman EM, Califf RM, Topol EJ, et al: Consequences 

of reocclusion after successful reperfusion 

therapy in acute myocardial infarction. Circulation 


82:781, 1990. 

53. Pilote L, Miller DP, Califf RM, et al: Determinants 

of the use of coronary angiography and revascularization 

after thrombolysis for acute myocardial 


54. Barbarsh GI, Birnbaum Y, Bogaerts K, et al: Treatment 

of reinfarction after thrombolytic therapy for 

acute myocardial infarction. An analysis of outcome 

and treatment choices in the Global Utilization of 

Streptokinase and Tissue Plasminogen Activator 

for Occluded Coronary Arteries (GUSTO I) and 

Assessment of the Safety of a New Thrombolytic 

(ASSENT 2) studies. Circulation 103:954, 2001. 

55. White HD: Thrombolytic treatment for recurrent 

myocardial infarction. Avoid repeating streptokinase 

or anistreplase. BMJ 302:429, 1991. 

56. Barbash GI, Hod H, Roth A. et al: Repeat infusions 

of recombinant tissue-type plasminogen activator 

in patients with acute myocardial infarction and 

recurrent myocardial ischemia. J Am Coll Cardiol 

16:779, 1990. 

57. Wijeysundera HC, Vijayraghavan R, Brahamjee K 

et al. Rescue angioplasty or repeat fibrinolysis after 

failed therapy for ST-segment myocardial infarction. 

A meta-analysis of randomized trials. J Am 


58. Anderson JL, Karagounis LA, Becker LC, et al: 

TIMI perfusion grade 3 but not grade 2 results 

improve outcome after thrombolysis for myocardial 

infarction. Ventriculographic enzymatic, and 

electrocardiographic evidence from the TEAM-3 


59. Simes RJ, Topol EJ, Holmes DR: Link between angiographic 

substudy and mortality outcomes in a 

large randomized trial of myocardial reperfusion. 

Importance of early and complete infarct artery reperfusion. 


60. Gibson CM, Murphy SA, Rizzo MJ et al: Relationship 

between TIMI frame count and clinical 

outcomes after thrombolytic administration. Circulation 

99:1945, 1999. 

61. Grines CL, DeMaria AN: Optimal utilization of 

thrombolytic therapy for acute myocardial infarction: 

Concepts and controversies. J Am Coll Cardiol 

16:223, 1990. 

62. Fibrinolytic Therapy Trialists (FTT) Collaborative 

Group: Indications for fibrinolytic therapy in suspected 

acute myocardial infarction: Collaborative 

overview of early mortality and major morbidity 

in results from all randomized trials of more than 

1000 patients. Lancet 343:311, 1994. 

63. The TIMI IIIB Investigators: Effects of tissue plasminogen 

activator and comparison of early invasive 

and conservative strategies in unstable angina


and non-Q wave myocardial infarction. Results of 

the TIMI IIIB trial. Circulation 89:1545, 1994. 

64. Braunwald E, Cannon PC: Non Q wave and ST segment 

depression myocardial infarction: Is there a 

role for thrombolytic therapy? J Am Coll Cardiol 

27:1333, 1996. 

65. Langes A, Goodman SG, Topol EJ, et al: Late assessment 

of thrombolytic efficacy (LATE) Study: 

Prognosis in patients with non-Q wave myocardial 

infarcts. J Am Coll Cardiol 27:1327, 1996. 

66. Sgarbossa EB, Pinski SL, Barbagelata A, et al for 

GUSTO-1 investigators. Electrocardiographic diagnosis 

of evolving acute myocardial infarction in 

the presence of left bundle branch block. N Eng J 

Med 344:481, 1996. 

67. Holmes DR, Bates ER, Kleinman NS, et al: Contemporary 

reperfusion therapy for cardiogenic 

shock: The GUSTO-1 trial experience. J Am Coll 

Cardiol 26:668, 1995. 

68. Hochman JS, Sleeper LA, Webb JG, et al: Early 

revascularization in acute myocardial infarction 

complicated by cardiogenic shock. N Eng J Med 

341:625, 1999. 

69. Berger AK, Radford MJ, Wang Y, Krumholz HM: 

Thrombolytic therapy in older patients. J Am Coll 

Cardiol 36:366, 2000. 

70. Ayanian JZ, Braunwald E: Thrombolytic therapy 

for patients with myocardial infarction who are 

older than 75 years. Do the risks outweigh the benefits? 

Circulation 101:2224, 2000. 

71. Mateen FJ, Nasser M, Spencer BR, et al: Outcomes 

of intravenous tissue plasminogen activator for 

acute ischemic stroke in patients aged 90 years or 

older. Mayo Clin Proc 84: 334, 2009. 

72. Lenefsky EJ, Lundergan CF, Hodgson JMcB, et al: 

Increased left ventricular dysfunction in elderly 

patients despite successful thrombolysis. The GUS- 

TO-1 angiographic experience. J Am Coll Cardiol 

28:331, 1996. 

73. Thiemann DZR, Coresh J, Schulman SP, et al: Lack 

of benefit for intravenous thrombolysis in patients 

with myocardial infarction who are older than 75 

years. Circulation 101:2239, 2000. 

74. White HD: Thrombolytic therapy in the elderly 

(editorial). Lancet 356:2028, 2000. 

75. Ridker PM, Hennekens CH: Age and thrombolytic 

therapy. Circulation 94:1807, 1996. 

76. Antman EM, Giugliano RP, Gibson C.M., et al: 

Abciximab facilitates the rate and extent of thrombolysis. 

Results of the Thrombolysis in Myocardial 

Infarction (TIMI) 14 trial. Circulation 99:2720, 

1999. 

77. Neumann F-J, Zohlnhofer D, Fakhoury D, et al: Effect 

of glycoprotein IIb/IIIa. Receptor blockade on 

platelet/leukocyte interaction and surface expression 

of the leukocyte integrin Mac-1 in acute myocardial 

infarction. J Am Coll Cardiol 34:1420, 1999. 

78. Ohman EM, Kleiman NS, Gacioch G, et al for 

IMPACT-AMI Investigators: Combined accelerated 

tissue plasminogen activator and platelet glycoproteins 

IIb/IIIa. Integrin receptor blockage with 

integrelin in acute myocardial infarction. Results 

of a randomized, placebo-controlled dose-ranging 


79. Strategies for Patency Enhancement in the Emergency 

Department (SPEED) Group Trial of abciximab 

with and without low-dose reteplase for acute 


80. Gibson CM., deLemos JA, Murphy SA, et al: 

Combination therapy with abciximab reduces angiographically 

evident thrombus in acute myocardial 

infarction. A TIMI 14 Sub-study. Circulation 

103:2550, 2001. 

81. The GUSTO V Investigators. Reperfusion therapy 

for acute myocardial infarction with fibrinolytic 

therapy or combination reduced fibrinolytic therapy 

and platelet glycoprotein IIb/IIIa inhibition: 

The GUSTO V randomized Trial. Lancet 357:1905, 

2001. 

82. Assessment of the Safety and Efficacy of a New 

Thrombolytic regimen (ASSENT-3) investigators: 

Efficacy and safety of tenecteplase in combination 

with enoxaparin, abciximab or unfractionated 

heparin: The ASSENT-3 randomized trial in acute 

myocardial infarction. Lancet 358:605, 2001. 

83. Eisenberg PR, Sherman LA, Jaffe AS: Paradoxical 

elevation of fibrinopeptide A: Evidence for continued 

thrombosis despite intensive fibrinolysis. J Am 


84. Aronson DL, Chang P, Kessler CM: Platelet-dependent 

thrombin generation after in vitro-fibrinolytic 

treatment. Circulation 85:1706, 1992. 

85. Fitzgerald DJ, Catella F, Roy L, et al: Marked platelet 

activation in vivo after intravenous streptokinase 

in patients with acute myocardial infarction. 


86. Keller NM, Feit F: Thrombolytic therapy in acute 

MI, Part 2: Update on adjuvants. J Crit Illness 

13:646, 1998. 

87. Handin, R.I.: Platelets and coronary artery disease. 

N Engl J Med 334:1126, 1996. 

88. Sabatine MC, Cannon CP, Gibson CM et al. Addition 

of clopidogrel to aspirin and fibrinolytic 

therapy for myocardial infarction with ST-segment 

elevation. N Eng J Med 352:1179, 2005. 

89. Granger CB, Becker R, Tracy RP, et al for the 

GUSTO-I Hemostasis Substudy Group: Thrombin 

generation, inhibition and clinical outcomes in pa-

tients with acute myocardial infarction treated with 

thrombolytic therapy and heparin: Results from 

the GUSTO-I trial. J Am Coll Cardiol 31:497, 1998. 

90. Topol EJ, George BS, Kareiakes DJ, et al: A randomized 

trial of intravenous tissue plasminogen 

activator and early intravenous heparin in acute 


91. Hsia JA, Hamilton WP, Kleinman N, et al: A comparison 

between heparin and low dose aspirin as 

adjunctive therapy with tissue plasminogen activator 


323:1433, 1990. 

92. DeBono DP, Simoons ML, Tijssen J: Effect of early 

intravenous heparin on coronary patency, infarct 

size, and bleeding complications after alteplase. 

Thrombolysis: Results of a randomized doubleblind 

European Cooperative Study Group Trial. Br 

Heart J 67:122, 1992. 

93. Hirsh J, Fuster V: Guide to anticoagulant therapy, 

part 1: Heparin. Circulation 89:1449, 1994. 

94. International Study Group: In-hospital mortality 

and clinical course of 20,891 patients with suspected 

acute myocardial infarction randomized 

between alteplase and streptokinase. Lancet 336:71, 

1990. 

95. The SCATI (Studio sulla Calciparina nell’Angina e 

nella Trombosi Ventricolare nell’ Infarto) Group: 

Randomized controlled trial of subcutaneous calcium 

heparin in acute myocardial infarction. Lancet 

2:182, 1989. 

96. The Global Use of Strategies to Open Occluded 

Coronary Arteries (GUSTO) IIa Investigators: 

Randomized trial of intravenous heparin versus recombinant 

hirudin for acute coronary syndromes. 


97. Antman EM for TIMI9A Investigators: Hirudin in 

acute myocardial infarction safety report from the 

thrombolysis and thrombin inhibitors in myocardial 

infarction (TIMI) 9A trial. Circulation 90:1624, 

1994. 

98. Nehaus KL, Essen R, Tebbe U, et al: Safety observations 

from the pilot phase of randomized versus hirudin 

for improvement of thrombolysis (HIT-III) 


99. Jang I-K, Brown DFM, Giugliano RP, et al for the 

MINT Investigators: A multicenter, randomized 

study of argatroban versus heparin as adjunct to 

tissue plasminogen activator (TPA) in acute myocardial 

infarction: Myocardial Infarction with Novastan 

and TPA (MINT) Study. J Am Col Cardiol 

33:1879, 1999. 

100. American College of Cardiology/American Heart 

Association Task Force on Practice Guidelines: 

1999 Update: ACC/AHA guidelines for manage- 


ment of patients with acute myocardial infarction: 

Executive summary and recommendations Circulation 

100:1016, 1999. 

101. Antman EM, Morrow DA, McCabe CH et al. 

Enoxaparin versus unfractionated heparin with 

fibrinolysis for ST-elevation myocardial infarction. 

N Eng J Med 1477:354 2006. 

102. Collet JP, Montalescot G, Le May M et al Percutaneous 

coronary intervention after fibrinolysis: a 

multiple meta-analysis approach according to the 

type of strategy. J Am Coll Cardiol. 48:1326, 2006. 

103. Assessment of safety and efficiency of a new treatment 

strategy with percutaneous coronary intervention 

(ASSENT-4PCI) investigators. Primary 

versus tenectplase- facilitated percutaneous coronary 

intervention in patients with ST-segment elevation 

acute myocardial infarction (ASSENT-4 

PCI): randomized trial, Lancet 367:569, 2006. 

104. Cantor WJ, Fitchett D, Borgundvaag B et al. Routine 

early angioplasty after fibrinolysis for acute 

myocardial infarction. N Eng J Med 360-2705, 

2009. 

105. Khawaja FJ and Ting H. Quality dimensions of primary 

percutaneous coronary intervention. Timeliness, 

access, and availability. Circulation 120:2411, 

2009. 

106. Aguirre FA, Varghese JJ, Kelly MP et al. Rural interhospital 

transfer of ST-elevation myocardial infarction 

patients for revascularization. The stat heart 

program. Circulation. 117:1145, 2008. 

107. Keely EC, Boura JA, and Grines CL. Primary angioplasty 

versus intravenous thrombolytic therapy 

for acute myocardial infarction: a quantitative review 

of 23 randomized trials. Lancet 361:12, 2003. 

108. Patel SC, Mody A: Cerebral hemorrhage complications 

of thrombolytic therapy. Prog Cardiovasc Dis 

42:217, 1999. 

109. Berkowitz SD, Granger CB, Pieper KS, et al for the 

GUSTO I Investigators: Incidence and predictors 

of bleeding after contemporary thrombolytic therapy 

for myocardial infarction. Circulation 95:2508, 

1997. 

110. Sloan MA, Gore JM: Ischemic stroke and intracranial 

hemorrhage following thrombolytic therapy 

for acute myocardial infarction: Benefit analysis. 

Am J Cardiol 69:21A, 1991. 

111. DeJaegere PP, Arnold AA, Balk AH, Simoons 

ML: Intracranial hemorrhage in association with 

thrombolytic therapy: Incidence and clinical predictive 

factors. J Am Coll Cardiol 19:289, 1992. 

112. Longstreth WT, Litwin PE, Weaver WD, MITI 

project group: Myocardial infarction, thrombolytic 

therapy and stroke. A community-based study. 

Stroke 24:587, 1993.


113. Gore JM, Sloan M, Price TR, et al: Intracranial 

hemorrhage, cerebral infarction, and subdural 

hematoma after acute myocardial infarction and 

thrombolytic therapy in thrombolysis in myocardial 

infarction study. Thrombolysis in Myocardial 

Infarction. Phase II Pilot and Clinical Trial. Circulation 

83:448, 1991. 

114. Sane DE, Califf RM, Topol EJ, et al: Bleeding during 

thrombolytic therapy for acute myocardial infarction: 

Mechanisms and management. Ann Interrn 

Med 3:1012, 1989. 

115. Patel MR, Meine TJ, Lindblad L, et al: Cardiac tamponade 

in the fibrinolytic era: analysis of >100 000 

patients with ST-segment elevation myocardial infarction. 

Am Heart J 151: 316, 2006. 

116. Honan MB, Harrell FE, Reiner KA, et al: Cardiac 

rupture, mortality and timing of thrombolytic 

therapy: A meta-analysis. J Am Coll Cardiol 16:359, 

1990. 

117. Becker RC, Charlesworth A, Wilcox RG, et al: Cardiac 

rupture associated with thrombolytic therapy: 

Impact of time to treatment in the Late Assessment 

of Thrombolytic Efficacy (LATE) Study. J Am Coll 

Cardiol 25:1063, 1995. 

118. Deviri E, Sareli P, Wisenbaugh T, Cronje SL: Obstruction 

of mechanical heart valve prostheses: 

Clinical aspects and surgical management. J Am 


119. Kontos GJ, Schaft HV, Orszulak TA, et al: Thrombolytic 

obstruction of disc valves: Clinical recognition 

and surgical management. Ann Thorac Surg 

48:60, 1989. 

120. Roudaut R, Labbe T, Lorient-Roudaut MF, et al: 

Mechanical cardiac valve thrombosis: Is fibrinolysis 

justified? Circulation 86(Suppl. 2):II-8, 1992. 

121. Hurrell DG, Schaft HV, Tajik AJ: Thrombolytic 

therapy for obstruction of mechanical prosthetic 

valves. Mayo Clin Proc 71:605, 1996. 

122. Tong AT, Roudaut R, Ozkan M et al. Transesophageal 

echocardiography improves the risk 

assessment of thrombolysis of prosthetic valve 

thrombosis: results of the international PRO-TEE 

registry. Circulation 43: 77, 2004. 

123. Shapiro Y, Herz I, Vaturi M, et al. Thrombolysis 

is an effective and safe therapy in stuck bi-leaflet 

mitral valves in the absence of high-risk thrombi. J 


124. Ozkan M, Kaymaz C, Kirma C et al: Intravenous 

thrombolytic treatment of mechanical prosthetic 

valve thrombosis: A study using serial transesophageal 

echocardiography. J Am Coll Cardiol 35:1881, 

2000. 

125. Bonow RO, Carabello BA, Chatterjee K et al. 2008 

focused update incorporated into the ACC/AHA 

guidelines for management of patients with valvular 

heart disease. Circulation 118: e523, 2008. 

126. Sasahara AA, Myers TH, Cole CM, et al: The Urokinase 

Pulmonary Embolism Trial. A national cooperative 


127. Dalla-Volta S, Palla A, Santolicandro A, et al: PAIMS 

2: Alteplase combined with heparin versus heparin 

in the treatment of acute pulmonary embolism. 

Plasminogen Activator Italian Multicenter Study 2. 

J Am Coll Cardiol 20; 520, 1992. 

128. Meyer G, Sors H, Charbonnier B, et al: Effects of 

intravenous urokinase versus alteplase on total 

pulmonary resistance in acute massive pulmonary 

embolism: A European multicenter double-blind 


128a. Wang C, Zhai Z, Yang Y, et al: Efficacy and safety 

of low dose recombinant tissue-type plasminogen 

activator for the treatment of acute pulmonary 

thromboembolism. A randomized, multicenter, 

controlled trial. Chest 137: 254, 2010. 

129. Goldhaber SZ: Contemporary pulmonary embolism 

thrombolysis. Chest 107:45, 1995. 

130. Goldhaber SZ, Kessler CM, Heit JA, et al: A randomized 

control trial of recombinant tissue 

plasminogen activator versus urokinase in the 

treatment of acute pulmonary embolism. Lancet 

2:193, 1988. 

131. Goldhaber SZ, Kessler CM, Heit JA, et al: Recombinant 

tissue type plasminogen activator versus a 

novel dosing regimen of urokinase in acute pulmonary 

embolism: A randomized controller multicenter 

trial. J Am Coll Cardiol 20:20,1992. 

132. Goldhaber SZ, Haire WD, Feldstein ML, et al: Alteplase 

versus heparin in acute pulmonary embolism: 

Randomized trial assessing right ventricular 

and pulmonary perfusion. Lancet 341:507, 1993. 

133. Goldhaber SZ: Thrombolytic therapy for patients 

with pulmonary embolism who are hemodynamically 

stable but have right ventricular dysfunction. 

Pro. Arch Intern Med 165: 2197, 2005. 

134. Verstraete M, Miller GAH, Bounamcaux H, et al: 

Intravenous and intra pulmonary recombinant tissue 

- type plasminogen activator in the treatment 

of acute massive pulmonary embolism. Circulation 

77:353, 1988. 

135. Kanstantinedes S, Geibel A, Olschewski M, et al: 

Association between thrombolytic treatment and 

prognosis of hemodynamically stable patients with 

major pulmonary embolism. Circulation 96:882, 

1997. 

136. Thabut G, Thabut D, Myers RP et al. Thrombolytic 

therapy of pulmonary embolism. A meta-analysis. 


137. Wan S, Quinlan DJ, Agnelli G et al. Thrombolysis

compared with heparin for the initial treatment of 

pulmonary embolism. A meta-analysis of the randomized 

control trials. Circulation 110:744,2004. 

138. Konstantinides S, Giebel A, Heusel G, et al. Heparin 

plus alteplase compared with heparin alone in 

patients with submassive pulmonary embolism. N 

Eng J Med 347:1143, 2002. 

139. Goldhaber SZ: Pulmonary embolism thrombolysis. 

Broadening the paradigm for its administration. 


140. Hommel M, Boissel JP, Connu C, et al: Termination 

of trial: Streptokinase in severe acute ischemic 

stroke. Lancet 345:57, 1995. 

141. Donnan GA, Hommel M, Davis SM, McNeil JJ: 

Streptokinase in acute ischemic stroke. Lancet 

346:56, 1995. 

142. The Multicenter Acute Stroke Trial—Europe Study 

Group: Thrombolytic therapy with streptokinase in 

acute ischemic stroke. N Engl J Med 335:145, 1996. 

143. Hacke W, Kaste M, Fieschi C, et al: Intravenous 

thrombolysis with recombinant tissue plasminogen 

activator for acute hemispheric stroke. JAMA 

274:1017, 1995. 

144. The National Institute of Neurological Disorders 

and Stroke rt-PA Stroke Study Group: Tissue plasminogen 

activator for acute ischemic stroke. N 

Engl J Med 333:1581, 1995. 

145. Wahlgren N, Ahmed N, Davalos A, et al for the 

SITS-MOST Investigators: Thrombolysis with alteplase 

for acute ischaemic stroke in the Safe Implementation 

of Thrombolysis in Stroke-Monitoring 

Study (SITS-MOST): an observational study. Lancet 

369: 275, 2007. 

146. Hacke W, Kaste M, Bluhmki E. et al. Thrombolysis 

with alteplase 3 to 4.5 hours after acute ischemic 

stroke. N Eng J Med 359:1317, 2008. 

147. The ATLANTIS, ECASS and NINDS rt-PA Study 

Group Investigators. Association of outcome with 

early stroke treatment; pooled analysis of ATLAN- 

TIS, ECASS, and NINDS rt-PA stroke trials. Lancet 

363:768, 2004. 

148. Adams HP, del Zoppo G, Alberts MJ et al. Guidelines 

for the early management of adults with ischemic 

stroke: a guideline from the American Heart 

Association/ American Stroke Association Stroke 

Council, and the Quality of Care Outcomes in 

Research Interdisciplinary Working Groups: the 

American Academy of Neurology affirms the value 

of this guideline as an educational learning tool for 

neurologists. Stroke 38:1655, 2007. 

149. Weintraub MI: Thrombolysis (tissue plasminogen 

activator) in stroke. A medicolegal quagmire. 

Stroke 37: 1917, 2006. 

150. Furlan A, Higaohida R, Wechsler L, et al: Intra- 


arterial pro-urokinase for acute ischemic stroke: 

The PROACT II Study: A randomized control trial. 

JAMA 282:2003, 1999. 

151. Argaral P, Kumar S, Hariharan S, et al: Hyperdense 

middle cerebral artery sign: can it be used to select 

intra-arterial versus intravenous thrombolysis 

in acute ischemic stroke? Cerebrovasc Dis 17:182, 

2004. 

152. Francis CW, Marde VJ: Fibrinolytic therapy for 

venous thrombosis. Progr Cardiovasc Dis 34:193, 

1991. 

153. Comeroto AJ, et al: Venous thromboembolism. In: 

Rutherford RB, ed. Vascular Surgery, 4th ed. Philadelphia: 

Saunders, 1995:1800. 

154. Schweizer J, Kirch W, Koch R, et al: Short- and 

long-term results after thrombolytic treatment 

of deep venous thrombosis. J Am Coll Cardiol 

36:1336, 2000. 

155. Kearon C, Kahn SR, Angelli G et al. Anti thrombotic 

therapy for venous thromboembolic disease. 

American College of Chest Physicians evidencebased 

clinical practice guidelines (8th edition) 

Chest 2008; 133:454S-554S. 

156. Wagstaff AJ, Gillis JC, Goa KL: Alteplase. A reappraisal 

of its pharmacology and therapeutic use in 

vascular disorders other than acute myocardial infarction. 

Drugs 50:289, 1995. 

157. Hess H: Thrombolytic therapy in peripheral vascular 

disease. Br J Surg 77:1083, 1990. 

158. Lonsdale RJ, Berridge DC, Earnshaw JJ: Recombinant 

tissue-type plasminogen activator is superior 

to streptokinase for local intra-arterial thrombolysis. 

Br J Surg 79:272, 1992. 

159. The Stile Investigators: Results of a prospective randomized 

trial evaluating surgery versus thrombolysis 

for ischemia of the lower extremity. Ann Surg 

220:251, 1994. 

160. Tabriziani H, Schieu A, Frishman WH, Brandt LJ: 

Drug therapies for mesenteric vascular disease. 

Heart Dis 4:306, 2002. 

161. Trans Atlantic Intersociety Consensus (TASC): 

Management of peripheral vascular disease. J Vasc 

Surg 31:S151, 2000. 

162. Sobel M, Verhaeghe R. Antithrombotic therapy 

for peripheral artery occlusive disease. American 

College of Chest Physicians evidence-based clinical 

practice guidelines (8th edition) Chest 133;815S, 

2008. 

163. New applications for thrombolytics: Alteplase in 

the periphery. Formulary 36(Suppl 4): 4, 2001. 

164. Clase CM, Crowther MA, Ingram AJ, Cina CS: 

Thrombolysis for restoration of patency to haemodialysis 

central venous catheters: A systematic 

review. J Thromb Thrombolysis 11:127, 2001.


Lipid-Lowering Drugs 


Wilbert S. Aronow, MD 

1. Stamler J, Wentworth D, Neaton J: Is the relationship 

between serum cholesterol and risk of death 

from coronary heart disease continuous and graded? 

JAMA 256:2823, 1986. 

2. LaRosa JC, Hunninghake D, Bush D, et al: The cholesterol 

facts: A summary of the evidence relating 

dietary fats, serum cholesterol, and coronary heart 

disease. A joint statement by the American Heart 

Association and the National Heart, Lung and 

Blood Institute. Circulation 81:1721, 1990. 

3. Verschuren WMM, Jacobs DR, Bloemberg BPM, 

et al: Serum total cholesterol and s-term coronary 

heart disease mortality in different cultures. Twenty-five 

year follow-up of the Seven Countries Study. 

JAMA 274:131, 1995. 

4. Chien PC, Frishman WH: Lipid disorders. In: 

Crawford MH, ed. Current Diagnosis and Treatment 

in Cardiology, 2nd ed. New York: McGraw 

Hill, 2002:17. 

5. Aronow WS, Ahn C. Risk factors for new coronary 

events in a large cohort of very elderly patients with 

and without coronary artery disease. Am J Cardiol 

77:864, 1996. 

6. Aronow WS, Ahn C. Correlation of serum lipids 

with the presence or absence of coronary artery 

disease in 1,793 men and women aged ³62 years. 

Am J Cardiol 73:702, 1994. 

7. Lipid Research Clinics Program: The Lipid Research 

Clinics Coronary Primary Prevention Trial 

Results: I. Reduction in the incidence of coronary 

heart disease. JAMA 251:351, 1986. 

8. Canner PL, Berge KG, Wenger NK, et al: Fifteen 

year mortality in Coronary Drug Project patients: 

Long-term benefit with niacin. J Am Coll Cardiol 

8:1245, 1986. 

9. Frick MH, Elo MO, Haapa K, et al: Helsinki Heart 

Study: Primary prevention trial with gemfibrozil in 

middle-aged men with dyslipidemia. N Engl J Med 

317:1237, 1987. 

10. Blankenhorn DH, Nessim SA, Johnson RL, et al: 

Beneficial effects of combined colestipol-niacin 

therapy on coronary atherosclerosis and coronary 

venous bypass grafts. JAMA 257:3233, 1987. 

11. The Post Coronary Artery Bypass Graft Investigators. 

The effect of aggressive and moderate lowering 

of low-density lipoprotein cholesterol levels and 

low-dose anticoagulation on obstructive changes 

in saphenous-vein coronary artery bypass grafts. N 

Engl J Med 336:153, 1997. 

12. Alaupovic P, Fesmire JD, Hunninghake D, et al: 

The effect of aggressive and moderate lowering 

of LDL-cholesterol and low dose anticoagulation 

on plasma lipids, apolipoproteins and lipoprotein 

families in post coronary artery bypass graft trial. 

Atherosclerosis 146:369, 1999. 

13. Frick MH, Syvänne M, Nieminen MS et al: Prevention 

of the angiographic progression of coronary 

and vein-graft atherosclerosis by gemfibrozil after 

coronary bypass surgery in men with low levels of 

HDL cholesterol. Circulation 96:2137, 1997. 

14. Ornish D, Brown SE, Scherwitz LW, et al: Can 

lifestyle reverse coronary heart disease? Lancet 

336:129, 1990. 

15. Kane JP, Malloy MJ, Ports TA, et al: Regression of 

coronary atherosclerosis during treatment of familial 

hypercholesterolemia with combined drug 

regimens. JAMA 264:3007, 1990. 

16. Brown G, Albers JJ, Fisher LD, et al: Regression 

of coronary artery disease as a result of intensive 

lipid-lowering therapy in men with high levels of 

apolipoprotein B. N Engl J Med 323:1289, 1990. 

17. Buchwald H, Varco RL, Matts JP, et al: Effect of par- 



20-1


tial ileal bypass surgery on mortality and morbidity 

from coronary heart disease in patients with hypercholesterolemia. 

N Engl J Med 323:946, 1990. 

18. Holme I: Cholesterol reduction and its impact on 

coronary artery disease and total mortality. Am J 

Cardiol 76:10C, 1995. 

19. Haskell WI, Alderman EL, Fair JM, et al: The effects 

of intensive multiple risk factor reduction on 

coronary atherosclerosis and clinical cardiac events 

in men and women with coronary artery disease: 

The Stanford Coronary Risk Intervention Project 

(SCRIP). Circulation 89:975, 1994. 

20. Gould AL, Rossouw JE, Santanello NC, et al: Cholesterol 

reduction yields clinical benefit. A new 

look at old data. Circulation 91:2274, 1995. 

21. Grundy SM, Friedman D: Rationale for cholesterol-lowering 

strategies. Curr Probl Cardiol 20:281, 

1995. 

22. Scandinavian Simvastatin Survival Study Group. 

Randomised trial of cholesterol lowering in 4444 

patients with coronary heart disease: The Scandinavian 

Simvastatin Survival Study (4S). Lancet 

344:1383, 1994. 

23. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering 

therapy in women and elderly 

patients with myocardial infarction or angina pectoris. 

Findings from the Scandinavian Simvastatin 

Survival Study (4S). Circulation 96:4211, 1997. 

24. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of 

simvastatin on ischemic signs and symptoms in the 

Scandinavian Simvastatin Survival Study (4S). Am 

J Cardiol 81:333, 1998. 

25. Pedersen TR, Wilhelmsen L, Faergeman O, et al. 

Follow-up study of patients randomized in the 

Scandinavian Simvastatin Survival Study (4S) of 

cholesterol lowering. Am J Cardiol 86: 257, 2000. 

26. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of 

pravastatin on coronary events after myocardial infarction 

in patients with average cholesterol levels. 

N Engl J Med 335:1001, 1996. 

27. The Long-Term Intervention with Pravastatin 

in Ischaemic Disease (LIPID) Study Group. Prevention 

of cardiovascular events and death with 

pravastatin in patients with coronary heart disease 

and a broad range of initial cholesterol levels. N 

Engl J Med 339:1349, 1998. 

28. The LIPID Study Group: Long-term effectiveness 

and safety of pravastatin in 9014 patients with 

coronary heart disease and average cholesterol 

concentrations: the LIPID trial follow-up. Lancet 

359:1379, 2002. 

29. Heart Protection Study Collaborative Group. 

MRC/BHF Heart Protection Study of cholesterol 

lowering with simvastatin in 20,536 high-risk in- 

dividuals: a randomised placebo-controlled trial. 

Lancet 360:7, 2002. 

30. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin 

in elderly individuals at risk of vascular disease 

(PROSPER): a randomised controlled trial. 

Lancet 360:1623, 2002. 

31. Schwartz GG, Olsson AG, Ezekowitz MD, et al. 

Effects of atorvastatin on early recurrent ischemic 

events in acute coronary syndromes. The MIRA- 

CL study: a randomized controlled trial. JAMA 

285:1711, 2001. 

32. Sever PS, Dahlof B, Poulter NR, et al. Prevention 

of coronary and stroke events with atorvastatin in 

hypertensive patients who have average or lowerthan-average 

cholesterol concentrations, in the 

Anglo-Scandinavian Cardiac Outcomes Trial— 

Lipid Lowering Arm (ASCOT-LLA): a multicentre 

randomised controlled trial. Lancet 361:1149, 2003. 

33. Colhoun HM, Betteridge DJ, Durrington PN, et al. 

Primary prevention of cardiovascular disease with 

atorvastatin in type 2 diabetes mellitus in the Collaborative 

Atorvastatin Diabetes Study (CARDS): 

multicentre randomized placebo-controlled trial. 

Lancet 364: 685, 2004. 

34. Hitman GA, Colhoun H, Newman C, et al on behalf 

of the CARDS investigators:Stroke prediction 

and stroke prevention with atorvastatin in the Collaborative 

Atorvastatin Diabetes Study (CARDS). 

Diabet Med 24: 1313, 2007. 

35. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect 

of intensive compared with moderate lipid-lowering 

therapy on progression of coronary atherosclerosis. 

A randomized controlled trial. JAMA 

291:1071, 2004. 

36. Cannon CP, Braunwald E, McCabe CH, et al. Comparison 

of intensive and moderate lipid lowering 

with statins after acute coronary syndromes. N Engl 

J Med 350:1495, 2004. 

37. Murphy SA, Cannon CP, Wiviott SD, et al. Effect of 

intensive lipid-lowering therapy on mortality after 

acute coronary syndrome (a patient analysis of the 

Aggrastat to Zocor and Pravastatin or Atorvastatin 

Evaluation and Infection Therapy-Thrombolysis in 

Myocardial Infarction 22 trials). Am J Cardiol 100: 

1047, 2007. 

37a. Murphy SA, Cannon CP, Wiviott SD, et al: Reduction 

in recurrent cardiovascular events with intensive 

lipid-lowering statin therapy compared with 

moderate lipid-lowering statin therapy after acute 

coronary syndromes. From the PROVE-IT-TIMI 

22 (Pravastatin or Atorvastatin Evaluation and Infection 

Therapy-Thrombolysis in Myocardial Infarction 

22) trial. J Am Coll Cardiol 54: 2358, 2009. 

38. LaRosa JC, Grundy SM, Waters DD, et al. Intensive

lipid lowering with atorvastatin in patients with 

stable coronary disease. N Eng J Med 352: 1425, 

2005. 

39. Waters DD, LaRosa JC, Barter P, et al: Effects of 

high-dose atorvastatin on cerebrovascular events 

in patients with stable coronary disease in the TNT 

(Treating to New Targets) study. J Am Coll Cardiol 

48: 1793, 2006. 

40. Cholesterol Treatment Trialists’ (CTT) Collaborators. 

Efficacy and safety of cholesterol-lowering 

treatment: prospective meta-analysis of data from 

90 056 participants in 14 randomised trials of 

statins. Lancet 366:1267, 2005. 

41. Deedwania P, Stone PH, Merz CNB, et al. Effects 

of intensive versus moderate lipid-lowering therapy 

on myocardial ischemia in older patients with 

coronary heart disease. Results of the Study Assessing 

Goals in the Elderly (SAGE). Circulation 115: 

700,2007. 

42. Ridker PM, Danielson E, Francisco MIA, et al. Rosuvastatin 

to prevent vascular events in men and 

women with elevated C-reactive protein. N Engl J 

Med 359: 2195, 2008. 

43. Aronow WS, Ahn C. Incidence of new coronary 

events in older persons with prior myocardial infarction 

and serum low-density lipoprotein cholesterol 

≥125 mg/dL treated with statins versus no 

lipid-lowering drug. Am J Cardiol 89:67, 2002. 

44. Aronow WS, Ahn C. Reduction of coronary events 

with aspirin in older patients with prior myocardial 

infarction treated with and without statins. Heart 

Disease 4:159, 2002. 

45. Aronow WS, Ahn C, Gutstein H. Reduction of 

new coronary events and of new atherothrombotic 

brain infarction in older persons with diabetes mellitus, 

prior myocardial infarction, and serum lowdensity 

lipoprotein cholesterol ³125 mg/dL treated 

with statins. J Gerontol: Med Sci 57A:M747, 2002. 

46. Pedersen TR, Faergeman O, Kastelein JJP, et al. 

High-dose atorvastatin vs usual-dose simvastatin 

for secondary prevention after myocardial infarction. 

The IDEAL study: a randomized controlled 

trial. JAMA 294: 2437, 2005. 

47. Aronow WS, Ahn C. Frequency of new coronary 

events in older persons with peripheral arterial disease 

and serum low-density lipoprotein cholesterol 

≥125 mg/dl treated with statins versus no lipidlowering 

drug. Am J Cardiol 90:789, 2002. 

48. Executive Summary of the Third Report of the 

National Cholesterol Education Program (NCEP) 

Expert Panel on Detection, Evaluation and Treatment 

of High Blood Cholesterol in Adults (Adult 

Treatment Panel III). JAMA 285:2486, 2001. 

49. Kannel WB, Castelli WP, Gordon T: Cholesterol 


in the prediction of atherosclerotic disease: New 

perspectives in the Framingham Study. Ann Intern 

Med 90:85, 1979. 

50. Stampfer MJ, Sacks FN, Salvini S, et al: A prospective 

study of cholesterol, apolipoproteins, and 

the risk of myocardial infarction. N Engl J Med 

325:373, 1991. 

51. Gordon DJ, Probstfeld JL, Garrison RJ, et al: Highdensity 

lipoprotein cholesterol and cardiovascular 

disease: Four prospective American series. Circulation 

79:8, 1989. 

52. Rubins HB, Robins SJ, Collins D et al: Gemfibrozil 

for the secondary prevention of coronary heart 

disease in men with low levels of high-density lipoprotein 

cholesterol. N Engl J Med 341:410, 1999. 

53. Hodis HN, Mack WJ: Triglyceride-rich lipoproteins 

and the progression of coronary artery disease. 

Curr Opin Lipidol 6:209, 1995. 

54. Pasternak RC, Grundy SM, Levy D, Thompson PD: 

Task Force 3: spectrum of risk factors for coronary 

heart disease. J Am Coll Cardiol 27:978, 1996. 

55. Kannel WB, Neaton JD, Wentworth D, et al: Overall 

and CHD mortality rates in relation to major risk 

factors in 325,348 men screened for the MRFIT. 

Am Heart J 112:825, 1986. 

56. Gould AL, Roussouw JE, Santanello NC, et al: Cholesterol 

reduction yields clinical benefit. Impact of 

statin trials. Circulation 97:946–952, 1998. 

57. Steinberg D, Gotto AM Jr: Preventing coronary 

artery disease by lowering cholesterol levels. Fifty 

years from bench to bedside. JAMA 282:2043, 1999. 

58. Faergeman O: Hypertriglyceridemia and the fibrate 

trials. Curr Opin Lipidol 11:609, 2000. 

58a. Triglyceride Coronary Disease Genetics Consortium 

and Emerging Risk Factors Collaboration: 

Triglyceride-mediated pathways and coronary disease: 

collaborative analysis of 101 studies. Lancet 

375: 1634, 2010. 

58b. Jun M, Foote C, Lv J, et al: Effects of fibrates on 

cardiovascular outcomes: a systematic review and 

meta-analysis. Lancet 375: 1875, 2010. 

59. Stampfer MJ, Krauss RM, Ma J, et al: A prospective 

study of triglyceride level, low-density lipoprotein 

particle diameter, and risk of myocardial infarction. 

JAMA 276:882, 1996. 

60. Lemieux I, Pascot A, Couillard C, et al: Hypertriglyceridemic 

waist. A marker of the atherogenic 

metabolic triad (hyperinsulinemia; hyperapolipoprotein 

B; small, dense LDL) in men? Circulation 

102:179, 2000. 

61. Myers LH, Phillips NR, Havel RJ: Mathematical 

evaluation of methods for estimation of the concentration 

of the major lipid components of human 

serum lipoproteins. J Lab Clin Med 88:491, 1976.


62. Crouse JR III, Byington RP, Furberg CD: HMG- 

CoA reductase inhibitor therapy and stroke risk 

reduction: An analysis of clinical trials data. Atherosclerosis 

138:11, 1998. 

63. Warshafsky S, Packard D, Marks SJ, et al: Efficacy 

of 3-hydroxy-3-methylglutaryl coenzyme A reductase 

inhibitors for prevention of stroke. J Gen Intern 

Med 14:763, 1999. 

64. Tsimikas S, Brilakis ES, Miller ER, et al: Oxidized 

phospholipids, Lp(a) lipoprotein, and coronary artery 

disease. N Engl J Med 353: 46, 2005. 

65. Sharrett AR, Ballantyne CM, Coady SA, et al: 

Coronary heart disease prediction from lipoprotein 

cholesterol levels, triglycerides, lipoprotein(a), 

apolipoproteins A-I and B, and HDL density subfractions: 

The Atherosclerosis Risk in Communities 

(ARIC) Study. Circulation 104:1108, 2001. 

66. Johnson CL, Rifkind BM, Sempos CT, et al: Declining 

serum total cholesterol levels among US adults. 

The National Health and Nutrition Examination 

Surveys. JAMA 269:3002, 1993. 

67. Ridker PM, Stampfer MJ, Rifai N: Novel risk factors 

for systemic atherosclerosis. A comparison of 

C-reactive protein, fibrinogen, lipoprotein (a), and 

standard cholesterol screening as predictors of peripheral 

arterial disease. JAMA 285:2481, 2001. 

68. American College of Physicians: Guidelines for 

using serum cholesterol, high-density lipoprotein 

cholesterol, and triglyceride levels as screening 

tests for preventing coronary heart disease in 

adults. Ann Intern Med 124:515, 1996. 

69. Task Force on Risk Reduction, American Heart Association: 

Cholesterol screening in asymptomatic 

adults. No cause to change. Circulation 93:1067, 

1996. 

70. Lauer RM, Clarke WR: Use of cholesterol measurements 

in childhood for the prediction of adult hypercholesterolemia. 

The Muscatine Study. JAMA 

264:3034, 1990. 

71. Newman TB, Browner WS, Hulley SB: The case 

against childhood cholesterol screening. JAMA 

264:3039, 1990. 

72. Grundy SM, Cleeman JI, Merz CNB, et al. Implications 

of recent clinical trials for the National Cholesterol 

Education Program Adult Treatment Panel 

III guidelines. Circulation 2004; 110: 227-239. 

73. Sarwar N, Sattar N: Triglycerides and coronary heart 

disease: have recent insights yielded conclusive answers? 

Curr Opin Lipidol 20: 275, 2009. 

74. Sarwar N, Danesh J, Eiriksdottier G, et al: Triglycerides 

and the risk of coronary heart disease. 

10,158 incident cases among 262,525 participants 

in 29 western prospective studies. Circulation 115: 

450, 2007. 

75. Brunzell JD: Hypertriglyceridemia. N Engl J Med 

357: 1009, 2007. 

76. Ford ES, Li C, Zhao G, et al: Hypertriglyceridemia 

and its pharmacologic treatment among US adults. 


77. Phillips NR, Havel RJ, Kane JP: Levels and interrelationships 

of serum and lipoprotein cholesterol 

and triglycerides: association with adiposity and 

the consumption of ethanol, tobacco, and beverages 

containing caffeine. Arteriosclerosis 1:13, 1981. 

78. Ashen MD, Blumenthal RS: Low HDL cholesterol 

levels. N Engl J Med 353: 1252, 2005. 

79. Brown BG, Zhao X-Q, Chait A, et al: Simvastatin 

and niacin, antioxidant vitamins, or the combination 

for the prevention of coronary disease. N Engl 

J Med 345:1583, 2001. 

80. von Eckardstein A, Assmann G: Prevention of 

coronary heart disease by raising high-density lipoprotein 

cholesterol? Curr Opin Lipidol 11:627, 

2000. 

80a. Ridker PM, Genest J, Boekholdt M, et al: HDL 

cholesterol and residual risk of first cardiovascular 

events after treatment with potent statin therapy: 

an analysis from the JUPITER trial. Lancet 376: 

333, 2010. 

81. Diabetes Atherosclerosis Intervention Study 

(DAIS) Investigators. Effect of fenofibrate on progression 

of coronary-artery disease in type 2 diabetes. 

Lancet 357:905, 2001. 

82. Betteridge D: Lipid-lowering trials in diabetes. 


83. Haffner SM, Alexander CM, Cook TJ et al: Reduced 

coronary events in simvastatin-treated patients 

with coronary heart disease and diabetes or 

impaired fasting glucose levels. Subgroup analysis 

in the Scandinavian Simvastatin Survival Study. 


84. Goldberg R, Mellies MJ, Scaks FM, et al: Cardiovascular 

events and their reduction with pravastatin 

in diabetic and glucose-intolerant myocardial 

infarction survivors with average cholesterol levels. 

Subgroup analysis in the Cholesterol and Recurrent 

Events (CARE) Trial. Circulation 98:2513, 1998. 

85. The Long-Term Intervention with Pravastatin 

in Ischaemic Disease (LIPID) Study Group: Prevention 

of cardiovascular events and death with 

pravastatin in patients with coronary heart disease 

and a broad range of initial cholesterol levels. N 

Engl J Med 339:1349, 1998. 

86. Grover SA, Coupal L, Zowall H, Dorais M: Costeffectiveness 

of treating hyperlipidemia in the 

presence of diabetes. Who should be treated? Circulation 

102:722, 2000. 

87. Solano MP, Goldberg RB: Management of dyslipid-

emia in diabetes. Cardiol in Rev 14: 125, 2006. 

88. Haffner SM, Lehto S, Ronnemaa T, et al: Mortality 

from coronary heart disease in subjects with type 

2 diabetes and in nondiabetic subjects with and 

without prior myocardial infarction. N Engl J Med 

339:229, 1998. 

89. Howard BV, Robbins DC, Sievers ML, et al: LDLcholesterol 

as a strong predictor of coronary heart 

disease in diabetic individuals with insulin resistance 

and low LDL. The Strong Heart Study. Arterioscler 

Thromb Vasc Biol 20:830, 2000. 

90. American Diabetes Association: Management of 

dyslipidemia in adults with diabetes. Diabetes Care 

25(Suppl 1):S74, 2002. 

91. Anonymous: Intensive blood-glucose control 

with sulfonylureas or insulin compared with conventional 

treatment and risk of complications in 

patients with type 2 diabetes (UKPDS 33). UK Prospective 

Diabetes Study (UKPDS) Group. Lancet 

352:837, 1998. 

92. Wenger NK: Lipid abnormalities in women. Data 

for risk, data for management. Cardiol in Rev 14: 

276, 2006. 

92a. Sattar N, Preiss D, Murray HM, et al: Statins and 

risk of incident diabetes: a collaborative meta-analysis 

of randomised statin trials. Lancet 375: 735, 

2010. 

93. Lerner DJ, Kanner WB: Patterns of coronary heart 

disease morbidity and mortality in the sexes: a 26 

year follow-up of the Framingham population. Am 

Heart J 111:383, 1986. 

94. Cholesterol Treatment Trialists’ (CTT) Collaborators: 

Efficacy of cholesterol-lowering therapy in 

18,686 people with diabetes in 14 randomised trials 

of statins: a meta-analysis. Lancet 371: 117, 2008. 

95. Scandinavian Simvastatin Survival Study Group. 

Randomized trial of cholesterol lowering in 4444 

patients with coronary heart disease: the Scandinavian 

Simvastatin Survival Study (4S). Lancet 

344:1383, 1994. 

96. Downs JR, Clearfield M, Weis S, et al: Primary prevention 

of acute coronary events with lovastatin 

in men and women with average cholesterol levels: 

Results of AFCAPS/TexCAPS. Air Force/Texas 

Coronary Atherosclerosis Prevention Study. JAMA 

279:1615, 1998. 

97. The Writing Group for the PEPI Trial. Effects of 

estrogen or estrogen/progestin regimens on heart 

disease risk factors in postmenopausal women. The 

Postmenopausal Estrogen Progestin Interventions 

(PEPI). JAMA 273:199, 1995. 

98. Hulley S, Grady D, Bush T, et al: Randomized trial 

of estrogen plus progestin for secondary prevention 

of coronary heart disease in post-menopausal 


women. JAMA 280:605, 1998. 

99. Wakatsuki A, Ikenoue N, Okatani Y, et al: Estrogen-induced 

small low density lipoprotein particles 

may be atherogenic in postmenopausal women. J 


100. Herrington DM, Reboussin DM, Brosnihan KB, et 

al: Effects of estrogen replacement on the progression 

of coronary artery atherosclerosis. N Engl J 

Med 343:522, 2000. 

101. Writing Group for the Women’s Health Initiative 

Investigators: Risks and benefits of estrogen plus 

progestin in healthy postmenopausal women. 

Principal results from the Women’s Health Initiative 

Randomized Controlled Trial. JAMA 288:321, 

2002. 

102. Report of the National Cholesterol Education Program 

Expert Panel on Blood Cholesterol Levels 

in Children and Adults. Pediatrics 89(3 Pt 2):525, 

1992. 

103. McCrindle BW, Urbina EM, Dennison BA, et al: 

Drug therapy of high-risk lipid abnormalities in 

children and adolescents. A scientific statement 

from the American Heart Association, Atherosclerosis, 

Hypertension, and Obesity in Youth Committee, 

Council of Cardiovascular Disease in the 

Young, with the Council on Cardiovascular Nursing. 

Circulation 115: 1948, 2007. 

104. Arnold SV, Rich MW: Hyperlipidemia in older 

adults. Clin Geriat 17: 18, 2009/ 

105. Zimetbaum P, Frishman WH, Ooi WL, et al: Plasma 

lipids and lipoproteins and the incidence of 

cardiovascular disease in the old: The Bronx Longitudinal 

Aging Study. Arteriol Thromb 12:416, 1992. 

106. Szadkowska I, Stanczyk A, Aronow WS, et al: Statin 

therapy in the elderly. A review. Arch Geront Geriatr 

50: 114, 2010. 

107. Alexander KP, Blazing MA, Rosenson RS, et al: 

Management of hyperlipidemia in older adults. J 

Cardiovasc Pharmacol Therap 14: 49, 2009. 

108. O’Regan C, Wu P, Aror P, et al: Statin therapy 

in stroke prevention: a meta-analysis involving 

121,000 patients. Am J Med 121: 24, 2008. 

109. Lemaitre RN, Psaty BM, Heckbert SR, et al: Therapy 

with hydroxymethylglutaryl coenzyme A reductase 

inhibitors (statins) and associated risk of 

incident cardiovascular events in older adults: Evidence 

from the Cardiovascular Health Study. Arch 

Intern Med 162:1395, 2002. 

110. Working Group on Management of Patients with 

Hypertension and High Blood Cholesterol: National 

Education Programs Working Group Report 

on the Management of Patients with Hypertension 

and High Blood Cholesterol. Ann Intern Med 

114:224, 1991.


111. Bonaa KH, Thelle DS: Association between blood 

pressure and serum lipids in a population. Circulation 

83(4):1305, 1991. 

112. Frishman WH, Clark A, Johnson B: The effects of 

cardiovascular drugs on plasma lipids and lipoproteins. 

In: Frishman WH, Sonnenblick EH (eds). 

Cardiovascular Pharmacotherapeutics. New York: 

McGraw-Hill, 1997, p 1515. 

113. Smith SC Jr, Blair SN, Bonow RO, et al: AHA/ACC 

guidelines for preventing heart attack and death in 

patients with atherosclerotic cardiovascular disease: 

2001 update. Circulation 104:1577, 2001. 

114. Ahnve S, Angelin B, Edhag O, et al: Early determination 

of serum lipids and apolipoproteins in acute 

myocardial infarction: Possibility for immediate intervention. 

J Intern Med 226:297, 1989. 

115. Aronow HD, Topol EJ, Roe MT, et al: Effect of lipid-lowering 

therapy on early mortality after acute 

coronary syndromes: An observational study. Lancet 

357:1063, 2001. 

116. Rossouw JE: Lipid-lowering interventions in angiographic 

trials. Am J Cardiol 76:86C, 1995. 

117. Falk E: Why do plaques rupture? Circulation 

86(Suppl III):III30, 1992. 

118. Fuster V, Badimon L, Badimon JJ, Chesebro JH: 

The pathogenesis of coronary artery disease and 

the acute coronary syndromes. N Engl J Med 

326:310, 1992. 

119. Richardson PD, Davies MJ, Born GV: Influence of 

plaque configuration and stress distribution on fissuring 

of coronary atherosclerotic plaques. Lancet 

2:941, 1989. 

120. OKeefe JH Jr., Conn RD, Lavie CJ Jr., Bateman TM: 

The new paradigm for coronary artery disease: 

altering risk factors, atherosclerotic plaques, and 

clinical prognosis. Mayo Clin Proc 71:957, 1996. 

121. Farmer JA, Gotto AM Jr: Dyslipidemia and the vulnerable 

plaque. Prog Cardiovasc Dis 44:415, 2002. 

122. Fayad ZA, Fuster V: Clinical imaging of the highrisk 

or vulnerable atherosclerotic plaque. Circ Res 

89:305, 2001. 

123. Schini VB, Vanhoutte P: Endothelium-derived vasoactive 

factors. In: Loscalzo J, Schaefer AI (eds). 

Thrombosis and Hemorrhage. Boston: Blackwell 

Science, 1994, p 349. 

124. Egashira K, Hirooka Y, Kai H, et al: Reduction 

in serum cholesterol with pravastatin improves 

endothelium-dependent coronary vasomotion in 

patients with hypercholesterolemia. Circulation 

89:2519, 1994. 

125. Shiode N, Nakayama K, Morishima N, et al: Nitric 

oxide production by coronary conductance and resistance 

vessels in hypercholesterolemia patients. 

Am Heart J 131:1051, 1996. 

126. Campeau L, Enjalbert M, Lesperance J, et al: The 

relation of risk factors to the development of atherosclerosis 

in saphenous vein bypass grafts and 

the progression of disease in the native Circulation: 

A study 10 years after aortocoronary bypass surgery. 

N Engl J Med 311:1329, 1984. 

127. Popma JJ, Sawyer M, Selwyn AP, Kinlay S: Lipidlowering 

therapy after coronary revascularization. 

Am J Cardiol 86(Suppl H):18H, 2000. 

128. Shah SJ, Waters DD, Barter P, et al: Intensive lipid-lowering 

with atorvastatin for secondary prevention 

in patients after coronary artery bypass 

surgery. J Am Coll Cardiol 51: 1938, 2008. 

129. Knatterud GL, Rosenberg Y, Campeau L, et al: 

Long-term effects on clinical outcomes of aggressive 

lowering of low-density lipoprotein cholesterol 

levels and low-dose anticoagulation in the 

post coronary artery bypass graft trial. Circulation 

102:157, 2000. 

130. Leimgruber PP, Roubin GS, Hollman J, et al: Restenosis 

after successful coronary angioplasty in patients 

with single vessel disease. Circulation 73:710, 

1986. 

131. Virmani R, Farb A: Pathology of in-stent restenosis. 


132. Austin GE, Ratliff NB, Hollman J, et al: Intimal proliferation 

of smooth muscle cells as an explanation 

for recurrent coronary artery stenosis after percutaneous 

transluminal coronary angioplasty. J Am 


133. Ross R, Bowen-Pope D, Raines EW: Platelets, macrophages, 

endothelium and growth factors: Their 

effects upon cells and their possible roles in atherogenesis. 

Ann NY Acad Sci 454:254, 1985. 

134. Serruys PWJC, de Feyter P, Macaya C, et al for the 

Lescol Intervention Prevention Study (LIPS) Investigators: 

Fluvastatin for prevention of cardiac 

events following successful first percutaneous coronary 

intervention: A randomized controlled trial. 

JAMA 287:3215, 2002. 

135. Meng CQ: Restenosis drug discovery—a formidable 

task. Curr Opin Invest Drugs 2:1237, 2001. 

136. de Feyter PJ, Vos J, Rensing BJ: Anti-restenosis trials. 

Curr Intervent Cardiol Rep 2:326, 2000. 

137. Chan AW, Moliterno DJ: In-stent restenosis: Update 

on intracoronary radiotherapy. Cleve Clin J 

Med 68:796, 2001. 

138. Butman S: Hyperlipidemia after cardiac transplantation: 

Be aware and possibly wary of drug therapy 

for lowering of serum lipids. Am Heart J 121:1585, 

1991. 

139. Ballantyne CM, Podet EJ, Patsch WP, et al: Effects 

of cyclosporine therapy on plasma lipoprotein levels. 

JAMA 262:53, 1989.

140. Olivari MT, Homans DC, Wilson RF, et al: Coronary 

artery disease in cardiac transplant patients 

receiving triple-drug immunosuppressive therapy. 

Circulation 80(Suppl III):III-111, 1989. 

141. Johnson DE, Gao SZ, Schroeder JS, et al: The spectrum 

of coronary artery pathological findings in 

human cardiac allografts. J Heart Transplant 8:349, 

1989. 

142. Kobashigawa JA, Katznelson S, Laks H, et al: Effect 

of pravastatin on outcomes after cardiac transplantation. 

N Engl J Med 333:621, 1995. 

143. Wenke K, Meiser B, Thiery J, et al: Simvastatin reduces 

graft vessel disease and mortality after heart 

transplantation: A four-year randomized trial. Circulation 

96:1398, 1997. 

144. Kobashigawa J: What is the optimal prophylaxis for 

treatment of cardiac allograft vasculopathy? Curr 

Control Trials Cardiovasc Med 1:166, 2000. 

145. Crouse JR: Effects of statins on carotid disease and 

stroke. Curr Opin Lipidol 10:535, 1999. 

146. Aronow WS, Ahn C, Gutstein H. Incidence of new 

atherothrombotic brain infarction in older persons 

with prior myocardial infarction and serum lowdensity 

lipoprotein cholesterol ≥125 mg/dL treated 

with statins versus no lipid-lowering drug. J Gerontol: 

Med Sci 57A: M333, 2002. 

147. Ravipati G, Aronow WS, Ahn C, et al. Incidence of 

new stroke or new myocardial infarction or death 

in patients with severe carotid arterial disease treated 

with and without statins. Am J Cardiol 98: 1170, 

2006. 

148. Amarenco P, Bogousslvsky J, Callahan A, 3rd, et 

al. High-dose atorvastatin after stroke or transient 

ischemic attack. N Engl J Med 355: 549, 2006. 

148a. Zambon D, Quintana M, Mata P, et al: Higher incidence 

of mild cognitive impairment in familial 

hypercholesterolemia. Am J Med 123: 267, 2010. 

149. Jick H, Zomberg GL, Jick SS, et al. Statins and the 

risk of dementia. Lancet 356: 1627, 2000. 

150. Rockwood K, Kirkland S, Hogan DB, et al. Use of 

lipid-lowering agents, indication bias, and the risk 

of dementia in community-dwelling elderly people. 

Arch Neurol 59: 223, 2002. 

151. Attman P-O, Samuelsson O: Dyslipidemia of kidney 

disease. Curr Opin Lipid 20: 293, 2009. 

152. Joven J, Villabona C, Vilella E, et al: Abnormalities 

of lipoprotein metabolism in patients with nephrotic 

syndrome. N Engl J Med 323:579, 1990. 

153. Keane WF, Kasiske BL: Hyperlipidemia in nephrotic 

syndrome. N Engl J Med 323:603, 1990. 

154. Vega GL, Grundy SM: Lovastatin therapy in nephrotic 

hyperlipidemia. Effects on lipoprotein metabolism. 

Kidney Int 33:1160, 1988. 

155. Chui MCK, Newby DE, Panarelli M, et al: Asso- 


ciation between calcific aortic stenosis and hypercholesterolemia: 

Is there a need for a randomized 

controlled trial of cholesterol-lowering therapy? 

Clin Cardiol 24:52, 2001. 

156. RaJAMAnnan NM, Subramaniam M, Springett M, 

et al: Atorvastatin inhibits hypercholesterolemiainduced 

cellular proliferation and bone matrix 

production in the rabbit aortic valve. Circulation 

105:2660, 2002. 

157. Aronow WS, Ahn C, Kronzon I, Goldman ME. Association 

of coronary risk factors and use of statins 

with progression of mild valvular aortic stenosis in 

older persons. Am J Cardiol 88:693, 2001. 

158. Aontonini-Canterin F,Leiballi E, Enache R, et al: 

Hydroxymethylglutaryl coenzyme-A reductase 

inhibitors delay the progression of rheumatic aortic 

valve stenosis. A long-term echocardiographic 


159. Novaro GM, Tiong IY, Pearce GL, et al. Effect of hydroxymethylglutaryl 

coenzyme A reductase inhibitors 

on the progression of calcific aortic stenosis. 

Circulation 104: 2205, 2001. 

160. Bellamy MF, Pellikka PA, Klarich KW, et al. Association 

of cholesterol levels, hydroxymethylglutaryl 

coenzyme-A reductase inhibitor treatment, and 

progression of aortic stenosis in the community. J 


161. Moura LM, Ramos SF, Zamorano JL, et al. Rosuvastatin 

affecting aortic valve endothelium to slow 

the progression of aortic stenosis. J Am Coll Cardiol 

49: 554, 2007. 

162. Cowell SJ, Newby DE, Preston RJ, et al. A randomized 

trial of intensive lipid-lowering therapy in calcific 

aortic stenosis. N Engl J Med 352: 2389, 2005. 

163. Rossebo AB, Pedersen TR, Boman K, et al. Intensive 

lipid lowering with simvastatin and ezetimibe 

in aortic stenosis. N Engl J Med 359: 1343, 2008. 

163a. Hermans H, Herijgers P, Holvoet P, et al: Statins 

for calcific aortic valve stenosis: into oblivion after 

SALTIRE and SEAS? An extensive review from 

bench to bedside. Curr Probl Cardiol 35: 277, 2010. 

164. Rosenhek R: Statins for aortic stenosis. N Engl J 

Med 352: 2441, 2005. 

165. Davidson MH, Dillon MA, Gordon B, et al: Colesevelam 

hydrochloride (Cholestagel). A new, 

potent bile acid sequestrant associated with a low 

incidence of gastrointestinal side effects. Arch Intern 

Med 159:1893, 1999. 

166. Frishman WH, Ast M: Bile acid sequestrants. 

In: Frishman WH (ed). Medical Management of 

Lipid Disorder. Focus on Prevention of Coronary 

Artery Disease. Mt. Kisco: Futura Publ. Co. Inc., 

1992:103–123. 

167. Lipid Research Clinics Program: The Lipid Re-


search Clinics Coronary Primary Prevention Trial 

Results: II. The relationship in reduction of incidence 

of coronary heart disease to cholesterol lowering. 

JAMA 251:365, 1984. 

168. Glueck CJ: Pediatric primary prevention of atherosclerosis. 

N Engl J Med 314:175, 1986. 

169. Witzum J: Drugs used in the treatment of hyperlipoproteinemias. 

In: Hardman JG, Limbird LE 

(eds). In: Goodman & Gilman’s The Pharmacological 

Basis of Therapeutics, 9th ed, New York: Mc- 

Graw Hill, 1996, pp 875–897. 

170. Grundy SM, Ahrens EH, Salen S: Interruption of 

the enterohepatic Circulation of bile acids in man: 

Comparative effects of cholestyramine and ileal exclusion 

on cholesterol metabolism. J Lab Clin Med 

78:94, 1971. 

171. Packard CJ, Shepherd J: The hepatobiliary axis and 

lipoprotein metabolism: Effects of bile acid sequestrants 

and ileal bypass surgery. J Lipid Res 23:1081, 

1982. 

172. Shepherd J: Mechanism of action of bile acid sequestrants 

and other lipid lowering drugs. Cardiology 

76(Suppl 1):65, 1982. 

173. Innis SM: The activity of HMG-CoA reductase and 

acyl- CoA cholesterol acyltransferase in hepatic 

microsomes in male, female and pregnant rats. 

The effect of cholestyramine treatment and the relationship 

of enzyme activity to microsomal lipid 

composition. Biochim Biophys Acta 875:355, 1986. 

174. Shepherd J, Packard CJ, Bicker S, et al: Cholestyramine 

promotes receptor-mediated low-density lipoprotein 

catabolism. N Engl J Med 302:1219, 1980. 

175. Donovan JM, Stypinski D, Stiles MR, et al: Drug interactions 

with colesevelam hydrochloride, a novel, 

potent lipid-lowering agent. Cardiovasc Drugs Ther 

14:681, 2000. 

176. Illingworth RD: Lipid lowering drugs: An overview 

of indications and optimum therapeutic use. Drugs 

33:259, 1987. 

177. Davidson MH, Dillon MA, Gordon B, et al: Colesevelam 

hydrochloride (cholestagel): A new, potent 

bile acid sequestrant associated with a low incidence 

of gastrointestinal side effects. Arch Intern 

Med 159:1893, 1999. 

178. Runeberg L, Miettinen TA, Nikkils EA: Effect of 

cholestyramine on mineral excretion in man. Acta 

Med Scand 192:71, 1972. 

179. Brensike JF, Levy RI, Kelsey SF, et al: Effects of 

therapy with cholestyramine on progression of coronary 

arteriosclerosis: Results of the NHLBI type 

II coronary intervention study. Circulation 69:313, 

1984. 

180. Levy RI, Brensike JF, Epstein SE, et al: The influence 

of changes in lipid values induced by chole- 

styramine and diet on progression of coronary 

artery disease: Results of the NHLBI type II coronary 

prevention study. Circulation 69:325, 1984. 

181. Krauss RM, Williams PT, Brensike J, et al: Intermediate-density 

lipoproteins and progression of coronary 

artery disease in hypercholesterolemic men. 

Lancet 2:62, 1987. 

182. Blankenhorn DH, Nessim SA, Johnson RL, et al: 

Beneficial effects of combined colestipol-niacin 

therapy on coronary atherosclerosis and coronary 

venous bypass grafts. JAMA 257:3233, 1987. 

183. Cashin-Hemphill L, Mack WJ, Pogoda JM, et al: 

Beneficial effects of colestipol-niacin on coronary 

atherosclerosis. JAMA 264:3013, 1990. 

184. Brown G, Albers JJ, Fisher LD, et al: Regression of 

coronary artery disease as a result of intensive lipid 

lowering therapy in men with high levels of apolipoprotein 

B. N Engl J Med 323:1289, 1990. 

185. Kane JP, Malloy MJ, Ports TA, et al: Regression of 

coronary atherosclerosis during treatment of familial 

hypercholesterolemia with combined drug 

regimens. JAMA 264:3007, 1990. 

186. Watts GF, Lewis B, Brunt JNH, et al: Effects of coronary 

artery disease on lipid-lowering diet or diet 

plus cholestyramine, in the St. Thomas Atherosclerosis 

Regression Study (STARS). Lancet 339:563, 

1992. 

187. Duffield RGT, Lewis B, Miller NE, et al: Treatment 

of hyperlipidaemia retards progression of symptomatic 

femoral atherosclerosis: A randomized 


188. Blankenhorn DH, Azen SP, Crawford DW, et al: Effects 

of colestipol-niacin therapy on human femoral 

atherosclerosis. Circulation 83:438. 1991. 

189. Marais AD: Therapeutic modulation of low-density 

lipoprotein size. Curr Opin Lipidol 11:597, 2000. 

190. Witzum JL, Schonfeld G, Weidman JW, et al: Bile 

sequestrant therapy alters the composition of lowdensity 

and high-density lipoprotein. Metabolism 

28:221, 1979. 

191. Goldberg RB, Fonseca VA, Truitt KE, Jones MR: 

Efficacy and safety of colesevelam in patients with 

type 2 diabetes mellitus and inadequate glycemic 

control receiving insulin-based therapy. Arch Intern 

Med 168: 1531, 2008. 

192. Beil U, Crouse JR, Einarsson K, Grundy SM: Effect 

of interruption of the enterohepatic Circulation of 

bile acids on the transport of very low density lipoprotein 

triglycerides. Metabolism 31:438, 1982. 

193. Crouse JR: Hypertriglyceridemia: A contraindication 

for use of bile acid binding resins. Am J Med 

83:243, 1987. 

194. Gordon DJ, Knoke J, Probstfield JL, et al, for the 

Lipid Research Clinics Program: High-density li-

poprotein cholesterol and coronary heart disease 

in hypercholesterolemic men: The Lipid Research 

Clinics Coronary Primary Prevention Trial. Circulation 

74:1217, 1986. 

195. Lyons D, Webster J, Fowler G, et al: Colestipol at 

various dosage intervals in the treatment of moderate 

hypercholesterolemia. Br J Clin Pharmacol 

37:59, 1994. 

196. Tonstad S, Bing RF, Frohlich J, et al: Effectiveness of 

colestipol tablets vs granules in patients with moderate 

to severe hypercholesterolaemia. Clin Drug 

Invest 10:257, 1995. 

197. Insull W, Marquis NR, Tsianco MC: Comparison of 

the efficacy of Questran Light, a new formulation 

of cholestyramine powder, to regular Questran in 

maintaining lowered plasma cholesterol levels. Am 

J Cardiol 67:501, 1991. 

198. Kane JP, Malloy MJ, Tun P, et al: Normalization of 

low-density lipoprotein levels in heterozygous familial 

hypercholesterolemia with a combined drug 

regimen. N Engl J Med 304:251, 1981. 

199. Hoogerbrugge N, Mol M, VanDormaal JJ, et al: Efficacy 

and safety of pravastatin, compared to and 

in combination with bile acid binding resins in familial 

hypercholesterolemia. J Intern Med 228:261, 

1990. 

200. Schrott HG, Stein EA, Dujoune CA, et al: Enhanced 

low-density lipoprotein cholesterol reduction 

and cost-effectiveness by low dose colestipol 

plus lovastatin combination therapy. Am J Cardiol 

75:34, 1995. 

200a. Goldberg RB, Fonseca VA, Truitt KE, Jones MR: 

Efficacy and safety of colesevelam in patients with 

type 2 diabetes mellitus and inadequate glycemic 

control receiving insulin-based therapy. Arch Intern 

Med 168: 1531, 2008. 

200b. Fonseca VA, Rosenstock J, Wang AC, et al: Colesevelam 

HCl improves glycemic control and reduces 

LDL cholesterol in patients with inadequately 

controlled type 2 diabetes on sulfonylurea-based 

therapy. Diabetes Care 31: 1479, 2008. 

200c. Bays HE, Goldberg RB, Truitt KE, Jones MR: Colesevelam 

hydrochloride therapy in patients with 

type 2 diabetes mellitus treated with metformin: 

glucose and lipid effects. Arch Intern Med 168: 

1975, 2008. 

201. Masclee AAM, Jansen JBMJ, Rovati LC, et al: Effect 

of cholestyramine and cholecystokinin receptor 

antagonist CR1505 (loxiglumide) on lower esophageal 

sphincter pressure in man. Dig Dis Sci 38:1889, 

1993. 

202. Pattison M, Lee SM: Life-threatening metabolic acidosis 

from cholestyramine in an infant with renal 

insufficiency (letter). Am J Dis Child 141:479, 1987. 


203. Kleinman PA: Cholestyramine and metabolic acidosis 

(letter). N Engl J Med 290:861, 1974. 

204. Hartline JV: Hyperchloremia, metabolic acidosis, 

and cholestyramine. J Pediatri 89:155, 1976. 

205. Scheel PJ, Whelton A, Rossiter K, Watson A: Cholestyramine 

induced hyperchloremic metabolic 

acidosis. J Clin Pharmacol 32:536, 1992. 

206. Melkem MF, Galoriet HF, Eskander ED, Rao KN: 

Cholestyramine promotes 7,12 dimethylbenzanthracene 

induced mammary cancer in Wistar rats. 

J Cancer 56:45, 1987. 

207. Shosania AM, Grewar D: Hypoprothrombinemic 

hemorrhage due to cholestyramine therapy. Can 

Med Assn J 134:609, 1986. 

208. Witztum JL, Jacobs LS, Schonfeld G: Thyroid hormone 

and thyrotropin levels in patients placed on 

colestipol hydrochloride. J Clin Endocrinol Metab 

46:838, 1978. 

209. Hertz R, Bishara-Shieban J, Bar-Tana J: Mode of action 

of peroxisome proliferators as hypolipidemic 

drugs suppression of apolipoprotein C-III. J Biol 

Chem 270:13470, 1995. 

210. Gervois P, Torra IP, Fruchart JC, et al: Regulation of 

lipid and lipoprotein metabolism by PPAR activators. 

Clin Chem Lab Med 38:3, 2000. 

211. Staels B, Dallongeville J, Auwerx J, et al: Mechanism 

of action of fibrates on lipid and lipoprotein 

metabolism. Circulation 98:2088, 1998. 

212. Thorp JM: Modification of metabolism and distribution 

of lipids by chlorphenoxyisobutyrate. Nature 

194:948, 1962. 

213. Report from the Committee of Principal Investigators: 

A cooperative trial in the primary prevention 

of ischaemic heart disease using clofibrate. Br 

Heart J 40:1069, 1978. 

214. Coronary Drug Project Research Group: Clofibrate 

and niacin in coronary artery disease. JAMA 

231:360, 1975. 

215. Zimetbaum P, Frishman WH, Kahn S: Effects of 

gemfibrozil and other fibric acid derivatives on 

blood lipids and lipoproteins. In: Frishman WH 

(ed). Medical Management of Lipid Disorders: Focus 

on Prevention of Coronary Artery Disease. Mt. 

Kisco: Futura Publishing Co Inc. 1992:125–151. 

216. Manninen V, Elo O, Frick H, et al: Lipid alterations 

and decline in the incidence of coronary heart disease 

in the Helsinki Heart Study. JAMA 260:41, 

1988. 

217. Spencer CM, Barradell LB: Gemfibrozil. Drugs 

51:982, 1996. 

218. Brown WV: Potential use of fenofibrate and other 

fibric acid derivatives in the clinic. Am J Med 

83(5B):85, 1987. 

219. Balfour JA, Heel RC: Fenofibrate: A review of its


pharmacodynamic and pharmacokinetic properties 

and therapeutic use in dyslipidaemia. Drugs 

40:260, 1990. 

220. Grutzmacher P, Scheuermann EH, Siede W, et al: 

Lipid lowering treatment with bezafibrate in patients 

on chronic haemodialysis: Pharmacokinetics 

and effects. Klin Wochenschr 64(19):910, 1986. 

221. Betteridge DJ: Ciprofibrate—a profile. Postgrad 

Med J 69(Suppl 1):S42, 1993. 

222. Monk JP, Todd PA: Bezafibrate: a review of its 

pharmacodynamic and pharmacokinetic properties, 

and therapeutic use in hyperlipidaemia. Drugs 

33:539, 1987. 

223. Auboeuf D, Rieusset J, Fajas L, et al: Tissue distribution 

and quantification of the expression of the 

peroxisome proliferator activated receptors and of 

LXR alpha mRNAs in human: Effect of obesity and 

NIDDM in adipose tissue. Diabetes 46:1319, 1997. 

224. Shepherd J: Mechanism of action of fibrates. Postgrad 

Med J 69(Suppl 1):S34,1993. 

225. Grundy SM, Vega GL: Fibric acids: Effects on lipids 

and lipoprotein metabolism. Am J Med 83(5B):9, 

1987. 

226. Eckel RH: Lipoprotein lipase: A multifunctional 

enzyme relevant to common metabolic disease. N 

Engl J Med 320:1060, 1989. 

227. Heller F, Harvengt C: Effect of clofibrate, bezafibrate, 

fenofibrate and probucol on plasma lipolytic 

enzymes in normolipidemic subjects. Eur J Clin 

Pharmacol 25:57, 1983. 

228. Gavish D, Oschry Y, Fainaru M, Eisenberg S: 

Changes in very low, low, and high density lipoproteins 

during lipid lowering (bezafibrate) therapy: 

Studies in type IIA and IIB hyperlipoproteinemia. 

Eur J Clin Invest 16(1):61, 1986. 

229. Gervaise, N, Garrigue MA, Lasfargues G, et al: Triglycerides, 

apo C3 and Lp B:C3 and cardiovascular 

risk in type II diabetes. Diabetologia 43:703, 2000. 

230. Luc G, Fievet C, Arveiler D, et al: Apolipoproteins 

C3 and E in apoB-and non apo B-containing lipoproteins 

in two populations at contrasting risk for 

myocardial infarction: the ECTIM study. J Lipid 

Res 37:508, 1996. 

231. Sacks FM, Alaupovic P, Moye LA, et al: VLDL, apolipoproteins 

B, CIII, and E, and risk of recurrent 

coronary events in the Cholesterol and Recurrent 

Events (CARE) trial. Circulation 102:1886–1892, 

2000. 

232. Hunninghake DB, Peters JR: Effects of fibric acid 

derivatives on blood lipid and lipoprotein levels. 

Am J Med 83(5B):44, 1987. 

233. Eisenberg S, Gavish D, Oschry Y, et al: Abnormalities 

in very low, low and high density lipoproteins 

in hypertriglyceridemia. J Clin Invest 74:470, 1984. 

234. Vega GL, Grundy SM: Kinetic heterogeneity of low 

density lipoproteins in primary hypertriglyceridemia. 

Arteriosclerosis 6:395, 1986. 

235. Ginsberg HN: Changes in lipoprotein kinetics during 

therapy with fenofibrate and other fibric acid 

derivatives. Am J Med 83(5B):66, 1987. 

236. Kasaniemi YA, Grundy SM: Influence of gemfibrozil 

and clofibrate on metabolism of cholesterol and 

plasma triglycerides in man. JAMA 251(17):2241, 

1984. 

237. Shepard J, Caslake MJ, Lorimer AR, et al: Fenofibrate 

reduces low density catabolism in hypertriglyceridemic 

subjects. Arteriosclerosis 5:162, 1985. 

238. Packard CJ, Clegg RJ, Dominiczak MH, et al: Effect 

of bezafibrate on apolipoprotein B metabolism 

in type III hyperlipidemic subjects. J Lipid Res 

27(9):930, 1986. 

239. Eisenberg S: High density lipoprotein metabolism. 

J Lipid Res 25:1012, 1984. 

240. Schwandt P, Weisweiler P: Effect of bezafibrate on 

the high density lipoprotein subfractions HDL2 

and HDL3 in primary hyperlipoproteinemia type 

IV. Artery 7(6):464, 1980. 

241. Kleinman Y, Eisenberg S, Oschry Y, et al: Defective 

metabolism of hypertriglyceridemic lipoprotein in 

cultured human skin fibroblasts. Normalization 

with bezafibrate. J Clin Invest 75:1796, 1985. 

242. Grundy SM, Ahrens EGJ, Salen G, et al: Mechanism 

of action of clofibrate on cholesterol metabolism 

in patients with hyperlipidemia. J Lipid Res 

13:531, 1972. 

243. Hudson K, Mojumder S, Day AJ: The effect of 

bezafibrate and clofibrate on cholesterol ester metabolism 

in rabbit peritoneal macrophages stimulated 

with acetylated low density lipoproteins. Exp 

Mol Pathol 38(1):77, 1983. 

244. Schneider A, Stange EF, Ditschuneit HH, Ditschuneit 

H: Fenofibrate treatment inhibits HMG- 

CoA reductase activity in mononuclear cells from 

hyperlipoproteinemic patients. Atherosclerosis 

56(3):257, 1985. 

245. Blasi F, Sommariva D, Cosentini R, et al: Bezafibrate 

inhibits HMG-CoA reductase activity in incubated 

blood mononuclear cells from normal subjects and 

patients with heterozygous familial hypercholesterolemia. 

Pharmacol Res 21(3):247, 1989. 

246. Palmer RH: Effects of fibric acid derivatives on biliary 

lipid composition. Am J Med 83(5B):37, 1987. 

247. Kasaniemi YA, Grundy SM: Clofibrate, caloric restriction, 

supersaturation of bile, and cholesterol 

crystals. Scand J Gastroenterol 18:897, 1983. 

248. Blane GF: Review of European clinical experience 

with fenofibrate. Cardiology 76(Suppl 1):1, 1989. 

249. Leiss O, Meyer-Krahmer K, Von Bergmann K: Bili-

ary lipid secretion in patients with heterozygous 

familial hypercholesterolemia and combined hyperlipidemia. 

Influence of bezafibrate and fenofibrate. 

J Lipid Res 27(7):213, 1986. 

250. Carvalho ACA, Colman RW, Lees RS: Platelet 

function in hyperlipoproteinemia. N Engl J Med 

290:434, 1974. 

251. Hamsten A, Wiman B, DeFaire U, Blomback M: Increased 

plasma levels of a rapid inhibitor of tissue 

plasminogen activator in young survivors of myocardial 


252. Torstila I, Kaukola S, Malkonen M, et al: Effect of 

gemfibrozil on plasma lipoproteins, apolipoproteins 

and the kallikrein-kinin system Proceedings of 

an International Symposium: 8th Asian Pacific Congress 

of Cardiology. 1984, pp 36–42. 

253. Laustiola K, Lassila R, Koskinen P, et al: Gemfibrozil 

decreases platelet reactivity in patients with 

hypercholesterolemia during physical stress. Clin 

Pharm Ther 43:302, 1988. 

254. Sirtori CR, Franceschini G, Gianfranceschi G, et 

al: Effects of gemfibrozil on plasma lipoproteinapolipoprotein 

distribution and platelet reactivity 

in patients with hypertriglyceridemia. J Lab Clin 

Med 110:279, 1987. 

255. Kloer HU: Structure and biochemical effects of fenofibrate. 

Am J Med 83(5B):3, 1987. 

256. Niort G, Bulgarelli A, Cassader M, Pagano G: Effect 

of short term treatment with bezafibrate on 

plasma fibrinogen, fibrinopeptide A, platelet activation, 

and blood filterability in atherosclerotic 

hyperfibrinogenemic patients. Arteriosclerosis 

71(2–3):113, 1988. 

257. Ericsson C-G, Hamsten A, Nilsson J, et al: Angiographic 

assessment of effects of bezafibrate on progression 

of coronary artery disease in young male 

postinfarction patients. Lancet 347:849, 1996. 

258. Lesch M, Hoffken H, Schmidtsdorff A, et al: Effect 

of fenofibrate on fibrinogen concentration 

and blood viscosity. Consequences for myocardial 

microCirculation in coronary heart disease? Dtsch 

Med Wochenschr 114(24):939, 1989. 

259. Gotto AM: The Helsinki Heart Study Trial. Cardiol 

Bd Rev 6(3 Suppl):47, 1989. 

260. Faergeman O: Hypertriglyceridemia and the fibrate 

trials. Curr Opin Lipidol 11:609, 2000. 

261. Tenkanen L, Manttari M, Kovanen PT, et al: Gemfibrozil 

in the treatment of dyslipidemia. An 18-year 

mortality follow up of the Helsinki Heart Study. 


262. Ruotolo G, Ericsson CG, Tettamanti C, et al: Treatment 

effects on serum lipoprotein lipids, apolipoproteins 

and low density lipoprotein particle size 

and relationships of lipoprotein variables to pro- 


gression of coronary artery disease in the Bezafibrate 

Coronary Atherosclerosis Intervention Trial 

(BECAIT). J Am Coll Cardiol 32:1648, 1998. 

263. Goldenberg I, Benderly M, Goldbourt U for the 

BIP Study Group: Secondary prevention with 

bezafibrate therapy for the treatment of dyslipidemia. 

An extended follow up of the BIP trial. J Am 

Coll Cardiol 51: 459, 2008. 

264. Mooney A: Treating patients with hypertriglyceridemia 

saves lives: Triglyceride revisited. Curr Med 

Res Opin 15:65, 1999. 

265. Rubins HB, Davenport J, Babikian V, et al for the 

VA-HIT Study Group: Reduction in stroke with 

gemfibrozil in men with coronary heart disease 

and low HDL cholesterol. The Veterans Affairs 

HDL Intervention Trial (VA-HIT). Circulation 

103:2828, 2001. 

266. The FIELD Study Investigators: Effects of longterm 

fenofibrate therapy on cardio-vascular events 

in 9795 people with type 2 diabetes mellitus (the 

FIELD study): randomised controlled trial. Lancet 

366: 1849, 2005. 

267. Keech AC, Mitchell P, Summanen PA, et al: for the 

FIELD study investigators: Effect of fenofibrate on 

the need for laser treatment for diabetic retinopathy 

(FIELD study): a randomised controlled trial. 

Lancet 370: 1687, 2007. 

267a. The ACCORD Study Group: Effects of combination 

lipid therapy on type 2 diabetes mellitus. N 

Engl J Med 362: 1563, 2010. 

267b. Tonkin AM, Chen L: Effects of combination lipid 

therapy in the management of patients with type 2 

diabetes mellitus in the Action to Control Cardiovascular 

Risk in Diabetes (ACCORD) trial. Circulation 

122: 850, 2010. 

268. Gordon DJ, Rifkind BM: High density lipoprotein—the 

clinical implications of recent studies. N 

Engl J Med 321:1311, 1989. 

269. Virtamo J, Manninen V, Malkonen M: A placebo 

controlled rising dose, double-blind trial with gemfibrozil 

in dieting patients with primary hyperlipoproteinemia. 

Vasc Med 2:22, 1984. 

270. Goldberg AC, Bays HE, Ballantyne CM, et al: Efficacy 

and safety of ABT-335 (fenofibric acid) in 

combination with atorvastatin in patients with 

mixed dyslipidemia. Am J Cardiol 103: 515, 2009. 

271. Fenofibric acid (Trilipix). The Medical Letter 51: 33, 

2009. 

272. Knopp R: Review of the effects of fenofibrate on lipoproteins, 

apoproteins, and bile saturability. U.S. 

Studies. Cardiology 76(Suppl 1):14, 1989. 

273. Pierce LR, Gysowski DK, Gross TP: Myopathy and 

rhabdomyolitis associated with lovastatin-gemfibrozil 

combination therapy. JAMA 264:71, 1990.


274. Manninen V, Tenkanen L, Koskinen P, et al: Joint 

effects of serum triglycerides and LDL-cholesterol 

and HDL cholesterol concentrations on coronary 

heart disease risk in the Helsinki Heart Study: Implications 

for treatment. Circulation 85:37, 1992. 

275. Remick J, Weintraub H, Setton R, et al: Fibrate 

therapy, an update. Cardiol in Rev 16: 129, 2008. 

276. Keating GM, Croom KF: Fenofibrate. A review of 

its use in primary dyslipidaemia, the metabolic 

syndrome and type 2 diabetes mellits. Drugs 67: 

121, 2007. 

277. Alberts AW, Chen J, Kuron G, et al: Mevinolin: A 

highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme 

A reductase and a cholesterol-lowering 

agent. Proc Natl Acad Sci U S A 

77:3957, 1980. 

278. Endo A, Kuroda M, Tsijita Y: ML-236B and ML- 

236C, new inhibitors of cholesterogenesis produced 

by Penicillium citrium. J Antibiot 29:1346, 

1976. 

279. Brown MS, Goldstein JL: Multivalent feedback regulation 

of HMG-CoA reductase, a control mechanism 

coordinating isoprenoid synthesis and cell 

growth. J Lipid Res 21:505, 1980. 

280. Alberts AW: Discovery, biochemistry and biology 

of lovastatin. Am J Cardiol 62(15):10J, 1988. 

281. Tobert JA: New developments in lipid-lowering 

therapy. The role of inhibitors of hydroxymethylglutaryl 

coenzyme A reductase. Circulation 76:534, 

1987. 

282. Krukemyer JJ, Talbert RL: Lovastatin: A new cholesterol-lowering 

agent. Pharmacotherapy 7:198, 

1987. 

283. Parker TS, McNamara DJ, Brown C: Mevalonic 

acid in human plasma: relationship of concentration 

and circadian rhythm to cholesterol synthesis 

rates in man. Proc Natl Acad Sci U S A 79:3037, 

1982. 

284. Cromwell WC, Ziajka PE: Development of tachyphylaxis 

among patients taking HMG CoA reductase 

inhibitors. Am J Cardiol 86:1123, 2000. 

285. Grundy SM: HMG-CoA reductase inhibitors for 

treatment of hypercholesterolemia. N Engl J Med 

319:24, 1988. 

286. Henwood JM, Heel AC: Lovastatin. Drugs 36:429, 

1988. 

287. Vega GL, Grundy SM: Treatment of primary moderate 

hypercholesterolemia with lovastatin (Mevinolin) 

and colestipol. JAMA 257:33, 1987. 

288. Bradford RH, Shear CL, Chremos AN, et al: Expanded 

Clinical Evaluation of Lovastatin (EXCEL) 

study. Results: I. Efficacy in modifying plasma lipoproteins 

and adverse effect profile in 8245 patients 

with moderate hypercholesterolemia. Arch Intern 

Med 151:43, 1991. 




B. N Engl J Med 323:1289, 1990. 

290. Blankenhorn DH, Azen SP, Kramsch DM, et al: 

Coronary angiographic changes with lovastatin 

therapy. The Monitored Atherosclerosis Regression 

Study (MARS). Ann Intern Med 119:969, 1993. 

291. Hodis HN, Mack WJ, LaBree L, et al: Reduction in 

carotid arterial wall thickness using lovastatin and 

dietary therapy. A randomized, controlled clinical 


292. Waters D, Higginson L, Gladstone P, et al: Effects of 

monotherapy with an HMG-CoA reductase inhibitor 

on the progression of coronary atherosclerosis 

as assessed by serial quantitative arteriography. The 

Canadian Coronary Atherosclerosis Intervention 

Trial. Circulation 89:959, 1994. 

293. Waters D, Higginson L, Gladstone P, et al: Effects 

of cholesterol lowering on the progression of coronary 

atherosclerosis in women. A Canadian Coronary 

Atherosclerosis Intervention Trial (CCAIT) 

substudy. Circulation 92:2404, 1995. 

294. Furberg CD, Adams HP, Applegate WB, et al: Effect 

of lovastatin on early carotid atherosclerosis and 

cardiovascular events. Circulation 90:1679, 1994. 

295. Probstfield JL, Margitic SE, Byington RP, et al: Results 

of the primary outcome measure and clinical 

events from the Asymptomatic Carotid Artery Progression 

Study. Am J Cardiol 76:47C, 1995. 

296. Downs JR, Clearfield M, Weis S, et al: Primary prevention 

of acute coronary events with lovastatin in 

men and women with average cholesterol levels. 

JAMA 279:1615, 1998. 

297. Cobb MM, Teitelbaum HS, Breslow JL: Lovastatin 

efficacy in reducing low-density lipoprotein cholesterol 

levels on high vs low fat diets. JAMA 265:997, 

1991. 

298. Gupta EK, Ito MK: Lovastatin and extended-release 

niacin combination product. The first drug 

combination for the treatment of hyperlipidemia. 

Heart Dis 4:124, 2002. 

299. Kashyap ML, McGovern ME, Berra K, et al: Longterm 

safety and efficacy of a once-daily niacin/lovastatin 

formulation for patients with dyslipidemia. 

Am J Cardiol 89:672, 2002. 

300. Knodel LC, Talbert RL: Adverse effects of hypolipidaemic 

drugs. Med Toxicol 2:10, 1987. 

301. Davidson MH: Safety profile for the HMG-CoA 

reductase inhibitors. Treatment and trust. Drugs 

61:197, 2001. 

302. Blais L, Desgagne A, LeLorier J: 3-Hydroxy-3methylglutaryl 

coenzyme A reductase inhibitors

and the risk of cancer. Arch Intern Med 160:2363, 

2000. 

303. Norman DJ, Illingworth DR, Munson J, Hosenpud 

J: Myolysis and acute renal failure in a heart transplant 

recipient receiving lovastatin (letter). N Engl J 

Med 318:46, 1988. 

304. Harper CR, Jacobson TA: The broad spectrum of 

statin myopathy: from myalgia to rhabdomyolysis. 


305. Nawarskas JJ: HMG-CoA reductase inhibitors and 

coenzyme Q10. Cardiol in Rev 13: 76, 2005. 

306. Joy TR, Hegele RA: Narrative review: statin-related 

myopathy. Ann Intern Med 150: 858, 2009. 

307. Evans M, Rees A: The myotoxicity of statins. Curr 

Opin Lipidol 13:415, 2002. 

308. Pasternak RC, Smith SC Jr., Bairey-Merz CN, et 

al: ACC/AHA/NHLBT Clinical Advisory on the 

Use and Safety of Statins. J Am Coll Cardiol 40:567, 

2002. 

309. Frishman WH, Zimetbaum P, Nadelmann J: Lovastatin 

and other HMG CoA reductase inhibitors. J 


310. Neuvonen PJ, Jalava K-M: Intraconazole drastically 

increases plasma concentrations of lovastatin and 

lovastatin acid. Clin Pharmacol Ther 60:54, 1996. 

311. Kuo PC, Kirshenbaum JM, Gordon J, et al: Lovastatin 

therapy for hypercholesterolemia in cardiac 

transplant recipients. Am J Cardiol 64:631, 1989. 

312. Pierce LR, Wysowski DK, Gross T: Myopathy and 

rhabdomyolysis associated with lovastatin-gemfibrozil 

combination therapy. JAMA 264:71, 1990. 

313. Goldman JA, Fishman AB, Lee JE, Johnson RJ: 

The role of cholesterol-lowering agents in drug-induced 

rhabdomyolysis and polymyositis. Arthritis 

Rheum 32:358, 1989. 

314. Tobert JA: Efficacy and long-term adverse effect 

pattern of lovastatin. Am J Cardiol 62:28J, 1988. 

315. Tobert JA, Shear CL, Cremos AN, Mantell GE: 

Clinical experience with lovastatin. Am J Cardiol 

65:23F, 1990. 

316. Weir MR, Berger ML, Weeks ML, et al: Comparison 

of the effects on quality of life and the efficacy 

and tolerability of lovastatin versus pravastatin. Am 

J Cardiol 77:475, 1996. 

317. Plosker GL, McTavish D: Simvastatin: A reappraisal 

of its pharmacology and therapeutic efficacy in 

hypercholesterolemia. Drugs 50:334, 1995. 

318. Stalenhoef AFH, Mol MJTM, Stuyt PMJ: Efficacy 

and tolerability of simvastatin (MK 733). Am J Med 

87(4A):39S, 1989. 

319. Quercia RA: Focus on simvastatin: a potent HMG 

CoA reductase inhibitor for the treatment of hypercholesterolemia. 

Hosp Form 24:559, 1989. 

320. Pietro DA, Sidney A, Mantell G, et al: Effects of 


simvastatin and probucol in hypercholesterolemia 

(Simvastatin Multicenter Study Group II). Am J 

Cardiol 63:682, 1989. 

321. Stein E, Kreisberg R, Miller V, et al: Multicenter 

group l: Effects of simvastatin and cholestyramine 

in familial and nonfamilial hypercholesterolemia. 


322. Tikkanan XJ, Bocanegra TS, Walker JF, Cook T, the 

Simvastatin Study Group: Comparison of low-dose 

simvastatin and gemfibrozil in the treatment of elevated 

plasma cholesterol. Am J Med 87(4A):47S, 

1989. 

323. Erkelens DW, Baggen MGA, Van Doormaal JJ, et 

al: Clinical experience with simvastatin compared 

with cholestyramine. Drugs 36(Suppl 3):87, 1988. 

324. Dacol PG, Cattin L, Valenti M, et al: Efficacy of 

simvastatin plus cholestyramine in the two-year 

treatment of heterozygous hypercholesterolemia. 

Curr Ther Res Clin Exp 48:798, 1990. 

325. Havel RJ: Simvastatin: A once a day treatment of 

hypercholesterolemia: Introduction to a symposium. 

Am J Med 87(4A):2S, 1989. 

326. Mol MJT, Stalenhoef AFH: Adrenocortical function 

in patients with simvastatin. Lancet 335:412, 

1990. 

327. Stein E: Management of hypercholesterolemia: 

Guide to diet and drug therapy. Am J Med 

87(4A):24S, 1989. 

328. Illingworth DR, Stein EA, Knopp RH, et al: A randomized 

multicenter trial comparing the efficacy 

of simvastatin and fluvastatin. Cardiovasc Pharmacol 

Ther 1:23, 1996. 

328a. Study of the Effectiveness of Additional Reductions 

in Cholesterol and Homocysteine (SEARCH) 

Collaborative Group: Intensive lowering of LDL 

cholesterol with 80 mg versus 20 mg simvastatin 

daily in 12 064 survivors of myocardial infarction: 

a double-blind randomised trial. Lancet 376: 1658, 

2010. 

329. Rabelink AJ, Henle RJ, Erkelens DW, et al: Effects 

of simvastatin and cholestyramine on lipoprotein 

profile in hyperlipidaemia of nephrotic syndrome. 

Lancet 10:1335, 1988. 

330. Duane WC, Hunninghake DB, Freeman ML, et al: 

Simvastatin, a competitive inhibitor of HMG-CoA 

reductase, lowers cholesterol saturation index of 

gallbladder bile. Hepatology 8(5):1147, 1988. 

331. MAAS Investigators: Effect of simvastatin on coronary 

atheroma: The Multicentre Anti-Atheroma 

Study (MAAS). Lancet 344:633, 1994. 

332. Corti R, Fayad ZA, Fuster V, et al: Effects of lipidlowering 

by simvastatin on human atherosclerotic 

lesions. A longitudinal study by high-resolution, 

noninvasive magnetic resonance imaging. Circula-


tion 104:249, 2001. 

333. Kjekshus J, Pedersen TR for the Scandinavian Simvastatin 

Survival Study Group (4S): Reducing the 

risk of coronary events: Evidence from the Scandinavian 

Simvastatin Survival Study. Am J Cardiol 

76:64C, 1995. 

334. Pedersen TR, Kjekshus J, Berg K, et al: Cholesterol 

lowering and the use of healthcare resources. Results 

of the Scandinavian Simvastatin Survival 

Study. Circulation 93:1796, 1996. 

335. Alessandri C, Basili S, Maurelli M, et al: Effect of 

hydroxy methylglutaryl-coenzyme A reductase 

inhibitors on some blood coagulation parameters. 

Curr Ther Res 53:188, 1993. 

336. Giroux LM, Davignon J, Naruszewicz M: Simvastatin 

inhibits the oxidation of low-density lipoproteins 

by activated human monocyte derived 

macrophages. Biochim Biophys Acta 1165:335, 

1993. 

337. Szczeklik A, Musial J, Undas A, et al: Inhibition of 

thrombin generation by simvastatin and lack of 

additive effects of aspirin in patients with marked 

hypercholesterolemia. J Am Coll Cardiol 33:1286, 

1999. 

338. Undas A, Brummel KE, Musial J, et al: Simvastatin 

depresses blood clotting by inhibiting activation 

of prothrombin, factor V and factor XIII and 

by enhancing factor Va inactivation. Circulation 

103:2248, 2001. 

339. Ray JG, Mamdani M, Tsuyuki RT, et al: Use of 

statins and the subsequent development of deep 

vein thrombosis. Arch Intern Med 161:1405, 2001. 

340. Patel R, Nagueh SF, Tsybouleva N, et al: Simvastatin 

induces regression of cardiac hypertrophy 

and fibrosis and improves cardiac function in a 

transgenic rabbit model of human hypertrophic 

cardiomyopathy. Circulation 104:317, 2001. 

341. Knapp HH, Schrott H, Ma P, et al: Efficacy and 

safety of combination simvastatin and colesevelam 

in patients with primary hypercholesterolemia. Am 

J Med 110:352, 2001. 

342. Bays H, Weiss S, Gagne C, et al: Ezetimibe added 

to ongoing statin therapy for treatment of primary 

hypercholesterolemia (abst.). J Am Coll Cardiol 39 

(Suppl A): 245A, 2002. 

343. Davidson M, McGarry T, Bettis R, et al: Ezetimibe 

co-administered with simvastatin in 668 patients 

with primary hypercholesterolemia (abst.). J Am 

Coll Cardiol 39(Suppl A):226A, 2002. 

344. Sanford M, Curran MP: Niacin extended-release/ 

simvastatin. Drugs 68: 2373, 2008. 

345. McTavish D, Sorkin EM: Pravastatin. A review of 

its pharmacological properties and therapeutic 

potential in hypercholesterolaemia. Drugs 42:65, 

1991. 

346. Tsujita Y, Kuroda M, Simada Y, et al: CS 5l4, a competitive 

inhibitor of 3-hydroxy-3-methyl glutaryl 

coenzyme A reductase: Tissue selective inhibitor of 

steroid synthesis and hypolipidemic effects on various 

animal species. Biochem Biophys Acta 877:50, 

1986. 

347. Germershausen JI, Hunt VM, Bostedor RG, et al: 

Tissue selectivity of the cholesterol-lowering agents 

lovastatin, simvastatin and pravastatin in rats in 

vivo. Biochem Biophys Res Commun 158(3):667, 

1989. 

348. Reihner E, Rudling M, Stahlberg D, et al: Influence 

of pravastatin, a specific inhibitor of HMG CoA 

reductase, on hepatic metabolism of cholesterol. N 

Engl J Med 323:224, 1990. 

349. Hunninghake DB, Knopp RH, Schonfeld G, et al: 

Efficacy and safety of pravastatin in patients with 

primary hypercholesterolemia. 1. A dose-response 

study. Atherosclerosis 85:81, 1990. 

350. Mabuchi A, Kamon N, Fujita H, et al: The effects of 

CS 5l4 on serum lipoprotein, lipid and apolipoprotein 

levels in patients with familial hypercholesterolemia. 


351. Nakaya N, Yasuhiko H, Hiromitsu T, et al: The 

effect of CS 514 on serum lipids and apolipoproteins 

in hypercholesterolemic subjects. JAMA 

257(22):3088, 1987. 

352. Chan P, Lee C-B, Lin T-S, et al: The effectiveness 

and safety of low dose pravastatin in elderly hypertensive 

hypercholesterolemic subjects on antihypertensive 

therapy. Am J Hypertens 8:1099, 1995. 

353. LaRosa JC, Applegate W, Crouse JR, et al: Cholesterol 

lowering in the elderly. Arch Intern Med 

154:529, 1994. 

354. ALLHAT Collaborative Research Group: Major 

outcomes in moderately hyperchol-esterolemic, 

hypertensive patients randomized to pravastatin 

vs usual care: the Antihypertensive and Lipid- 

Lowering Treatment to Prevent Heart Attack Trial 

(ALLHAT-LLT). JAMA 288: 2998, 2002. 

355. Raskin P, Ganda OP, Schwartz S, et al: Efficacy and 

safety of pravastatin in the treatment of patients 

with type I or type II diabetes mellitus and hypercholesterolemia. 

Am J Med 99:362, 1995. 

356. Prisant LM, Downton M, Watkins LO: Efficacy and 

tolerability of lovastatin in 459 African-Americans 

with hypercholesterolemia. Am J Card 78:420, 

1996. 

357. The Simvastatin Pravastatin Study Group: Comparison 

of the efficacy, safety and tolerability of 

simvastatin and pravastatin for hypercholesterolemia. 

Am J Cardiol 71:1408, 1993. 

358. The Lovastatin Pravastatin Study Group: A multi-

center comparative trial of lovastatin and pravastatin 

in the treatment of hypercholesterolemia. Am 

J Cardiol 71:810, 1993. 

359. Bekhoonek BD, McGovern ME, Markowitz JS, et 

al: Effects of pravastatin in patients with total serum 

cholesterol levels from 5.2 to 7.8 mmol/liter 

(200 to 300 mg/dL) plus two additional atherosclerotic 

risk factors. Am J Cardiol 72:1031, 1993. 

360. Pitt B, Mancini J, Ellis SG, et al: Pravastatin Limitation 

of Atherosclerosis in the Coronary Arteries 

(PLAC I): Reduction in atherosclerosis progression 

and clinical events. J Am Coll Cardiol 26:1133, 

1995. 

361. Crouse JR III, Byington RP, Bond MG, et al: Pravastatin, 

lipids and atherosclerosis in the coronary arteries 

(PLAC II). Am J Cardiol 75:455, 1995. 

362. Salonen R, Nyyssonen K, Porkkala E, et al: Kuopio 

Atherosclerosis Prevention Study (KAPS). A population-based 

primary preventive trial of the effect 

of LDL lowering on atherosclerotic progression in 

carotid and femoral arteries. Circulation 92:1758, 

1995. 

363. Jukema JW, Bruschke AVG, van Boven AJ, et al: Effects 

of lipid lowering by pravastatin on progression 

and regression of coronary artery disease in 

symptomatic men with normal to moderately elevated 

serum cholesterol levels. The Regression 

Growth Evaluation Statin Study (REGRESS). Circulation 

91:2528, 1995. 

364. Byington RP, Jukema JW, Salonen JT, et al: Reduction 

in cardiovascular events during pravastatin 

therapy. Pooled analysis of clinical events of the 

Pravastatin Atherosclerosis Intervention Program. 


365. Albert MA, Danielson E, Rifai N, et al: Effect 

of statin therapy on C-reactive protein levels. 

The Pravastatin Inflammation/CRP Evaluation 

(PRINCE): A randomized trial and cohort study. 

JAMA 286:64, 2001. 

366. Azar RR, Waters DD: PRINCE’s prospects: Statins, 

inflammation, and coronary risk. Am Heart J 

141:881, 2001. 

367. Ridker PM, Rifai N, Pfeffer MA, et al: Long-term effects 

of pravastatin on plasma concentration of Creactive 

protein. Circulation 100:230, 1999. 

368. Horne BD, Muhlestein JB, Carlquist JF, et al: Statin 

therapy, lipid levels, C-reactive protein and the 

survival of patients with angiographically severe 

coronary artery disease. J Am Coll Cardiol 36:1774, 

2000. 

369. Glorioso N, Troffa C, Filigheddu F, et al: Effect 

of the HMG-CoA reductase inhibitors on blood 

pressure in patients with essential hypertension 

and primary hypercholesterolemia. Hypertension 


34:1281, 1999. 

370. Dupuis J, Tardif JC, Cernacek P, Theroux P: Cholesterol 

reduction rapidly improves endothelial 

function after acute coronary syndromes. The RE- 

CIFE (Reduction of Cholesterol in Ischemia and 

Function of the Endothelium) trial. Circulation 

99:3227, 1999. 

371. Kaesemeyer WH, Caldwell RB, Huang J, Caldwell 

RW: Pravastatin sodium activates endothelial nitric 

oxide synthase independent of its cholesterol-lowering 

actions. J Am Coll Cardiol 33:234, 1999. 

372. Dangas G, Badimon JJ, Smith DA, et al: Pravastatin 

therapy in hyperlipidemia: effects on thrombus formation 

and the systemic hemostatic profile. J Am 

Coll Cardiol 33:1294, 1999. 

373. Shepherd J, Cobbe SM, Ford I, et al: Prevention 

of coronary heart disease with pravastatin in men 

with hypercholesterolemia. N Engl J Med 333:1301, 

1995. 

374. Ford I, Murray H, Packard CJ, et al for the West of 

Scotland Coronary Prevention Study Group: Longterm 

follow up of the West of Scotland Coronary 

Prevention Study. N Engl J Med 357: 1477, 2007. 

375. Pfeffer MA, Sacks F, Moye LA, et al: Cholesterol 

and Recurrent Events: A secondary prevention 

trial for normolipidemic patients. Am J Cardiol 

76:98C, 1995. 

376. Plehn JF, Davis BR, Sacks FM, et al: Reduction of 

stroke incidence after myocardial infarction with 

pravastatin. The Cholesterol and Recurrent Events 

(CARE) study. Circulation 99:216, 1999. 

377. Tonkin AM, Colquhoun D, Emberson J, et al: Effects 

of pravastatin in 3260 patients with unstable 

angina: results from the LIPID study. Lancet 

355:1871, 2000. 

378. Hunt D, Young P, Simes J, et al: Benefits of pravastatin 

on cardiovascular events and mortality in older 

patients with coronary heart disease are equal to 

or exceed those seen in younger patients: Results 

from the LIPID trial. Ann Intern Med 134:931, 

2001. 

379. Simes RJ, Marschner IC, Hunt D, et al: Relationship 

between lipid levels and clinical outcomes in 

the Long-Term Intervention with Pravastatin in 

Ischemic Disease (LIPID) Trial. To what extent is 

the reduction in coronary events with pravastatin 

explained by on-study lipid levels? Circulation 

105:1162, 2002. 

380. White HD, Simes J, Anderson NE, et al: Pravastatin 

therapy and the risk of stroke. N Engl J Med 

343:317, 2000. 

381. Vgontzas AN, Kales A, Bixler EO, et al: Effects of 

lovastatin and pravastatin on sleep efficiency and 

sleep stages. Clin Pharmacol Ther 50:730, 1991.


382. Langtry HD, Markham A: Fluvastatin: A review of 

its use in lipid disorders. Drugs 57:583, 1999. 

383. Davidson MH, FLUENT investigation group: Fluvastatin 

Long-Term Extension Trial (FLUENT): 

Summary of efficacy and safety. Am J Med 96:4S, 

1994. 

384. Jacotot B, Banga JD, Waite R, et al: Long-term efficacy 

with fluvastatin as monotherapy, and combined 

with cholestyramine (a 156 week multicenter 

study). Am J Cardiol 76(Suppl): 41A, 1995. 

385. Leitersdorf E, Muratti EN, Eliav O, et al: Efficacy 

and safety of a combination fluvastatin-bezafibrate 

treatment for familial hypercholesterolemia: Comparative 

analysis with a fluvastatin-cholestyramine 

combination. Am J Med 96:401, 1994. 

386. Foley DP, Bonnier H, Jackson G, et al: Prevention 

of restenosis after coronary balloon angioplasty: 

Rationale and design of the Fluvastatin Angioplasty 

Restenosis (FLARE) trial. Am J Cardiol 73:5D, 

1994. 

387. Herd JA, Ballantyne C, Farmer JA, et al: Effects of 

fluvastatin on coronary atherosclerosis in patients 

with mild to moderate cholesterol elevations [Lipoprotein 

and Coronary Atherosclerosis Study 

(LCAS)]. Am J Cardiol 80:278, 1997. 

388. Liem A, van Boven AJ: Effects of fluvastatin administered 

immediately after an acute MI on myocardial 

ischemia. Presented at the American Heart 

Association Scientific Sessions 2000, New Orleans, 

La. Nov 12–15, 2000. 

389. Marz W, Scharnagl H, Abletshauser C, et al: Fluvastatin 

lowers atherogenic dense low-density lipoproteins 

in postmenopausal women with the 

atherogenic lipoprotein phenotype. Circulation 

103:1942, 2001. 

390. Sabia H, Prasad P, Smith HT, et al: Safety, tolerability, 

and pharmacokinetics of an extended-release 

formulation of fluvastatin administered once daily 

to patients with primary hypercholesterolemia. J 

Cardiovasc Pharmacol 37:502, 2001. 

391. Nawrocki JW, Weiss SR, Davidson MH, et al: Reduction 

of LDL-cholesterol by 25% to 69% in patients 

with primary hypercholesterolemia by atorvastatin: 

A new HMG-CoA reductase inhibitor. Arterioscler 


392. Bakker-Arkema RG, Davidson MH, Hgoldstein RJ, 

et al: Efficacy and safety of a new HMG-CoA reductase 

inhibitor, atorvastatin, in patients with hypertriglyceridemia. 

JAMA 275:128, 1996. 

393. Cilla DD Jr, Gibson DM, Whitfield LR, Sedman AJ: 

Pharmacodynamic effects and pharmacokinetics 

of atorvastatin after administration in normocholesterolemic 

subjects in the morning and evening. J 


393a. Athyros VG, Tziomalos K, Gossios TD, et al: Safety 

and efficacy of long-term statin treatment for cardiovascular 

events in patients with coronary heart 

disease and abnormal liver tests in the Greek Atorvastatin 

and Coronary Heart Disease Evaluation 

(GREACE) study: a post-hoc analysis. Lancet 376: 

1916, 2010. 

394. Smilde TJ, van Wissen S, Wollersheim H, et al: 

Effect of aggressive versus conventional lipid lowering 

on atherosclerosis progression in familial 

hypercholesterolaemia (ASAP): A prospective, 

randomised, double-blind trial. Lancet 357:577, 

2001. 

395. Illingworth DR, Crouse JR 3rd, Hunninghake DB, 

et al: A comparison of simvastatin and atorvastatin 

up to maximal recommended doses in a large multicenter 

randomized clinical trial. Curr Med Res 

Opin 17:43, 2001. 

396. Pitt B, Waters D, Brown WV, et al. Aggressive lipidlowering 

therapy compared with angioplasty in 

stable coronary artery disease. Atorvastatin versus 

Revascularization Treatment investigators. N Engl J 

Med 341: 70, 1999. 

397. Statins for high-risk patients without heart disease 

or high cholesterol. The Medical Letter 48: 1, 2006. 

398. Davidson MH: Rosuvastatin: A highly efficacious 

statin for the treatment of dyslipidaemia. Expert 

Opin Investig Drugs 11:125, 2002. 

399. McTaggart F, Buckett L, Davidson R, et al: Preclinical 

and clinical pharmacology of rosuvastatin, 

a new 3-hydroxy-3-methylglutaryl coenzyme A 

reductase inhibitor. Am J Cardiol 87(Suppl):28B, 

2001. 

400. Olsson AG: Statin therapy and reductions in lowdensity 

lipoprotein cholesterol: Initial clinical data 

on the potent new statin rosuvastatin. Am J Cardiol 

87(Suppl):33B, 2001. 

401. Jones PH, Davidson MH, Stein EA, et al. Comparison 

of the efficacy and safety of rosuvastatin 

versus atorvastatin, simvastatin, and pravastatin 

across doses (STELLAR trial). Am J Cardiol 2003; 

92: 152-160. 

402. Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas 

RH: The safety of rosuvastatin as used in common 

clinical practice. A postmarketing analysis. Circulation 

111: 3051, 2005. 

403. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very 

high-intensity statin therapy on regression of coronary 

atherosclerosis. The ASTEROID trial. JAMA 

2006; 295: 156-1565. 

404. Nicholls SJ, Tuzcu EM, Sipahi I, et al: Statins, highdensity 

lipoprotein cholesterol, and regression of 

coronary atherosclerosis. JAMA 297: 499, 2007. 

405. Ballantyne CM, Raichlen JS, Nicholls SJ, et al. Effect

of rosuvastatin therapy on coronary artery stenoses 

assessed by quantitative coronary angiography: a 

study to evaluate the effect of rosuvastatin on intravascular 

ultrasound-derived coronary atheroma 

burden. Circulation 2008; 117: 2458-2466. 

406. Crouse JR III, Raichlen JS, Riley WA, et al for the 

METEOR Study Group: Effect of rosuvastatin on 

progression of carotid intima-media thickness in 

low risk individuals with subclinical atherosclerosis. 

The METEOR trial. JAMA 297: 1344, 2007. 

406a. Ridker PM, MacFadyen J, Cressman M, Glynn RJ: 

Efficacy of rosuvastatin among men and women 

with moderate chronic kidney disease and elevated 

high-sensitive C-reactive protein. A secondary 

analysis from the JUPITER (Justification for the 

Use of Statins in Prevention-an Intervention Trial 

Evaluating Rosuvastatin) trial. J Am Coll Cardiol 

55: 1266, 2010. 

406b. Mora S, Glynn RJ, Hsia J, et al: Statins for the primary 

prevention of cardiovascular events in women 

with elevated high-sensitivity C-reactive protein 

or dyslipidemia. Results from the Justification for 

the Use of Statins in Prevention-an Intervention 

Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis 

of women from primary prevention trials. 

Circulation 121: 1069, 2010. 

407. Kjekshus J, Apetrei E, Barrios V, et al for the CO- 

RONA Group: Rosuvastatin in older patients with 

systolic heart failure. N Engl J Med 357: 2248, 2007. 

408. Fellstrom BC, Jardine AG, Schmieder RE, et al for 

the AURORA Study Group: Rosuvastatin and cardiovascular 

events in patients undergoing hemodialysis. 

N Engl J Med 360: 1395, 2009. 

409. Glynn RJ, Danielson E, Fonseca FAH, et al: A randomized 

trial of rosuvastatin in the prevention of 

venous thromboembolism. N Engl J Med 360: 1851, 

2009. 

410. Hiro T, Kimura T, Morimoto T, et al. Effect of intensive 

statin therapy on regression of coronary 

atherosclerosis in patients with acute coronary 

syndrome: a multicenter randomized trial evaluated 

by volumetric intravascular ultrasound using 

pitavastatin versus atorvastatin (JAPAN-ACS [Japan 

Assessment of pitavastatin and atorvastatin in 

acute coronary syndrome] study). J Am Coll Cardiol 

54: 293, 2009. 

411. Kawashiri M-a, Nohara A, Tada H, et al: Comparison 

of effects of pitavastatin and atorvastatin on 

plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: 

results from a crossover study. 

Clin Pharmacol Therap 83: 731, 2008. 

412. Aronow WS, Nayak D, Woodworth S, Ahn C. Effect 

of simvastatin versus placebo on treadmill 

exercise time until the onset of intermittent claudi- 


cation in older patients with peripheral arterial disease 

at six months and at one year after treatment. 

Am J Cardiol 92: 711, 2003. 

413. Mohler ER III, Hiatt WR, Creager MA, for the 

Study Investigators. Cholesterol reduction with 

atorvastatin improves walking distance in patients 

with peripheral arterial disease. Circulation 

108:1481, 2003. 

414. Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin 

on walking performance and symptoms of 

intermittent claudication in hypercholesterolemic 

patients with peripheral vascular disease. Am J Med 

114: 359, 2003. 

415. De Sutter J, Tavernier R, De Buyzere M, et al. Lipid 

lowering drugs and recurrences of life-threatening 

ventricular arrhythmias in high-risk patients. J Am 


416. Mitchell LB, Powell JL, Gillis AM, et al. Are lipidlowering 

drugs also antiarrhythmic drugs? An 

analysis of the Antiarrhythmics Versus Implantable 

Defibrillators (AVID) trial. J Am Coll Cardiol 

42: 81, 2003. 

417. Chiu JH, Abdelhadi RH, Chung MK, et al. Effect 

of statin therapy on risk of ventricular arrhythmia 

among patients with coronary artery disease 

and an implantable cardioverter-defibrillator. Am J 

Cardiol 95: 490, 2005. 

418. Vyas AK, Guo H, Moss AJ, et al. Reduction in ventricular 

tachyarrhythmias with statins in the Multicenter 

automatic Defibrillator Implantation trial 

(MADIT)-II. J Am Coll Cardiol 47: 769, 2006. 

419. Lai HM, Aronow WS, Kruger A, et al. Effect of beta 

blockers, angiotensin-converting enzyme inhibitors 

or angiotensin receptor blockers, and statins 

on mortality in patients with implantable cardioverter-defibrillators. 

Am J Cardiol 102: 77, 2008. 

420. Desai H, Aronow WS, Tsai FS, et al. Statins reduce 

appropriate cardioverter-defibrillator shocks and 

mortality in patients with heart failure and combined 

cardiac resynchronization and implantable 

cardioverter-defibrillator therapy. J Cardiovasc 

Pharmacol Therap 14: 176, 2009. 

421. Durazzo AES, Machado FS, Ikeoka DT, et al. Reduction 

in cardiovascular events after vascular surgery 

with atorvastatin: a randomized trial. J Vasc 

Surg 39: 967, 2004. 

422. Kertai MD, Boersma E, Westerhout CM, et al. Association 

between long-term statin use and mortality 

after successful abdominal aortic aneurysm 

surgery. Am J Med 116: 96, 2004. 

423. Poldermans D, Bax JJ, Kertai MD, et al. Statins are 

associated with a reduced incidence of perioperative 

mortality in patients undergoing major noncardiac 

vascular surgery. Circulation 107: 1848,


2003. 

424. O’Neil-Callahan K, Katsimaglia MR, Ryan J, et al. 

Statins decrease perioperative cardiac complications 

in patients undergoing noncardiac vascular 

surgery. The Statins for Risk Reduction in Surgery 

(StaRRS) Study. J Am Coll Cardiol 45: 336, 2005. 

425. Desai H, Aronow WS, Ahn C, et al. Incidence of 

perioperative myocardial infarction and of 2-year 

mortality in 577 elderly patients undergoing noncardiac 

vascular surgery treated with and without 

statins. Arch Gerontol Geriatr 51: 149, 2010. 

426. Abuissa H, O’Keefe JH, Bybee KA: Statins as antiarrhythmics: 

a systematic review. Part 1: effects on 

risk of atrial fibrillation. Clin Cardiol 32: 544, 2009. 

427. Abuissa H, O’Keefe JH, Bybee KA: Statins as antiarrhythmics: 

a systematic review. Part II: effects 

on risk of ventricular arrhythmias. Clin Cardiol 32: 

549, 2009. 

428. Patti G, Chello M, candura D, et al: Randomized 

trial of atorvastatin for reduction of postoperative 

atrial fibrillation in patients undergoing cardiac 

surgery. Results of the ARMYDA-3 Study. Circulation 

114: 1455, 2006. 

429. Majmudar MD, Tompkins C, Bachmann JM, et al: 

Effects of lipid-altering therapies on ventricular 

arrhythmias and sudden cardiac death. Cardiol in 

Rev 17: 60, 2009. 

430. Greenwood J, Steinman L, Zamvil SS: Statin therapy 

and autoimmune disease: from protein prenylation 

to immunomodulation. Nature Rev Immunol 

6: 358, 2006. 

431. Donnino MW, Cocchi MN, Howell M, et al: Statin 

therapy is associated with decreased mortality in 

patients with infection. Acad Emerg Med 16: 230, 

2009. 

432. Tleyjeh IM, Kashour T, Hakim FA, et al: Statins for 

the prevention and treatment of infections. A systematic 

review and meta-analysis. Arch Intern Med 

169: 1658, 2009. 

432a. Khemasuwan D, DiVietro ML, Tangdhanakanond 

K, et al: Statins decrease the occurrence of venous 

thromboembolism in patients with cancer. Am J 

Med 123: 60, 2010. 

433. Davignon J, Laaksonen R: Low-density lipoprotein-independent 

effects of statins. Curr Opin Lipidol 

10:543, 1999. 

433a. Hayward RA, Krumholz HM, Zulman DM, et al: 

Optimizing statin treatment for primary prevention 

of coronary artery disease. Ann Intern Med 

152: 69, 2010. 

433b. Cholesterol Treatment Trialists (CTT) Collaboration: 

Efficacy and safety of more intensive lowering 

of LDL cholesterol: a meta-analysis of data from 

170 000 participants in 26 randomised trials. Lan- 

cet 376: 1670, 2010. 

433c. Cheung BMY, Lam KS: Is intensive LDL-cholesterol 

lowering beneficial and safe? Lancet 376: 1622, 

2010. 

434. Gotto AM Jr., Farmer JA: Pleiotropic effects of 

statins: Do they matter? Curr Opin Lipidol 12:391, 

2001. 

435. Alber HF, Dulak J, Frick M, et al: Atorvastatin 

decreases vascular endothelial growth factor in 

patients with coronary artery disease. J Am Coll 

Cardiol 39:1951, 2002. 

436. Yeung AC, Tsao P: Statin therapy. Beyond cholesterol 

lowering and anti-inflammatory effects. Circulation 

105:2937, 2002. 

437. Wang PS, Solomon DH, Mogun H, Avorn J: HMG- 

CoA reductase inhibitors and the risk of hip fractures 

in elderly patients. JAMA 283:3211, 2000. 

438. Chan KA, Andrade SE, Boles M, et al: Inhibitors 

of hydroxymethylglutaryl-coenzyme A reductase 

and risk of fracture among older women. Lancet 

355:2185, 2000. 

439. Jick H, Zornberg GL, Jick SS, et al: Statins and the 

risk of dementia. Lancet 356:1627, 2000. 

440. Herrington DM, Vittinghoff E, Lin F, et al: Statin 

therapy, cardiovascular events, and total mortality 

in the Heart and Estrogen/Progestin Replacement 

Study (HERS). Circulation 105:2962, 2002. 

441. Marcelino JJ, Feingold KR: Inadequate treatment 

with HMG-CoA reductase inhibitors by health 

care providers. Am J Med 100:605, 1996. 

442. Teo KK, Burton JR: Who should receive HMG 

CoA reductase inhibitors? Drugs 62:1707, 2002. 

443. 443. Brown WV: Safety of statins. Curr Opin Lipidol 

19: 558, 2008. 

444. Kashani A, Phillips CO, Foody JM, et al: Risks associated 

with statin therapy. A systematic overview 

of randomized clinical trials. Circulation 114: 2788, 

2006. 

445. Aronow HD, Topol EJ, Roe MT, et al: Effect of lipid-lowering 

therapy on early mortality after acute 

coronary syndromes: An observational study. Lancet 

357:1063, 2001. 

446. Stenestrand U, Wallentin L, for the Swedish Register 

of Cardiac Intensive Care (RIKS-HIA): Early 

statin treatment following acute myocardial infarction 

and 1-year survival. JAMA 285:430, 2001. 

447. Newby LK, Kristinsson A, Bhapkar MV, et al: Early 

statin initiation and outcomes in patients with 

acute coronary syndromes. JAMA 287:3087, 2002. 

448. Heeschen C, Hamm CW, Laufs U, et al: Withdrawal 

of statins increases event rates in patients with 

acute coronary syndromes. Circulation 105:1446, 

2002. 

449. Altschul R, Hoffer A, Stephen JD: Influence of

nicotinic acid on serum cholesterol in man. Arch 

Biochem 54:558, 1955. 

450. Guyton JR: Niacin in cardiovascular prevention: 

mechanisms, efficacy, and safety. Curr Opin Lipidol 

18: 415, 2007. 

451. Fumagalli R: Pharmacokinetics of nicotinic acid 

and some of its derivatives. In: Gey KF, Caarlson 

LA (eds): Metabolic Effects of Nicotinic Acid and Its 

Derivatives. Bern: Hans Huber, 1971, pp 33–49. 

452. Petrack B, Greengard P, Kalinsky H: On the relative 

efficacy of nicotinamide and nicotinic acid as 

precursors of nicotinamide adenine dinucleotide. J 

Biol Chem 241(10):2367, 1966. 

453. See M, Hoppichler F, Reavely D, et al: Relation 

of serum lipoprotein(a) concentration and 

apolipoprotein(a) phenotype to coronary heart disease 

in patients with familial hypercholesterolemia. 

N Engl J Med 322:1494, 1990. 

454. Mahley RW, Bersot TP: Drug therapy for hypercholesterolemia 

and dyslipidemia. In: Hardman 

JG, Limbird LE (eds): Goodman and Gilman’s. The 

Pharmacological Basis of Therapeutics, 10th ed. 

New York: McGraw Hill 2001:971–1002. 

455. Alderman JD, Pasternak RC, Sacks FM, et al: Effect 

of a modified, well-tolerated niacin regimen 

on serum total cholesterol, high density lipoprotein 

cholesterol and the cholesterol to high density lipoprotein 

ratio. Am J Cardiol 64:725, 1989. 

456. Arner P, Ostman J: Effect of nicotinic acid on acylglycerol 

metabolism in human adipose tissue. Clin 

Sci 64:235, 1983. 

457. Canner PL, Berge KG, Wenger NK, et al: Fifteen 

year mortality in Coronary Drug Project patients: 

Long term benefit with niacin. J Am Coll Cardiol 

8(6):1245, 1986. 

458. Carlson LA, Danielson M, Ekberg I, et al: Reduction 

of myocardial reinfarction by the combined 

treatment with clofibrate and nicotinic acid. Atherosclerosis 

28:81, 1977. 

459. Azen SP, Mack WJ, Cashin-Hemphill L, et al: Progression 

of coronary artery disease predicts clinical 

coronary events. Long-term follow-up from the 

Cholesterol Lowering Atherosclerosis Study. Circulation 

93:34, 1996. 




B. N Engl J Med 323:1289, 1990. 

461. Blumenthal RS, Michos ED: The HALTS trialhalting 

atherosclerosis or halted too early? N Engl J 

Med 361: 2178, 2009. 

462. Witztum JL: Current approaches to drug therapy 

for the hypercholesterolemic patient. Circulation 

80(5):1101, 1989. 


463. McCormack PL, Keating GM: Prolonged-release 

nicotinic acid. A review of its use in the treatment 

of dyslipidaemia. Drugs 65: 2719, 2005. 

464. Knopp RH, Ginsberg J, Albers JJ, et al: Contrasting 

effects of unmodified and time-release forms of 

niacin on lipoproteins in hyperlipidemic subjects: 

Clues to mechanism of action of niacin. Metabolism 

34(7):642, 1985. 

465. Goldberg A, Alagona P Jr., Capuzzi DM, et al: Multiple 

dose efficacy and safety of an extended-release 

form of niacin in the management of hyperlipidemia. 

Am J Cardiol 85:1100, 2000. 

466. Etchason JA, Miller TD, Squires RW, et al: Niacininduced 

hepatitis: A potential side effect with lowdose 

time-release niacin. Mayo Clin Proc 66:23, 

1991. 

467. Dalton TA, Berry RS: Hepatotoxicity associated 

with sustained-release niacin. Am J Med 93:102, 

1992. 

468. Grundy SM, Vega GL, McGovern ME, et al: Efficacy, 

safety and tolerability of once-daily niacin for 

the treatment of dyslipidemia associated with Type 

2 diabetes: Results of the Assessment of Diabetes 

Control and Evaluation of the Efficacy of Niaspan 

Trial. Arch Intern Med 162:1568, 2002. 

469. Morgan JM, Capuzzi DM, Guyton JR, et al: Treatment 

effect of Niaspan, a controlled-release niacin 

in patients with hypercholesterolemia: A placebocontrolled 

trial. J Cardiovasc Pharmacol Ther 1:195, 

1996. 

470. Keenan JM, Fontaine PL, Wenz JB, et al: Niacin revisited. 


471. Lauring B, Dishy V, Luo W-L, et al: Laropiprant in 

combination with extended-release niacin does not 

alter urine 11-dehydrothromboxane B2, a marker 

of in vivo platelet function, in healthy, hypercholesterolemia 

and diabetic subjects. J Clin Pharmacol 

49: 1426, 2009. 

472. Gibbons LW, Gonzalez V, Gordon N, Grundy S: 

The prevalence of side effects with regular and 

sustained-release nicotinic acid. Am J Med 99:378, 

1995. 

472a. Jacobson TA: A “hot” topic in dyslipidemia management 

– “how to beat a flush”: optimizing niacin 

tolerability to promote long-term treatment adherence 

and coronary disease prevention. Mayo Clin 

Proc 85: 365, 2010. 

473. Patterson DJ, Dew EW, Gyorkey F, Graham DY: 

Niacin hepatitis. South Med J 76(2):239, 1983. 

474. Clementz GL, Holmes AW: Nicotinic-acid-induced 

fulminant hepatic failure. J Clin Gastroenterol 

9(5):582, 1987. 

475. Elam MB, Hunninghake DB, Davis KB, et al: Effect 

of niacin on lipid and lipoprotein levels and


glycemic control in patients with diabetes and peripheral 

arterial disease. The ADMIT Study: A randomized 

trial. JAMA 284:1263, 2000. 

476. Litin SC, Anderson CF: Nicotinic-acid associated 

myopathy: A report of three cases. Am J Med 

86:481, 1989. 

477. Reaven P, Witztum JL: Lovastatin, nicotinic acid, 

and rhabdomyolysis (letter). Ann Intern Med 

109:597, 1988. 

478. Rader JI, Calvert RJ, Hathcock JN: Hepatic toxicity 

of unmodified and time-release preparations of 

niacin. Am J Med 92:77, 1992. 

478a. Udiawar MV, Rees A: Therapy and clinical trials: 

nicotinic acid in the management of atherosclerotic 

disease. Curr Opin Lipidiol 21: 286, 2010. 

479. Ashikaga H, Blumenthal RS, Jones SR: Utility of 

ezetimibe. Am J Cardiol 103: 1321, 2009. 

480. Garcia-Calvo M, Lisnock J, Bull HG, et al: The target 

of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1). 

Proc Natl Acad Sci USA 102: 8132, 2005. 

481. Yatskar L, Fisher EA, Schwartzbard A: Ezetimibe: 

rationale and role in the management of hypercholesterolemia. 

Clin Cardiol 29: 52, 2006. 

482. Dujoyve CA, Ettinger MP, McNeer F, et al for the 

Ezetimibe Study Group: Efficacy and safety of a potent 

new selective cholesterol absorption inhibitor, 

ezetimibe, in patients with primary hypercholesterolemia. 

Am J Cardiol 90: 1092, 2002. 

483. Gagne C, Bays HE, Weiss SR, et al for the Ezetimibe 

Study Group: Efficacy and safety of ezetimibe 

added to ongoing stating therapy for treatment of 

patients with primary hyper-cholesterolemia. Am J 

Cardiol 90: 1084, 2002. 

484. Davidson MH, McGarry T, Bettis R, et al: Ezetimibe 

coadministered with simvastatin in patients 

with primary hypercholesterolemia. J Am Col Cardiol 

40: 2135, 2002. 

485. Kastelein JJP, Akdim F, Stroes ESG, et al for the EN- 

HANCE Investigators: Simvastatin with or without 

ezetimibe in familial hypercholesterolemia. N Engl 

J Med 358: 1431, 2008. 

486. Greenland P, Lloyd-Jones D: Critical lessons from 

the ENHANCE trial (commentary). JAMA 299: 

953, 2008. 

487. Fleg JL, Mete M, Howard BV, et al: Effect of statins 

alone versus statins plus ezetimibe on carotid atherosclerosis 

in type 2 diabetes. The SANDS (Stop 

Atherosclerosis in Native Diabetics Study) trial. J 


488. Taylor AJ, Villines TC, Stanek EJ, et al: Extendedrelease 

niacin or ezetimibe and carotid intima-media 

thickness. N Engl J Med 361: 2113, 2009. 

488a. Villines TC, Stanek EJ, Devine PJ, et al: The AR- 

BITER 6-HALTS trial (arterial biology for the 

investigation of the treatment effects of reducing 

cholesterol 6-HDL and LDL treatment strategies in 

atherosclerosis). J Am Coll Cardiol 55: 2721, 2010. 

489. Kastelein JJP, Bots ML: Statin therapy with ezetimibe 

or niacin in high-risk patients. N Engl J Med 

361: 2180, 2009. 

490. Shachter NS, Frishman WH: Lipid-lowering drugs. 

In Frishman WH, Sonnenblick EH, Sica DA (eds): 

Cardiovascular Pharmacotherapeutics Manual 2nd 

ed. New York: McGraw Hill 2004: 328. 

491. Gagne C, Gaudet D, Bruckert E, for the Ezetimide 

Study Group. Efficacy and safety of ezetimide coadministered 

with atorvastatin or simvastatin in 

patients with homozygous familial hypercholesterolemia. 

Circulation 105: 2469, 2002. 

492. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of 

fibrates on metabolism of statins in human hepatocytes. 


493. Fish oil supplements. The Medical Letter 48: 59, 

2006. 

494. Burr ML, Fehily AM, Filbert JF, et al: Effects of 

changes in fat, fish and fibre intakes on death and 

myocardial reinfarction: diet and reinfarction trial 

(DART). Lancet 2: 757, 1989. 

495. Marchioli R, Barzi F, Bomba E, et al: Early protection 

against sudden death by n-3 polyunsaturated 

fatty acids after myocardial infarction: time-course 

analysis of the results of the Gruppo Italiano per lo 

Studio della Sopravvivenza nell-Infarto Miocardico 

(GISSI) Prevenzione. Circulation 105: 1897, 2002. 

495a. Kromhout D, Giltay EJ, Geleijnse JM for the Alpha 

Omega Trial Group: n-3 fatty acids and cardiovascular 

events after myocardial infarction. N Engl J 

Med 363: 2015, 2010. 

496. Burr ML, Ashfield-Watt PA, Dunstan FD, et al: 

Lack of benefit of dietary advice to men with angina: 

results of a controlled trial. Eur J Clin Nutri 

57: 193, 2003. 

497. Raitt MH, Connor WE, Morris C, et al: Fish oil 

supplementation and risk of ventricular tachycardia 

and ventricular fibrillation in patients with 

implantable defibrillators: a randomized controlled 

trial. JAMA 293: 2884, 2005. 

498. Leaf A: Omega-3 fatty acids and prevention of arrhythmias. 


499. Hartweg J, Farmer AJ, Holman RR, Neil A: Potential 

impact of omega-3 treatment on cardiovascular 

disease in type 2 diabetes. Curr Opin Lipidol 20: 30, 

2009. 

500. Harris WS, Miller M, Tighe AP, et al: Omega-3 

fatty acids and coronary heart disease risk: clinical 

and mechanistic perspectives. Atherosclerosis 197: 

12, 2008. 

500a. Saravanan P, Davidson NC, Schmidt EB, Calder

PC: Cardiovascular effects of marine omega-3 fatty 

acids. Lancet 375: 540, 2010. 

501. Kakar P, Watson T, Lip GYH: New approaches to 

therapy with omega-3 fatty acids. Curr Athero Rep 

10: 79, 2008. 

502. Leaf A: The role of omega-3 fatty acids in heart disease 

prevention. JCOM 16: 323, 2009. 

503. Frishman WH, Gomberg-Maitland M, Freeman 

R, et al: Hormones as cardiovascular drugs: estrogens, 

progestins, thyroxine, growth hormone, 

corticosteroids and testosterone. In Frishman WH, 

Sonnenblick EH, Sica DA (eds): Cardiovascular 

Pharmacotherapeutics 2nd ed. 2003: 617. 

504. Schwartz J, Freeman R, Frishman W: Clinical 

pharmacology of estrogens: focus on their cardiovascular 

actions and cardioprotective benefits of 

replacement therapy in postmenopausal women. J 

Clin Pharm 35:314, 1995. 

505. Grodstein F, Stampfer MJ, Manson JE, et al: Postmenopausal 

estrogen and progestin use and 

the risk of cardiovascular disease. N Engl J Med 

335:453, 1996. 

506. Hulley S, Grady D, Bush T, et al: Randomized trial 

of estrogen plus progestin for secondary prevention 

of coronary heart disease in postmenopausal 

women. JAMA 280:7, 1998. 

507. Walsh BW, Schiff I, Rosner B, et al: Effects of postmenopausal 

estrogen replacement on the concentrations 

and metabolism of plasma lipoproteins. N 

Engl J Med 325:1196, 1991. 

508. The Writing Group for the PEPI Trial: Effects of 

estrogen or estrogen/progestin regimens on heart 

disease risk factors in postmenopausal women. The 

postmenopausal estrogen/progestin interventions 

(PEPI) trial. JAMA 273:199, 1995. 

509. Wakatsuki A, Ikenoue N, Sagara Y: Effect of estrogen 

on the size of low-density lipoprotein particles 

in postmenopausal women. Obstet Gynecol 90:22, 

1997. 

510. Wakatsuki A, Ikenoue N, Okatani Y, Fukaya T: 

Estrogen-induced small low density lipoprotein 

particles may be atherogenic in postmenopausal 

women. J Am Coll Cardiol 37: 425, 2001. 

511. Herrington DM, Howard TD, Hawkins GA, et al: 

Estrogen-receptor polymorphisms and effects of 

estrogen replacement on high-density lipoprotein 

cholesterol in women with coronary disease. N 

Engl J Med 346:967, 2002. 

512. Hodis HN, St John JA, Xiang M, et al: Inflammatory 

markers and progression of subclinical atherosclerosis 

in healthy postmenopausal women (from 

the Estrogen in the Prevention of Atherosclerosis 

Trial). Am J Cardiol 101: 1131, 2008. 

513. Kuller LH for the Womens Health Initiative: Hor- 


mone replacement therapy and risk of cardiovascular 

disease: implications of the results of the 

Womens Health Initiative. Arterioscler Thromb 

Vasc Biol 23: 11, 2003. 

514. Steele RE, Wasvary JM, Dardik BN, et al: CGS 

26214, the thyroxine connection revised. In: 

Woodford FP, Davignon J, Sniderman A, eds. Atherosclerosis 

X. Amsterdam: Elsevier, 1995:321–324. 

514a. Angelin B, Rudling M: Lipid lowering with thyroid 

hormone and thyromimetics. Curr Opin Lipidol 21: 

499, 2010. 

515. Chong PH, Bachenheimer BS: Current, new and 

future treatments in dyslipidaemia and atherosclerosis. 

Drugs 60: 55, 2000. 

516. Taylor AH, Stephan ZF, Steele RE, Wong NCW: 

Beneficial effects of a novel thyromimetic on lipoprotein 

metabolism. Mol Pharmacol 52: 542, 1997. 

517. Knopp RH, Superko HR, Davidson M, et al: Longterm 

blood cholesterol-lowering effects of a dietary 

fiber supplement. Am J Prev Med 17:18, 1999. 

518. Maki KC, Davidson MH, Malik KC, et al: Cholesterol 

lowering with high-viscosity hydroxypropylmethylcellulose. 

Am J Cardiol 84:1198, 1999. 

519. Wolk A, Manson JE, Stampfer MJ, et al: Long-term 

intake of dietary fiber and decreased risk of coronary 

heart disease among women. JAMA 281:1998, 

1999. 

520. Petchetti L, Frishman WH, Petrillo R, Raju K: Nutriceuticals 

in cardiovascular disease. Psyllium. 


521. Stamler J: Coronary heart disease: Doing the right 

things. N Engl J Med 312:1053,1985. 

522. Wright A, Burstyn PG, Gibney MJ: Dietary fiber 

and blood pressure. Br Med J 2:1541, 1979. 

523. Anderson JW, Ward K: High-carbohydrate, highfiber 

diets for insulin-treated men with diabetes 

mellitus. Am J Clin Nutr 32:2312, 1979. 

524. Anderson JW: Dietary fiber and diabetes, in Vahouny 

GV, Kritchevsky D (eds): Dietary Fiber in 

Health and Disease. New York: Plenum Press, 1982, 

pp 151–165. 

525. Miettinen TA: Dietary fiber and lipids. Am J Clin 

Nutr 45(Suppl): 1237, 1987. 

526. Eastwood MA, Passmore R: Dietary fibre. Lancet 

2:202, 1983. 

527. Chan JKC, Wypyszyk V: A forgotten natural dietary 

fiber: Psyllium mucilloid. Cereal Foods World 

33:919, 1988. 

528. Jenkins DJA, Kendall CWC, Axelsen M, et al: Viscous 

and nonviscous fibres, nonabsorbable and low 

glycaemic index carbohydrates, blood lipids and 

coronary heart disease. Curr Opin Lipidol 11:49, 

2000. 

529. Jenkins DJ, Axelsen M, Kendall CW, et al: Dietary


fibre, lente carbohydrates and the insulin-resistant 

diseases. Br J Nutr 83:S157, 2000. 

530. Kennedy JF, Sandhu JS, Southgate DAT: Structural 

data for the carbohydrate of ispaghula husk (ex 

Plantago ovata Forsk). Carbohydr Res 75:269, 1979. 

531. Levin EG, Miller VT, Muesing RA, et al: Comparison 

of psyllium hydrophilic mucilloid and cellulose 

as adjuncts to a prudent diet in the treatment of 

mild to moderate hypercholesterolemia. Arch Intern 

Med 150:1822, 1990. 

532. Pietinen P, Rimm EB, Korhonen P, et al: Intake of 

dietary fiber and risk of coronary artery disease in 

a cohort of Finnish men: The Alpha Tocopherol, 

Beta-Carotene Cancer Prevention Study. Circulation 

94:2320, 1996. 

533. Chen WL, Anderson JW, Jennings D: Propionate 

may mediate the hypocholesterolemic effects of 

certain soluble plant fiber in cholesterol fed rats. 

Proc Soc Exp Biol Med 175:215, 1984. 

534. Lantner RR, Espiritu BR, Zumerchik P, Tobin MC: 

Anaphylaxis following ingestion of a psyllium-containing 

cereal. JAMA 264:2534, 1990. 

535. Behall KM, Scholfield DJ, Lee K, et al: Mineral balance 

in adult men: Effect of 4 refined fibers. Am J 

Clin Nutr 46:307, 1987. 

536. Kwiterovich PO Jr: The role of fiber in the treatment 

of hypercholesterolemia in children and adolescents. 

Pediatrics 96(5, Pt 2 of 2):1005, 1995. 

537. Rimm EB, Ascherio A, Giovannucci E, et al: Vegetable, 

fruit, and cereal fiber intake and risk of coronary 

heart disease among men. JAMA 275:447, 

1996. 

538. Davidson MH, Dugan LD, Burns JH, et al: The 

hypocholesterolemic effects of b-glucan in oatmeal 

and oat bran. A dose-controlled study. JAMA 

265:1833, 1991. 

539. Lipsky H, Gloger M, Frishman WH: Dietary fiber 

for reducing blood cholesterol. J Clin Pharmacol 

30:699, 1990. 

540. Spence JD, Huff MW, Heidenheim P, et al: Combination 

therapy with colestipol and psyllium mucilloid 

in patients with hyperlipidemia. Ann Intern 

Med 123:493, 1995. 

541. Ikeda I, Tanaka K, Sugano M, et al: Inhibition of 

cholesterol absorption in rats by plant sterols. J 

Lipid Res 29:1573, 1988. 

542. Ikeda I, Tanaka K, Sugano M, et al: Discrimination 

between cholesterol and sitosterol for absorption in 

rats. J Lipid Res 29:1583, 1988. 

543. Gylling H, Radhakrishnan R, Miettinen TA: Reduction 

of serum cholesterol in post-menopausal 

women with previous myocardial infarction and 

cholesterol malabsorption induced by dietary sitostanol 

ester margarine. Circulation 16:4226, 1997. 

544. Hallikainen MA, Uusitupa MIJ: Effects of 2 low-fat 

stanol ester-containing margarines on serum cholesterol 

concentrations as part of a low-fat diet in 

hypercholesterolemic Am J Clin Nutr 69:403, 1999. 

545. Miettinen TA, Puska P, Gylling H, et al: Reduction 

of serum cholesterol with sitostanol-ester margarine 

in a mildly hypercholesterolemic population. 

N Engl J Med 333:1308, 1995. 

546. Kesaniemi YA, Miettinen TA: Cholesterol absorption 

efficiency regulates plasma cholesterol level in 

the Finnish population. Eur J Clin Invest 17:391, 

1987. 

547. Miettinen TA, Kesaniemi YA: Cholesterol absorption: 

Regulation of cholesterol synthesis and elimination 

and within-population variations of serum 

cholesterol levels. Am J Clin Nutr 49:629, 1989. 

548. von Bergmann K: Lipid-lowering drugs working in 

the intestine. Curr Opin Lipid 1:48, 1990. 

549. Boberg KM, Akerlund J-E, Bjorkhem I: Effects of 

sitosterol on the rate-limiting enzymes in cholesterol 

synthesis and degradation. Lipids 24:9, 1989. 

550. Shefer S, Salen G, Nguyen L, et al: Competitive 

inhibition of bile acid synthesis by endogenous 

cholestanol and sitosterol in sitosterolemia with 

xanthomatosis. Effect of cholesterol 7-alpha hydroxylase. 

J Clin Invest 82:1833, 1988. 

551. Heinemann T, Pietruck B, Kullak-Ublick G, von 

Bergmann K: Comparison of sitosterol and sitostanol 

on inhibition of intestinal cholesterol absorption. 

Agents Actions 26(Suppl):117, 1988. 

552. Hallikainen MA, Sarkkinen ES, Uusitupa MIJ: 

Plant stanol esters affect serum cholesterol concentrations 

of hypercholesterolemic men and women 

in a dose-dependent manner. J Nutr 130:767, 2000. 

553. Nguyen TT, Dale LC, von Bergmann K, Croghar 

IT: Cholesterol-lowering effect of stanol ester in 

a U.S. population of mildly hypercholesterolemic 

men and women: Randomized, controlled trial. 

Mayo Clin Proc 74:1198, 1999. 

554. Gylling H, Miettinen TA: Effects of inhibiting cholesterol 

absorption and synthesis on cholesterol 

and lipoprotein metabolism in hypercholesterolemic 

non-insulin-dependent diabetic men. J Lipid 

Res 37:1776, 1996. 

555. Blair SN, Capuzzi DM, Gottlieb SO, et al: Incremental 

reduction of serum total cholesterol and 

low-density lipoprotein cholesterol with the addition 

of plant stanol ester-containing spread to 

statin therapy. Am J Cardiol 86:46, 2000. 

556. Stone NJ: Drugs for elevated LDL-cholesterol. In 

Antman EM (ed): Cardiovascular Therapeutics 3rd 

ed Saunders: Philadelphia, 2007: 528. 

557. Goldberg AC, Ostlund RE, Bateman JH, et al: Effect 

of plant stanol tablets on low-density lipo-

protein cholesterol lowering in patients on statin 

drugs. Am J Cardiol 97: 376, 2006. 

558. Gylling H, Siimes MA, Miettinen TA: Sitostanol ester 

margarine in dietary treatment of children with 

familial hypercholesterolemia. J Lipid Res 36:1807, 

1995. 

559. Davignon J: Prospects for drug therapy for hyperlipoproteinemia. 

Diabetes Metab 21:139, 1995. 

560. Batista JF, Stusser RJ, Padron R, et al: Functional 

improvement in coronary artery disease after 20 

months of lipid-lowering therapy with policosanol. 

Adv Ther 13:137, 1996. 

561. Gouni-Berthold I, Berthold HK: Policosanol: Clinical 

pharmacology and therapeutic significance of 

a new lipid-lowering agent. Am Heart J 143:356, 

2002. 

562. Batista J, Stusser R, Penichet M, Uguet E: Dopplerultrasound 

pilot study of the effects of long-term 

policosanol therapy on carotid-vertebral atherosclerosis. 

Curr Ther Res 56:906, 1995. 

563. Batista J, Stusser R, Saez F, Perez B: Effect of policosanol 

on hyperlipidemia and coronary heart 

disease in middle-aged patients. A 14-month pilot 

study. Int J Pharmacol Ther 34:134, 1996. 

564. Noa M, Mas R, Mesa R: A comparative study of 

policosanol vs lovastatin on intimal thickening in 

rabbit cuffed carotid artery. Pharm Res 43:31, 2001. 

565. Berthold HK, Unverdorben S, Degenhardt R, et al: 

Effect of policosanol on lipid levels among patients 

with hypercholesterolemia or combined hyperlipidemia. 

A randomized controlled trial. JAMA 295: 

2262, 2006. 

566. Vega G, Von Bergmann K, Grundy S, et al: Effect 

of lifibrol on the metabolism of low-density lipoproteins 

and cholesterol. J Intern Med 246:1, 1999. 

567. Schwandt P, Elsasser, Schmidt C, Gertz B, et al: 

Safety and efficacy of lifibrol upon four-week administration 

to patients with primary hypercholesterolaemia. 


568. Locker P, Jungbluth G, Francom S, Hughs G Jr, for 

the Lifibrol Study Group. Lifibrol: A novel lipidlowering 

drug for the therapy of hypercholesterolemia. 


569. Grundy S: HMG-CoA reductase inhibitors for 

treatment of hypercholesterolemia. N Engl J Med 

319:24, 1988. 

570. Todd P, Goa K: Simvastatin: A review of its pharmacological 

properties and therapeutic potential in 

hypercholesterolaemia. Drugs 40:583, 1990. 

571. McTavish D, Sorkin E: Pravastatin: A review of its 

pharmacological properties and therapeutic potential 

in hypercholesterolaemia. Drugs 42:65, 1990. 

572. Winkler K, Schaefer J, Klima B, et al: HDL steady 

state levels are not affected, but HDL apo A-I 


turnover is enhanced by lifibrol in patients with 

hypercholesterolemia and mixed hyperlipidemia. 

Atherosclerosis 150:113, 2000. 

573. Scharnagl H, Marz W, Wieland H: Lifibrol: First 

member of a new class of lipid-lowering drugs? Expert 

Opin Investig Drugs 6:583, 1997. 

574. Scharnagl H, Schliack M, Loser R, et al: The effects 

of lifibrol (K12.148) on the cholesterol metabolism 

of cultured cells: Evidence for sterol independent 

stimulation of the LDL pathway. Atherosclerosis 

153:69, 2000. 

575. Seiki S, Frishman WH: Pharmacologic inhibition 

of squalene synthase and other downstream enzymes 

of the cholesterol synthesis pathway. A new 

therapeutic approach to treatment of hypercholesterolemia. 


576. Nishimoto T, Amano Y, Tozawa R, et al. Lipidlowering 

properties of TAK-475, a squalene synthase 

inhibitor, in vivo and in vitro. Br J Pharmacol 

139:911, 2003. 

577. Piper E, Price G, Chen Y: TAK-475, a squalene synthase 

inhibitor provides lipid profile in hyperlipidemic 

subjects (abst). Circulation 114 (18 Suppl): 

II-288. 2006. 

578. Perez A, Kupfer S, Chen Y: Addition of TAK-475 

to atorvastatin provides incremental lipid benefits 

(abstr). Circulation 114 (18 Suppl): II-113, 2006. 

579. Goldstein J, Brown M. Regulation of the mevolonate 

pathway. Nature 343: 425. 1990. 

580. Ross R: The pathogenesis of atherosclerosis: A perspective 

for the 1990s. Nature 362: 801, 1993. 

581. Sliskovic D, White A: Therapeutic potential of 

ACAT inhibitors as lipid lowering and anti-atherosclerotic 

agents. Trends Pharmacol Sci 12:194, 1991. 

582. Rival Y, Junquéro D, Bruniguel F, et al: Anti-atherosclerotic 

properties of the acyl-coenzyme A: 

cholesterol acyltransferase inhibitor F 12511 in 

casein-fed New Zealand rabbits. J Cardiovasc Pharmocol 

39:181, 2002. 

583. Libby P, Geng YJ, Aikawa M, et al: Macrophages 

and atherosclerotic plaque stability. Curr Opin Lipidol 

7:330, 1996. 

584. Delsing D, Offerman E, van Duyvenvoorde W, et 

al: Acyl-CoA: cholesterol acyltransferase inhibitor 

avasimibe reduces atherosclerosis in addition to its 

cholesterol-lowering effect in ApoE3-Leiden mice. 

Circulation 103:1778, 2001. 

585. Schaefer EJ, Asztalos BF: Cholesteryl ester transfer 

protein inhibition, high-density lipoprotein metabolism 

and heart disease risk reduction. Curr Opin 

Lipidol 17: 394, 2006. 

586. Nissen SE, Tuzcu EM, Brewer HB, et al for the ACAT 

Intravascular Atherosclerosis Treatment Evaluation 

(ACTIVATE) Investigators: Effect of ACAT inhibi-


tion on the progression of coronary atherosclerosis. 

N Engl J Med 354: 1253, 2006. 

587. Meuwese MC, Franssen R, Stroes ESG, Kastelein 

JJP: And then there were acyl coenzyme A: cholesterol 

acyl transferase inhibitors. Curr Opin Lipidol 

17: 426, 2006. 

588. Fazio S, Linton M: Failure of ACAT inhibition to 

retard atherosclerosis. N Engl J Med 354: 1307, 

2006. 

589. Singh IM, Shishehbor MH, Ansell BJ: High-density 

lipoprotein as a therapeutic target. A systematic review. 

JAMA 298: 786, 2007. 

590. Barkowski RS, Frishman WH: HDL metabolism 

and CETP inhibition. Cardiol in Rev 16: 154, 2008. 

591. Inazu A, Brown M, Hesler C, et al. Increased highdensity 

lipoprotein levels caused by a common 

cholesteryl-ester transfer protein gene mutation. N 

Engl J Med 323:1234, 1990. 

592. Tall A. Plasma cholesteryl ester transfer protein. J 

Lipid Res 34:1255, 1993. 

592a. Sofat R, Hingorani AD, Smeeth L, et al: Separating 

the mechanism-based and off-target actions of 

cholesteryl ester transfer protein inhibitors with 

CETP gene polymorphisms. Circulation 121: 52, 

2010. 

593. Clark R, Ruggeri R, Cunningham D, Bamberger M. 

Description of the torcetrapib series of cholesteryl 

ester transfer protein inhibitors, including mechanism 

of action. J Lipid Res 47: 537, 2006. 

594. Plump A, Massuci-Magoulas L, Bruce C, et al. Increased 

atherosclerosis in apoE and LDL receptor 

knock-out mice as a result of human cholesteryl 

ester transfer protein transgene expression. Arterioscler 


595. Okamoto H, Yonemori F, Wakitani K, et al. A cholesteryl 

ester transfer protein inhibitor attenuates 

atherosclerosis in rabbits. Nature 406: 203, 2000. 

596. Boekholdt S, Kuivenhoven J, Wareham N, et al. 

Plasma levels of cholesteryl ester transfer protein 

and the risk of future coronary artery disease in 

apparently healthy men and women: the prospective 

EPIC (European Prospective Investigation into 

Cancer and nutrition)-Norfolk population study. 

Circulation. 110: 1338, 2004. 

597. Klerkx A, de Grooth G, Zwinderman A, et al Cholesteryl 

ester transfer protein concentration is associated 

with progression of atherosclerosis and 

response to pravastatin in men with coronary artery 

disease (REGRESS). Eur J Clin Invest 34: 21, 

2004. 

598. Clark R, Sutfin T, Ruggeri R, et al Raising high density 

lipoprotein in humans through inhibition of 

cholesteryl ester transfer protein: an initial multidose 

study of torcetrapib. Arterioscler Thromb Vasc 

Biol 24: 490, 2004. 

599. McKenney JM, Davidson MH, Shear CL, Revkin 

JH, Efficacy and safety of torcetrapib, a novel cholesteryl 

ester transfer protein inhibitor, in individuals 

with below average high-density lipoprotein 

cholesterol levels on a background of atorvastatin. 


600. Barter PJ, Caulfield M, Eriksson M, et al for the IL- 

LUMINATE Investigators: Effects of torcetrapib in 

patients at high risk for coronary events. N Engl J 

Med 357: 2109, 2007. 

601. Nissen S, Tardiff JC, Nicholis S, et al. Effect of 

torcetrapib on the progression of coronary atherosclerosis. 

New Engl J Med 356:1304, 2007. 

602. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect 

of torcetrapib on carotid atherosclerosis in familial 

hypercholesterolemia. New Engl J Med 356:1620, 

2007. 

603. Bots ML, Visseren FL, Evans GW, et al for the RA- 

DIANCE 2 Investigators: Torcetrapib and carotid 

intima-media thickness in mixed dyslipidaemia 

(RADIANCE 2 study): a randomized, double-blind 

trial. Lancet 370-153, 2007. 

604. Tall AR: CETP inhibitors to increase HDL cholesterol 

levels. N Engl J Med 356: 1364, 2007. 

605. Sviridov D, Nestel PJ: Genetic factors affecting 

HDL levels, structure, metabolism and function. 

Curr Opin Lipid 18: 157, 2007. 

606. Ansell BJ, Fonarow GC, Fogelman AM: The paradox 

of dysfunctional high-density lipo-protein. 


607. Krishna R, Anderson MS, Bergman AJ, et al: Effect 

of the cholesteryl ester transfer protein inhibitor, 

anacetrapib, on lipoproteins in patients with dyslipidaemia 

and on 24-h ambulatory blood pressure 

in health individuals: two double-blind, randomized 

placebo-controlled phase 1 studies. Lancet 

370: 1907, 2007. 

607a. Cannon CP, Shah S, Dansky HM, et al: Safety of 

anacetrapib in patients with or at high risk for coronary 

heart disease. N Engl J Med November 27, 

2010 (epub). 

608. Frishman WH, Barkowski RS: Cholesteryl ester 

transfer protein inhibition for coronary heart disease 

prevention: real hope or despair? Am J Med 

121: 644, 2008. 

609. Vergeer M, Stroes ESG: The pharmacology and offtarget 

effects of some cholesterol ester transfer protein 

inhibitors. Am J Cardiol 104(10A): 32E, 2009. 

610. Khakpour H, Frishman WH: Lipoprotein-associated 

phospholipase A2, an independent predictor of 

cardiovascular risk and a novel target for immunomodulation 

therapy. Cardiol in Rev 17: 222, 2009. 

611. Manolio T. Novel risk markers and clinical prac-

tice. N Engl J Med 349:1587, 2003. 

612. Khuseyinova N, Greven S, Ruckerl R, et al. Variability 

of serial lipoprotein-associated phospholipase 

A2 measurements in post myocardial infarction 

patients: Results from the AIRGENE study center 

Augsburg. Clin Chem. 54:124, 2008. 

613. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention 

and cardiovascular disease in patients 

with type 2 diabetes. N Engl J Med. 348:383, 2003. 

614. Koenig W. Treating residual cardiovascular risk: 

Will lipoprotein-associated phospholipase A2 inhibition 

live up to its promise? J Am Coll Cardiol. 

51:1642, 2008. 

614a. Rosenson RS: Phospholipase A2 inhibition and 

atherosclerotic vascular disease: prospects for targeting 

secretory and lipoprotein-associated phospholipase 

A2 enzymes. Curr Opin Lipidol 21: 473, 

2010. 

615. GlaxoSmithKline Website. Available at: http:// 

www.gsk.com/investors/product_pipeline/pp.htm. 

Accessed May 3, 2008. 

616. Blackie JA, Bloomer JC, Brown MJ, et al. The identification 

of clinical candidate SB-480848: A potent 

inhibitor of lipoprotein-associated phospholipase 

A2. Bioorg Med Chem Lett. 13:1067, 2003. 

617. Zalewski A, Macphee C, Nelson JJ. Lipoprotein-associated 

phospholipase A2: A potential therapeutic 

target for atherosclerosis. Curr Drug Targets Cardiovasc 

Haematol Disord. 5:527, 2005. 

618. Mohler ER,3rd, Ballantyne CM, Davidson MH, 

et al. The effect of darapladib on plasma lipoprotein-associated 

phospholipase A2 activity and 

cardiovascular biomarkers in patients with stable 

coronary heart disease or coronary heart disease 

risk equivalent: The results of a multicenter, randomized, 

double-blind, placebo-controlled study. J 

Am Coll Cardiol. 51:1632, 2008. 

619. Serruys PW, Garcia-Garcia HM, Buszman P, et al: 

Effects of the direct lipoprotein-associated phospholipase 

A2 inhibitor darapladib on human coronary 

atherosclerotic plaque. Circulation 118: 1172, 

2008. 

620. The stabilization of atherosclerotic plaque by initiation 

of darapladib therapy trial (STABILITY). 

http://clinicaltrials.gov/ct2/show/NCT00799903. 

Accessed 12/15/08. 

621. Wilensky RL, Macphee CH: Lipoprotein-associated 

phospholipase A2 and athero-sclerosis. Curr 

Opin Lipidol 20: 415, 2009. 

622. Kermani T, Frishman WH: Nonpharmacologic approaches 

for the treatment of hyperlipidemia. Cardiol 

in Rev 13: 247, 2005. 

622a. Waksman R, Torguson R, Kent KM, et al: A firstin-man, 

randomized, placebo-controlled study to 


evaluate the safety and feasibility of autologous 

delipidated high-density lipoprotein plasma infusions 

in patients with acute coronary syndrome. J 


623. Kannel WB, Neaton JD, Wentworth D, et al. Overall 

and coronary heart disease mortality rates in relation 

to major risk factors in 325,348 men screened 

for the MRFIT (Multiple Risk Factor Intervention 

Trial). Am Heart J 112:825, 1986. 

624. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence 

of coronary hart disease and lipoprotein 

cholesterol levels: the Framingham Study. JAMA. 

256:2835, 1986. 

625. Gordon DJ, Rifkind BM. High density lipoprotein: 

the clinical implications of recent studies. N Eng J 

Med. 321:1311, 1989. 

626. Stein O, Stein Y. Atheroprotective mechanisms of 

HDL. Atherosclerosis. 144:285, 1999. 

627. Spady DK. Reverse cholesterol transport and atherosclerosis 

regression. Circulation. 100:576, 1999. 

628. Franceschini G, Maderna P, Sirtori CR. Reverse 

cholesterol transport: physiology and pharmacology. 

Atherosclerosis. 88:99, 1991. 

629. Rothblat GH, de la Llera-Moya M, Atger V, et al. 

Cell cholesterol efflux: integration of old and new 

observations provides new insight. J Lipid Res. 

40:781, 1999. 

630. Navab M, Berliner JA, Watson AD, et al. The yin 

and yang of oxidation in the development of the 

fatty streak: a review based on the 1994 George 

Lyman Duff Memorial Lecture. Aterioscler Thomb 

Vasc Biol. 16:831, 1996. 

631. Bonnefont-Rousselot D, Therond P, Beaudeux JL, 

et al. High density lipoproteins (HDL) and the oxidative 

hypothesis of atherosclerosis. Clin Chem Lab 

Med. 37:939, 1999. 

632. Naqvi TZ, Shah PK, Ivey PA, et al. Evidence that 

high-density lipoprotein cholesterol is an independent 

predictor of acute platelet-dependent thrombus 

formation. Am J Cardiol. 84:1011, 1999. 

633. Saku K, Ahmad M, Glas-Greenwalt P, et al. Activation 

of fibrinolysis by apolipoproteins of high-density 

lipoproteins in man. Thromb Res. 39:1, 1985. 

634. Cockerill GW, Rye KA, Gamble JR, et al. Highdensity 

lipoproteins inhibit cytokine-induced expression 

of endothelial cell adhesion molecules. 

Arterioscler Thromb Vasc Biol. 15: 1987, 1995. 

635. Barter PJ. Inhibition of endothelial cell adhesion 

molecule expression by high-density lipoproteins. 

Clin Exp Pharmacol Physiol.24:286, 1997. 

636. Calabresi L, Franceschini G, Sirtori CR, et al. Inhibition 

of VCAM-1 expression in endothelial cells 

reconstituted high density lipoproteins. Biochem 

Biophys Res Commun. 238:61, 1997.


637. Franceschini G, Sirtori CR, Capurso A, et al. A-I 

Milano apoprotein: decreased high density lipoprotein 

cholesterol levels with significant lipoprotein 

modifications and without clinical atherosclerosis 

in an Italian family. J Clin Invest. 66:892,1980. 

638. Roma P, Gregg RE, Meng MS, et al. In vivo metabolism 

of a mutant form of apolipoprotein A-I, apo 

A-I milano, associated with familial hypo-alphalipoproteinemia. 

J Clin Invest. 38: 16307, 1993. 

639. Badimon JJ, Badimon L, Galvez A, et al. High 

density lipoprotein plasma fractions inhibit aortic 

fatty streaks in cholesterol-fed rabbits. Lab Invest. 

60:455, 1989. 

640. Badimon JJ, Badimon L, Fuster V. Regression of 

atherosclerotic lesions by high density lipoprotein 

plasma fraction in the cholesterol-fed rabbit. J Clin 

Invest. 85:1234, 1990. 

641. Miyazaki A, Sakuma S, Morikawa W, et al. Intravenous 

injection of rabbit apolipoprotein A-I inhibits 

the progression of atherosclerosis in cholesterolfed 

rabbits. Arterioscler Thromb Vasc Biol. 15:1882, 

1995. 

642. Shah PK, Nilsson J, Kaul S, et al. Effects of recombinant 

apolipoprotein A-I (Milano) on aortic atherosclerosis 

in apolipoprotein E-deficient mice. 

Circulation. 97:780, 1989. 

643. Nissen Se, Tsunoda T, Tuzcu EM, et al. Effect of recombinant 

apoA-I Milano on coronary atherosclerosis 

in patients with acute coronary syndromes. 

JAMA. 290:2292, 2003. 

644. Tardif J-C, Gregoire J, L’Allier PL, et al: Effects of 

reconstituted high-density lipoprotein infusions on 

coronary atherosclerosis. A randomized controlled 

trial. JAMA 297: 1675, 2007. 

645. Rader DJ. High-density lipoproteins as an emerging 

therapeutic target for atherosclerosis (editorial). 

JAMA. 290:2322, 2003. 

646. Erickson B, Sperber K, Frishman WH: Toll-like receptors. 

New therapeutic targets for the treatment 

of atherosclerosis, acute coronary syndromes and 

myocardial failure. Cardiol in Rev 16: 273, 2008. 

647. Sherman CB, Peterson SJ, Frishman WH: Apolipoprotein 

A-I mimetic peptides. A potential new 

therapy for the prevention of atherosclerosis. Cardiol 

in Rev 18: 141, 2010. 

648. Gordon T, Castelli WP, Hjortland MC, et al: High 

density lipoprotein as a protective factor against 

coronary heart disease. The Framingham Study. 

Am J Med 62:707, 1977. 

649. Shah PK: High-density lipoprotein mimetics: focus 

on synthetic high-density lipoprotein. Am J Cardiol 

100[suppl]:62N, 2007. 

650. Navab M, Anantharamaiah GM, Reddy ST, et al: 

Potential clinical utility of high-density lipopro- 

tein-mimetic peptides. Curr Opin Lipidol 17: 440, 

2006. 

651. Getz GS, Wool GD, Reardon CA: Apoprotein A-I 

mimetic peptides and their potential anti-atherogenic 

mechanisms of action. Curr Opin Lipidol 20: 

171, 2009. 

651a. Hovingh GK, Bochem AE, Kastelein JJP: Apolipoprotein 

A-1 mimetic peptides. Curr Opin Lipidol 

21: 481, 2010. 

652. Hara S, Higaki J, Higashino K, et al: S-8921, an ileal 

Na + /bile acid cotransporter inhibitor decreases serum 

cholesterol in hamsters. Life Sci 60:365, 1997. 

653. Ichihashi T, Izawa M, Miyata K, et al: Mechanism 

of hypocholesterolemic action of S-8921 in rats: 

S-8921 inhibits ileal bile acid absorption. J Pharmacol 

Exp Ther 284:43, 1998. 

654. Higaki J, Hara S, Takasu N, et al: Inhibition of ileal 

Na + /bile acid cotransporter by S-8921 reduces 

serum cholesterol and prevents atherosclerosis 

in rabbits. Arterioscler Thromb Vasc Biol 18:1304, 

1998. 

655. Benson M, Alston DR, Hickey DMB, et al: SK\&F 

97426-A: A novel bile acid sequestrant with higher 

affinities and slower dissociation rates for bile acids 

in vitro than cholestyramine. J Pharm Sci 86(1):76, 

1997. 

656. Benson GM, Alston DR, Bond BC, et al: SKYF 

97426, a more potent bile acid sequestrant and hypercholesterolemic 

agent than cholestyramine in 

the hamster. Atherosclerosis 101:51, 1993. 

657. Wilson TA, Nicolosi RJ, Rogers EJ, et al: Studies of 

cholesterol and bile acid metabolism, and early atherogenesis 

in hamsters fed GT16-239, a novel bile 

acid sequestrant (BAS). Atherosclerosis 140:315, 

1998. 

658. Eisenberg S: High-density lipoprotein metabolism. 

J Lipid Res 25:1017, 1984. 

659. Patsch J, Gotto A Jr, Olivecrona T, Eisenberg S: Formation 

of high density lipoprotein-like particles 

lipolysis of very low density lipoproteins in vitro. 

Proc Natl Acad Sci U S A 75:4519, 1978. 

660. Lewis B: Relation of high-density lipoproteins to 

coronary artery disease. Am J Cardiol 52:5B, 1983. 

661. Eckel R: Lipoprotein lipase: A multifunctional enzyme 

relevant to common metabolic diseases. N 

Engl J Med 320:1060, 1989. 

662. Tsutsumi K, Inoue Y, Shima A, et al: The novel 

compound NO-1886 increases lipoprotein lipase 

activity with resulting elevation of high density 

lipoprotein cholesterol, and long-term administration 

inhibits atherogenesis in the coronary arteries 

of rats with experimental atherosclerosis. J Clin Invest 

92:411, 1993. 

663. Tsutsumi K, Inoue Y, Hagi A, Murase T: The novel

compound NO-1886 elevates plasma high-density 

lipoprotein cholesterol levels in hamsters and rabbits 

by increasing lipoprotein lipase without any 

effect on cholesteryl ester transfer protein activity. 


664. Chiba T, Miura S, Sawamura F, et al: Antiatherogenic 

effects of a novel lipoprotein lipase-enhancing 

agent in cholesterol-fed New Zealand white 

rabbits. Arterioscler Thromb Vasc Biol 17:2601, 

1997. 

665. Tsutsumi K, Inoue Y, Shima A, Murase T: Correction 

of hypertriglyceridemia with low high-density 

lipoprotein cholesterol by the novel compound 

NO-1886, a lipoprotein lipase-promoting agent, in 

STZ-induced diabetic rats. Diabetes 44:414, 1995. 

666. Hara T, Cameron-Smith D, Cooney GJ, et al: The 

actions of a novel lipoprotein lipase activator, NO- 

1886, in hypertriglyceridemic fructose-fed rats. 


667. Kusunoki M, Hara T, Tsutsumi K, et al: The lipoprotein 

lipase activator, NO-1886, suppresses fat 

accumulation and insulin resistance in rats fed a 

high-fat diet. Diabetologia 43:875, 2000. 

668. Noshiro N, Nishimoto M, Morohashi K, Okuda 

K: Molecular cloning of cDNA for cholesterol 

7α-hydroxylase from rat liver microsomes. Nucleotide 

sequence and expression. FEBS Lett 257:97, 

1989. 

669. Chiang JYL, Kimmel R, Weinberger C, Stroup D: 

Farnesoid X receptor responds to bile acids and represses 

cholesterol 7α-hydroxylase gene (CYP7A1) 

transcription. J Biol Chem 275:10918, 2000. 

670. Gupta S, Stravitz RT, Ent P, Hylemon PB: Downregulation 

of cholesterol 7 α -hydroxylase (CY- 

P7A1) gene expression by bile acids in primary rat 

hepatocytes is mediated by the c-Jun N-terminal 

kinase pathway. J Biol Chem 276:15816, 2001. 

671. De Fabiani E, Mitro N, Anzulovich AC, et al: The 

negative effects of bile acids and tumor necrosis 

factor-α on the transcription of cholesterol 7 

α-hydroxylase gene (CYP7A1) converge to hepatic 

nuclear factor-4. A novel mechanism of feedback 

regulation of bile acid synthesis mediated by nuclear 

receptors. J Biol Chem 276:30708, 2001. 

672. Kuroki S, Naito T, Chijiiwa K, Tanaka M: Effects 

of cholestyramine on hepatic cholesterol 

7α-hydroxylase and serum 7α-hydroxycholesterol 

in the hamster. Lipids 34:817, 1999. 

673. Spady DK, Cuthbert JA, Willard MN, Meidell 

RS: Overexpression of cholesterol 7α-hydroxylase 

(CYP7A) in mice lacking the low-density lipoprotein 

(LDL) receptor gene. LDL transport and plasma 

LDL concentrations are reduced. J Biol Chem 

273:126, 1998. 


674. Wang J, Freeman DJ, Grundy SM, et al: Linkage between 

cholesterol 7α -hydroxylase and high-plasma 

low-density lipoprotein cholesterol concentrations. 

J Clin Invest 101:1283, 1998. 

675. Mangelsdorf D, Evans R: The RXR heterodimers 

and orphan receptors. Cell 83:841, 1995. 

676. Xu E, Lambert M, Montana V, et al: Molecular recognition 

of fatty acids by peroxisome proliferatoractivated 

receptors. Mol Cell 3:397, 1999. 

677. Schoonjans K, Staels B, Auwerx J: Role of the peroxisome 

proliferator-activated receptor (PPAR) in 

mediating the effects of fibrates and fatty acids on 

gene expression. J Lipid Res 37:907, 1996. 

678. Willson T, Wahli W: Peroxisome proliferatoractivated 

receptor agonists. Curr Opin Chem Biol 

1:235, 1997. 

679. Schoonjans K, Peinado-Onsurbe J, Lefebvre A, et 

al: PPARα and PPARγ activators direct a distinct 

tissue-specific transcriptional response via a PPRE 

in the lipoprotein lipase gene. EMBO J 15:5336, 

1996. 

680. Willson T, Brown P, Sternbach D, Henke B: The 

PPARs: From orphan receptors to drug discovery. J 

Med Chem 43:527, 2000. 

681. Israelian-Konaraki Z, Reaven PD: Peroxisome 

proliferator-activated receptor-alpha and atherosclerosis. 

From basic mechanisms to clinical implications. 


682. Staels B, Dallongeville J, Auwerx J, et al: Mechanism 

of action of fibrates on lipid and lipoprotein 

metabolism. Circulation 98:2088, 1998. 

683. Kockx M, Gervois P, Poulain P, et al: Fibrates suppress 

fibrinogen gene expression in rodents via 

activation of the peroxisome proliferator-activated 

receptor-α. Blood 93:2991, 1999. 

684. Bisgaier C, Essenburg A, Barnett B, et al: A novel 

compound that elevates high-density lipoprotein 

and activates the peroxisome proliferator-activated 

receptor. J Lipid Res 39:17, 1998. 

685. Windler E, Chao Y, Havel R: Regulation of the hepatic 

uptake of triglyceride-rich lipoproteins in the 

rat. J Biol Chem 255:8303, 1980. 

686. Willson T, Lambert M, Kliewer S: Peroxisome proliferator-activated 

receptor γ and metabolic disease. 

Annu Rev Biochem 70:341, 2001. 

687. Tontonoz P, Nagy L, Alvarez J, et al: PPAR γ promotes 

monocyte/macrophage differentiation and 

uptake of oxidized LDL. Cell 93:241, 1998. 

688. Ricote M, Huang J, Fajas L, et al: Expression of the 

peroxisome proliferator-activated receptor gamma 

(PPAR γ) in human atherosclerosis and regulation 

in macrophages by colony stimulating factors and 

oxidized low density lipoprotein. Proc Natl Acad 

Sci U S A 95:7614, 1998.


689. Oliver W Jr, Shenk J, Snaith M, et al: A selective 

peroxisome proliferator-activated receptor δ agonist 

promotes reverse cholesterol transport. Proc 

Natl Acad Sci U S A 98:5306, 2001. 

690. Brooks D, Etgen G, Rito C, et al: Design and synthesis 

of 2-methyl-{4-[2-(5-methyl-2-aryloxazol- 

4-yl)ethoxy]phynoxy}propionic acids: A new class 

of dual PPARα/γ agonists. J Med Chem 44:2061, 

2001. 

691. Riley E, Dasari V, Frishman WH, Sperber K: Vaccines 

in development to prevent and treat atherosclerotic 

disease. Cardiol in Rev 16: 288, 2008. 

692. Travis J: Army targets a potential vaccine against 

cholesterol. Science 262:1974, 1975. 

693. Bailey JM, Right R, Tomar R, Butler J: Antiatherogenic 

effects of cholesterol vaccination. Biochem 

Soc Trans 22:433S, 1994. 

694. Nilsson A, Calara F, Regnstrom J, et al: Immunization 

with homologous oxidized low-density lipoprotein 

reduces neointimal formation after balloon 

injury in hypercholesterolemia rabbits. J Am Coll 

Cardiol 30:1886, 1997. 

695. Parikh N, Frishman WH: The Liver X receptors. 

Cardiol in Rev 18: ____: 2010 in press. 

696. Torocsik D, Szanto A, Nagy L: Oxysterol signaling 

links cholesterol metabolism and inflammation via 

the liver X receptor in macrophages. Molec Aspects 

Med 30: 134, 2009. 

697. Kazuhiro O, Davis A, Chan L: Recent advances 

in liver-directed gene therapy: implications for 

the treatment of dyslipidemia. Curr Opin Lipidol 

11:176, 2000. 

698. Lehrman S: Virus treatment questioned after gene 

therapy death. Nature 401:517, 1999. 

699. Kockanek S: High-capacity adenoviral vectors for 

gene transfer and somatic gene therapy. Hum Gene 

Ther 10:2451, 1999. 

700. Herz J, Gerard R: Adenovirus-mediated transfer of 

low density lipoprotein receptor gene acutely accelerates 

cholesterol clearance in normal mice. Proc 


701. Kass-Eisler A, Falck-Pedersen E, Elfenbein D, et 

al: The impact of developmental stage, route of administration 

and the immune system on adenovirus-mediated 

gene transfer. Gene Ther 1:395, 1994. 

702. Yang Y, Nunes F, Berencsi K, et al: Cellular immunity 

to viral antigens limits E1-deleted adenoviruses 

for gene therapy. Proc Natl Acad Sci U S A 

91:4407, 1994. 

703. Stein C, Martins I, Davidson B: Long-term reversal 

of hypercholesterolemia in low density lipoprotein 

receptor (LDLR)-deficient mice by adenovirus-mediated 

LDLR gene transfer combined with 

CD154 blockade. J Gene Med 2:41, 2000. 

704. Desurmont C, Caillaud J-M, Emmanuel F, et al: 

Complete atherosclerosis regression after human 

apoE gene transfer in apoE-deficient/nude mice. 

Arterioscler Thromb Vasc Biol 20:435, 2000. 

705. Plump A, Smith J, Hayek T, et al: Severe hypercholesterolemia 

and atherosclerosis in apolipoprotein-e-deficient 

mice created by homologous 

recombination in ES cells. Cell 71:343, 1992. 

706. Chong P, Bachenheimer B: Current, new and future 

treatments in dyslipidaemia and atherosclerosis. 

Drugs 60:55, 2000. 

707. Akdim F, Stroes ESG, Kastelein JJP: Antisense apolipoprotein 

B therapy: where do we stand? Curr 

Opin Lipidol 18: 397, 2007. 

707a. Akdim F, Stroes ESG, Sijbrands EJG, e al: Efficacy 

and safety of mipomersen, an antisense inhibitor of 

apolipoprotein B, in hypercholesterolemic subjects 

receiving stable statin therapy. J Am Coll Cardiol 

55: 1611, 2010. 

707b. Akdim F, Visser ME, Tribble DL, et al: Effect of mipomersen, 

an apolipoprotein B synthesis inhibitor, 

on low-density lipoprotein cholesterol in patients 

with familial hypercholesterolemia. Am J Cardiol 

105: 1413, 2010. 

707c. Santos RFJ, Blom DJ, Marais AD, et al: Mipomersen, 

an apolipoprotein B synthesis inhibitor, for lowering 

of LDL cholesterol concentrations in patients 

with homozygous familial hypercholesterolaemia: 

a randomised, double-blind, placebo-controlled 

trial. Lancet 375: 998, 2010. 

708. Stephenson J: New method to repair faulty genes 

stirs interest in chimeraplasty technique. JAMA 

281:119, 1999. 

709. Mahley R, Huang Y, Rall S: Pathogenesis of type III 

hyperlipoproteinemia (dysbetalipoproteinemia). 

Questions, quandaries, and paradoxes. J Lipid Res 

40:1933, 1999. 

710. Alexeev V, Yoon K: Stable and inheritable changes 

in genotype and phenotype of albino melanocytes 

induced by an RNA-DNA oligonucleotide. Nat Biotechnol 

16:1343, 1998. 

711. Kren B, Parashar B, Bandyopadhyay P, et al: Correction 

of the UDP-glucuronosyltransferase gene 

defect in the Gunn rat model of Crigler-Najjar syndrome 

type I with a chimeric oligonucleotide. Proc 


712. Tagalakis A, Graham I, Riddell D, et al: Gene correction 

of the apolipoprotein (apo) E2 phenotype 

to wild-type apoE3 by in situ chimeraplasty. J Biol 

Chem 276:13226, 2001. 

713. Rondinone CM: RNAinterference to target lipid 

disorders. Curr Opin Lipidol 19:285, 2008. 

714. Peterson SJ, Frishman WH: Targeting heme oxygenase: 

therapeutic implications for diseases of the

cardiovascular system. Cardiol in Rev 17: 99, 2009. 

715. Dulak J, Loboda A, Jozkowicz A: Effect of heme oxygenase-1 

on vascular function and disease. Curr 

Opin Lipidol 19: 505, 2008. 

716. Cuchel M, Bloedon LT, Szapary PO, et al: Inhibition 

of microsomal triglyceride transfer protein in 

familial hypercholesterolemia. N Engl J Med 356: 

148, 2007. 


717. Lilly SM, Rader DJ: New targets and emerging 

therapies for reducing LDL cholesterol. Curr Opin 

Lipidol 18: 650, 2007.


New Aspects of Combination Therapy 

Focus on Hypertension 

Michael A. Weber, MD 

1. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal 

of European guidelines on hypertension 

management: a European Society of Hypertension 

Task Force document. J Hypertens 27:2121, 2009. 

2. Mancia G, De Backer G, Dominiczak A, et al. 2007 

Guidelines for the Management of Arterial Hypertension: 

The Task Force for the Management of 

Arterial Hypertension of the European Society of 

Hypertension (ESH) and the European Society of 

Cardiology (ESC). J Hypertens 25:1105, 2007. 

3. Chobanian AV, Bakris GL, Black HR, et al and the 

National High Blood Pressure Education Program 

Coordinating Committee. The seventh report of 

the Joint National Committee on prevention, detection, 

evaluation, and treatment of high blood 

pressure. The JNC7 Report. JAMA 289:2560, 2003. 

3a. Gradman AH, Basile JN, Carter BL, Bakris GL: 

Combination therapy in hypertension. J Am Soc 

Hypertens 4: 42, 2010. 

4. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure 

dependent and independent effects of antihypertensive 

treatment on clinical events in the 

VALUE Trial. Lancet 19:2049, 2004. 

5. Black HR: Triple fixed-dose combination therapy. 

Back to the past. Hypertension 54: 19, 2009. 

5a. ACCORD Study Group: Effects of intensive blood 

pressure control in type 2 diabetes mellitus. N Engl 

J Med 362: 1575, 2010. 

6. Izzo J, Neutel J, Dubiel R, Walker F. Efficacy of olmesartan 

medoxomil (O) and O/hydrochlorothiazide 

(H) in achieving blood pressure (BP) control 

and normalization in stage 2 systolic hypertension 

(HTN). Am J Hypertens 18:64A, 2005. 

7. Bakris GL, Smith DH, Giles TD, et al. Comparative 

antihypertensive efficacy of angiotensin receptor 

blocker-based treatment in African-American and 

white patients. J Clin Hypertens 10:587, 2005. 

8. Chrysant SG, Melino M, Karki S, et al. The combination 

of olmesartan medoxomil and amlodipine 

besylate in controlling high blood pressure: 

COACH, a randomized, double-blind, placebocontrolled, 

8-week factorial efficacy and safety 

study. Clin Ther 30:587, 2008. 

9. Philipp T, Smith TR, Glazer R, et al. Two multicenter, 

8-week, randomized, double-blind, placebo-controlled, 

parallel-group studies evaluating 

the efficacy and tolerability of amlodipine and valsartan 

in combination and as monotherapy in adult 

patients with mild to moderate essential hypertension. 

Clin Ther 29:563, 2007. 

10. Neutel JM, Smith DHG, Weber MA. A comparison 

of the effects of amlodipine 5 mg/benazepril 20 mg 

combination therapy to component monotherapy 

on arterial distensibility and left ventricular hypertrophy 

in patients with mild to moderate hypertension. 

Am J Hypertens 15: 166A, 2002. 

11. Dahlöf B, Sever PS, Poulter NR, et al for the AS- 

COT Investigators. Prevention of cardiovascular 

events with an antihypertensive regimen of amlodipine 

adding perindopril as required versus 

atenolol adding bendroflumethiazide as required, 

in the Anglo-Scandanavian Cardiac Outcomes Trial-Blood 

Pressure Lowering Arm (ASCOT-BPLA): 

a multicentre randomized controlled trial. Lancet 

366:895, 2005. 

12. Williams B, Lacy PS, Thom SM, et al. Differential 

impact of blood pressure-lowering drugs on central 

aortic pressure and clinical outcomes: principal 

results of the Conduit Artery Function Evaluation 

(CAFE) study. Circulation 113:1213, 2006. 

13. Jamerson K, Weber MA, Bakris GL, et al for the 

ACCOMPLISH investigators. Benazepril plus am- 



21-1


lodipine or hydrochlorothiazide for hypertension 

in high-risk patients. N Engl J Med 359:2417, 2008. 

13a. Bakris GL, Sarafidis PA, Weir MR, et al for the AC- 

COMPLISHG Trial Investigators: Renal outcomes 

with different fixed-dose combination therapies 

in patients with hypertension at high risk for cardiovascular 

events (ACCOMPLISH): a prespecified 

secondary analysis of a randomised controlled 

trial. Lancet 375: 1173, 2010. 

14. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, 

ramipril, or both in patients at high risk for vascular 

events. N Engl J Med 358:1547, 2008. 

15. Oparil S, Yarows SA, Patel S, et al. Efficacy and 

safety of combined use of aliskiren and valsartan in 

patients with hypertension: a randomised, doubleblind 

trial. Lancet 370:221, 2007. 

16. Calhoun DA, Lacourcière Y, Chiang YT, Glazer 

RD. Triple antihypertensive therapy with amlodipine, 

valsartan, and hydrochlorothiazide: a randomized 

clinical trial. Hypertension 54:32, 2009.


Pharmacotherapy for Smoking Cessation 


1. US Department of Health and Human Services: 

The Health Benefits of Smoking Cessation: A Report 

of the Surgeon General. Publication CDC 90-8416. 

Washington DC: DHHS, 1990. 

2. US Department of Health and Human Services: 

The Health Consequences of Smoking: Cardiovascular 

Disease. A Report of the Surgeon General’s Office 

on Smoking and Health. DHHS (PHS) 84-50204. 

Rockville, MD: DHHS, 1983. 

3. Hammond EC, Horn D: Smoking and death rates. 

Report on forty-four months of follow up of 187,783 

men: I. Total mortality. JAMA 166:1159,1958. 

4. US Public Health Service: Smoking and Health: Report 

of the Advisory Committee to the Surgeon General 

of the Public Health Service Center for Disease 

Control. PHS No. 1103. Washington, DC: DHHS, 

1964. 

5. US Department of Health, Education and Welfare: 

Smoking and Health: A Report of the Surgeon General’s 

Office on Smoking and Health. DHEW PHS 

79-50066. Washington, DC: DHHS, 1979. 

6. Matetzky S, Tani S, Kangavari S, et al: Smoking increases 

tissue factor expression in atherosclerotic 

plaques. Implications for plaque thrombogenicity. 

Circulation 2000; 102:602, 2000. 

7. Jee SH, Suh I, Kim IS, Appel LJ: Smoking and atherosclerotic 

cardiovascular disease in men with low 

levels of serum cholesterol. The Korea Medical Insurance 

Corporation Study. JAMA 282:2149,1999. 

7a. Rusanen M, Kivipelto M, Quesenberry CP Jr., et 

al: Heavy smoking in midline and long-term risk 

of Alzheimer disease and vascular dementia. Arch 

Intern Med October 25, 2010 (epub). 

8. Teo KK, Ounpuu S, Hawken S: Tobacco use and 

risk of myocardial infarction in 52 countries in the 

INTERHEART study: a case control study. Lancet 

368: 647, 2006. 

9. Al-Delaimy WK, Manson JE, Solomon CG, et al: 

Smoking and risk of coronary heart disease among 

women with type 2 diabetes mellitus. Arch Intern 

Med 162:273, 2002. 

10. Jacobs EJ, Thun MJ, Apicella LF: Cigar smoking and 

death from coronary heart disease in a prospective 

study of US men. Arch Intern Med 159:2413,1999. 

11. Escobedo LG, Caspersen CJ: Risk factors for sudden 

coronary death in the United States. Epidemiology 

8:175,1997. 

12. Escobedo LG, Zack MM: Comparison of sudden 

and nonsudden coronary deaths in the United 

States. Circulation 93:2033,1996. 

13. Suskin N, Sheth T, Negassa A, Yusuf S: Relationship 

of current and past smoking to mortality and morbidity 

in patients with left ventricular dysfunction. 


14. Heeringa J, Kors JA, Hofman A, et al: Cigarette 

smoking and risk of atrial fibrillation: the Rotterdam 

Study. Am Heart J 156: 1163, 2008. 

15. Critchley JA, Capewell S: Mortality risk reduction 

associated with smoking cessation in patients with 

coronary heart disease. JAMA 290:86, 2003. 

16. Goldenberg I, Jonas M, Tenenbaum A, et al: Current 

smoking, smoking cessation, and the risk of 

sudden cardiac death in patients with coronary artery 

disease. Arch Intern Med 163:2301, 2003. 

17. Taylor DH Jr, Hasselblad V, Henley SJ, et al: Benefits 

of smoking cessation for longevity. Am J Public 

Health 92:990, 2002. 

18. Anthonisen NR, Skeans MA, Wise RA, et al: The 

effects of a smoking cessation intervention on 14.5year 

mortality. A randomized clinical trial. Ann Intern 

Med 142:233, 2005. 

19. Fichtenberg CM, Glantz SA: Association of the 



22-1


California tobacco control program with declines 

in cigarette consumption and mortality from heart 

disease. N Engl J Med 343:1772, 2000. 

20. Jacobs DR Jr, Adachi H, Mulder I, et al: Cigarette 

smoking and mortality risk. Twenty-five-year follow-up 

of the Seven Countries Study. Arch Intern 

Med 159:733,1999. 

21. Ludvig J, Miner B, Eisenberg MJ: Smoking cessation 

in patients with coronary artery disease. Am 

Heart J 149: 565, 2005. 

22. Hilleman DE, Mohiuddin SM, Packard KA: Comparison 

of conservative and aggressive smoking 

cessation treatment strategies following coronary 

artery bypass graft surgery. Chest 125:435, 2004. 

23. Narkiewicz K, van de Borne PJH, Hausberg M, et 

al: Cigarette smoking increases sympathetic outflow 

in humans. Circulation 98:528, 1998. 

24. Fisher SD, Zareba W, Moss AJ, et al: Effect of smoking 

on lipid and thrombogenic factors two months 

after acute myocardial infarction. Am J Cardiol 

86:813, 2000. 

25. Hioki Y, Aoki N, Kawano K, et al: Acute effects of 

cigarette smoking on platelet-dependent thrombin 

generation. Eur Heart J 22:56, 2001. 

26. Newby DE, Wright RA, Labinjoh C, et al: Endothelial 

dysfunction, impaired endogenous fibrinolysis, 

and cigarette smoking. A mechanism for arterial 

thrombosis and myocardial infarction. Circulation 

99:1411,1999. 

27. Zedler BK, Kinser R, Oey J, et al: Biomarkers of 

exposure and potential harm in adult smokers 

of 3-7 mg tar yield (Federal Trade Commission) 

cigarettes and in adult non-smokers. Biomarkers 

11:201, 2006. 

28. Sobczak A, Wardas W, Zielinska-Danch W, Pawlicki 

K: The influence of smoking on plasma homocysteine 

and cysteine levels in passive and active 

smokers. Clin Chem Lab Med 42:408, 2004. 

29. Bazzano LA, He J, Muntner P, et al: Relationship 

between cigarette smoking and novel risk factors 

for cardiovascular disease in the United States. Ann 

Intern Med 138:891, 2003. 

30. Lu JT, Creager MA: The relationship of cigarette 

smoking to peripheral arterial disease. Rev Cardiovasc 

Med 5:189, 2004. 

31. Stenvinkel P: Interactions between inflammation, 

oxidative stress, and endothelial dysfunction in 

end-stage renal disease. J Ren Nutr 13:144, 2003. 

32. Rodriguez JJ, Al Dashti R, Schwarz ER: Linking 

erectile dysfunction and coronary artery disease. 

Int J Impot Res 17(Suppl 1):S12, 2005. 

33. Panagiotakos D, Pitsavos C, Chrysohoou C, et al: 

Effect of secondhand smoke on markers of inflammation: 

the ATTICA Study. Am J Med 116:145, 

2004. 

34. Sellers EM: Pharmacogenetics and ethnoracial differences 

in smoking. JAMA 280:179, 1998. 

35. Stapleton J: Cigarette smoking prevalence, cessation 

and relapse. Stat Methods Med Res 7:187, 1998. 

36. Pomerleau OF: Nicotine and the central nervous 

system: biobehavioral effects of cigarette smoking. 

Am J Med 93(1A):2S, 1992. 

37. Pomerleau OF, Pomerleau CS: Neuroregulators 

and the reinforcement of smoking: Towards a 

biobehavioral explanation. Neurosci Biobehav Rev 

8:503, 1984. 

38. Russell MAH, Peto J, Patel UA: The classification of 

smoking by factorial structure of motives. J R Statist 

Soc 137:313, 1974. 

39. Tate JC: Pharmacological and nonpharmacological 

smoking motives: A replication and extension. Addiction 

89:321, 1994. 

40. Lanca AJ, Adamson KL, Coen KM, et al: The pedunculopontine 

tegmental nucleus and the role of 

cholinergic neurons in nicotine self-administration 

in the rat: a correlative neuroanatomical and behavioral 

study. Neuroscience 96:735, 2000. 

41. Corrigall WA, Coen KM, Zhang J, Adamson L: 

Pharmacological manipulations of the pedunculopontine 

tegmental nucleus in the rat reduce 

self-administration of both nicotine and cocaine. 

Psychopharmacology (Berl) 160:198, 2002. 

42. Corringer PJ, Sallette J, Changeux JP: Nicotine enhances 

intracellular nicotinic receptor maturation: 

a novel mechanism of neural plasticity? J Physiol 

Paris 99:162, 2006. 

43. Gonzalez S, Cascio MG, Fernandez-Ruiz J, et al. 

Changes in endocannabinoid contents in the brain 

of rats chronically exposed to nicotine, ethanol or 

cocaine. Brain Res 954:73, 2002. 

44. Zhu PJ, Chiappinelli VA: Nicotinic receptors mediate 

increased GABA release in brain through a 

tetrodotoxin-insensitive mechanism during prolonged 

exposure to nicotine. Neuroscience 115:137, 

2002. 

45. Mathieu-Kia AM, Kellogg SH, Butelman ER, Kreek 

MJ: Nicotine addiction: insights from recent animal 

studies. Psychopharmacology (Berl) 162:102, 

2002. 

46. Li MD: The genetics of nicotine dependence. Curr 

Psychiatry Rep 8:158, 2006. 

47. Picciotto MR, Corrigall WA: Neuronal systems 

underlying behaviors related to nicotine addiction: 

neural circuits and molecular genetics. J Neurosci 

22:3338, 2002. 

48. Otsuka R, Watanabe H, Hirata K, et al: Acute effects 

of passive smoking on the coronary Circulation 

in healthy young adults. JAMA 286:436, 2001.

49. He J, Vupputuri S, Allen K, et al: Passive smoking 

and the risk of coronary heart disease – a metaanalysis 

of epidemiologic studies. N Engl J Med 

340:920, 1999. 

50. Kato M, Roberts-Thomson P, Phillips BG, et al: The 

effects of short-term passive smoke exposure on 

endothelium-dependent and independent vasodilation. 

J Hypertens 17:1395, 1999. 

51. Tonkin AM, Beauchamp A, Stevenson C: The importance 

of extinguishing secondhand smoke (editorial). 

Circulation 120: 1339, 2009. 

52. Lightwood JM, Glantz SA: Declines in acute myocardial 

infarction after smoke-free laws and individual 

risk attributable to secondhand smoke. 

Circulation 120: 1373, 2009. 

53. Benowitz N: Clinical pharmacology of inhaled 

drugs of abuse: Implications in understanding 

nicotine dependence. Natl Inst Drug Abuse Res 

Monogr 99:12, 1990. 

54. Patterson F, Benowitz N, Shields P, et al: Individual 

differences in nicotine intake per cigarette. Cancer 

Epidemiol Biomarkers Prev 12:468, 2003. 

55. Henningfield JE: Higher levels of nicotine in arterial 

than venous blood after cigarette smoking. Drug 

Alcohol Depend 33:23, 1993. 

56. Benowitz NL, Zevin S, Jacob P III: Sources of variability 

in nicotine and cotinine levels with use of 

nicotine nasal spray, transdermal nicotine, and cigarette 

smoking. Br J Clin Pharmacol 43:259, 1997. 

57. Benowitz NL: Establishing nicotine threshold for 

addiction: The implications for tobacco regulation. 

N Engl J Med 331:123, 1994. 

58. Jarvis MJ. ABC of smoking cessation. Why people 

smoke. BMJ 328: 277, 2004. 

59. Bliden KP, DiChiara J, Lawal L, et al: The association 

of cigarette smoking with enhanced platelet 

inhibition by clopidogrel. J Am Coll Cardiol 52: 

531, 2008. 

60. Ford CL, Zlabek JA: Nicotine replacement therapy 

and cardiovascular disease. Mayo Clin Proc 80:652, 

2005. 

61. Silagy C, Lancaster T, Stead L, et al: Nicotine replacement 

therapy for smoking cessation. Cochrane 

Database Syst Rev 2004; No.3:CD000146. 

62. Benowitz NL: Nicotine and coronary heart disease. 

Trends Cardiovasc Med 1:315, 1991. 

63. Benowitz NL: Nicotine patches. BMJ 310:1409, 

1995. 

64. Benowitz NL: Nicotine replacement therapy during 

pregnancy. JAMA 266:3174, 1991. 

65. Coleman T, Britton J, Thornton J: Nicotine replacement 

therapy in pregnancy. BMJ 328: 965, 2004. 

66. US Preventive Services Task force. Counseling and 

interventions to prevent tobacco use and tobacco- 


caused disease in adults and pregnant women: U.S. 

Preventive Services Task Force Reaffirmation Recommendation 

Statement. Ann Intern Med 150: 551, 

2009. 

67. US Department of Health and Human Services. 

The Health Consequences of Smoking: Nicotine Addiction. 

A Report of the Surgeon General. Publication 

CDC 88-8406. Washington, DC: DHHS, 1988. 

68. Connolly GN,Winn DM, Hecht SS, et al. The reemergence 

of smokeless tobacco. N Engl J Med 

314:1020, 1986. 

69. Critchley JA, Unal B: Is smokeless tobacco a risk 

factor for coronary heart disease? A systematic review 

of epidemiological studies. Eur J Cardiovasc 

Prev Rehabil 11:101, 2004. 

70. Gupta R, Gurm H, Bartholomew JR: Smokeless 

tobacco and cardiovascular risk. Arch Intern Med 

164:1845, 2004. 

70a. Piano MR, Benowitz NL, FitzGerald GA, et al: Impact 

of smokeless tobacco products on cardiovascular 

disease: implications for policy, prevention, 

and treatment. A policy statement from the American 

Heart Association. Circulation 122: 1520, 2010. 

71. US Department of Health and Human Services: The 

Health Consequences of Using Smokeless Tobacco: A 

Report of the Advisory Committee to the Surgeon 

General. publication (NIH) 86-2874. Washington, 

DC: DHHS, 1986. 

72. Frishman WH, Ky T, Ismail A. Tobacco smoking, 

nicotine and nicotine and non-nicotine smoking 

cessation therapies. In Frishman WH, Sonnenblick 

EH, Sica DA (eds): Cardiovascular Pharmacotherapeutics, 

2nd ed. New York: McGraw Hill, 2003; pp. 

369-80. 

73. Gorsline J, Benowitz NL, Rolf, CN, et al: Comparison 

of plasma nicotine concentrations for nicotine 

transdermal system (NTS), cigarette smoking and 

nicotine polacrilex (nicotine gum) [abstract]. Clin 


74. Fiore MC, Jorenby DE, Baker TB, Kenford SL: Tobacco 

dependence and the nicotine patch. Clinical 

guidelines for effective use. JAMA 268:2687, 1992. 

75. Hughes JR, Goldstein MG, Hurt RD, Shiffman S: 

Recent advances in the pharmacotherapy of smoking. 

JAMA 281: 72, 1999. 

76. Dale LC, Hurt RD, Offord KP, et al: High-dose nicotine 

patch therapy. Percentage of replacement and 

smoking cessation. JAMA 274:1353, 1995. 

77. Jorenby DE, Smith SS, Fiore MC, et al: Varying 

nicotine patch dose and type of smoking cessation 

counseling. JAMA 274:1347, 1995. 

78. Tonnesen P, Paoletti P, Gustavsson G, et al: Higher 

dosage nicotine patches increase one-year smoking 

cessation rates: Results from the European CEASE


trial. Eur Respir J 13:238, 1999. 

79. Daughton DM, Heatley SA, Prendergast JJ, et al: Effect 

of transdermal nicotine delivery as an adjunct 

to low-intervention smoking cessation therapy. 

A randomized, placebo-controlled, double-blind 

study. Arch Intern Med 151:749, 1991. 

79a. Lerman C, Jepson C, Wileyto EP, et al: Genetic 

variation in nicotine metabolism predicts the efficacy 

of extended-duration transdermal nicotine 

therapy. Clin Pharmacol Therap 87: 553, 2010. 

80. Page F, Coleman G, Conduit R: The effect of transdermal 

nicotine patches on sleep and dreams. 

Physiol Behav 88:425, 2006. 

81. Benowitz NL: Nicotine effects on eicosamoid formation 

and hemostatic function: Comparison of 

transdermal nicotine and cigarette smoking. J Am 


82. Working Group for the Study of Transdermal Nicotine 

in Patients with Coronary Artery Disease: 

Nicotine replacement therapy for patients with 

coronary artery disease. Arch Intern Med 154:989, 

1994. 

83. Kimmel SE, Berlin JA, Miles C, et al: Risk of acute 

myocardial infarction and use of nicotine patches 

in a general population. J Am Coll Cardiol 37:1297, 

2001. 

84. Meine TJ, Patel MR, Washam JB, et al: Safety and 

effectiveness of transdermal nicotine patch in 

smokers admitted with acute coronary syndromes. 

Am J Cardiol 95:976, 2005. 

85. Sachs DP. Effectiveness of the 4 mg dose of nicotine 

polacrilex for the initial treatment of high-dependent 

smokers. Arch Intern Med 155: 1973, 1995. 

86. Etter J-F, Huguelet P, Perneger TV, Cornuz J: Nicotine 

gum treatment before smoking cessation. A 

randomized trial. Arch Intern Med 169: 1028, 2009. 

87. Henningfield JE, Radzius A, Cooper TM, Clayton 

RR: Drinking coffee and carbonated beverages 

blocks absorption of nicotine from nicotine polacrilex 

gum. JAMA 264: 1560, 1990. 

88. Murray RP, Bailey WC, Daniels K, et al: Safety of 

nicotine polacrilex gum used by 3,094 participants 

in the Lung Health Study. Chest 109: 438, 1996. 

89. Shiffman S, Dresler CM, Hajek P, et al: Efficacy of a 

nicotine lozenge for smoking cessation. Arch Intern 

Med 162: 1267, 2002. 

90. West R. Glucose for smoking cessation: does it have 

a role?. CNS Drugs. 15: 261, 2001. 

91. Schneider NG, Lunell E, Olmstead RE, Fagerstrom 

KO: Clinical pharmacokinetics of nasal nicotine 

delivery: a review and comparison to other nicotine 

systems. Clin Pharmacokin 31: 65, 1996. 

92. Bohadana A, Nilsson F, Rasmussen T, Martinet Y: 

Nicotine inhaler and nicotine patch as a combina- 

tion therapy for smoking cessation. A randomized, 

double-blind, placebo-controlled trial. Arch Intern 

Med 160: 3128, 2000. 

93. Hughes JR: Dependence on and abuse of nicotine 

replacement: an update. In Benowitz NL (ed): Nicotine 

Safety and Toxicity. New York: Oxford University 

Press 1998: 147-60. 

94. Schuh KJ, Schuh LM, Henningfield JE, Stitzer ML: 

Nicotine nasal spray and vapor inhaler: abuse liability 

assessment. Psychopharmacol 130: 352, 1997. 

95. Sutherland G: Current approaches to the management 

of smoking cessation. Drugs 62 (Suppl 2):53, 

2002. 

96. Bolliger C, Zellweger JP, Danielsson MA, et al: 

Smoking reduction with oral nicotine inhalers: 

double-blind, randomized, clinical trial of efficacy 

and safety. Br Med J 321:329, 2000. 

97. Schneider NG, Olmstead RE, Franzon MA, Lunell 

E: The nicotine inhaler. Clinical pharmacokinetics 

and comparison with other nicotine treatments. 

Clin Pharmacokin 40:66, 2001. 

98. Lunell E, Molander L, Andersson SR: Temporary 

dependency of the release and bioavail-ability of 

nicotine from nicotine vapour inhaler: in vitro/ 

in vivo correlation. Eur J Clin Pharmacol 52: 495, 

1997. 

99. Blondal T, Gudmundsson LJ, Tomasson K, et al. 

The effects of fluoxetine combined with nicotine 

inhalers in smoking cessation—a randomized trial. 

Addiction. 94:1007,1999. 

99a. Yamin CK, Bitton A, Bates DW: E-cigarettes: a 

rapidly growing internet phenomenon. Ann Intern 

Med 153: 607, 2010. 

100. Etter JF: Cytisine for smoking cessation: a literature 

review and a meta-analysis. Arch Intern Med 166: 

1553, 2006. 

101. Slater Y, Houlihan L, Maskell P, et al: Halogenated 

cytisine derivatives as agonists at human neuronal 

nicotinic acetylcholine receptor subtypes. Neuropharmacol 

44:503, 2003. 

102. Gonzales D, Rennard SI, Nides M, et al: Varenicline, 

an a4b2 nicotinic acetylcholine receptor 

partial agonist vs sustained-release bupropion and 

placebo for smoking cessation. A randomized controlled 

trial. JAMA 296:47, 2006. 

103. Jorenby DE, Hays JT, Rigotti NA, et al: Efficacy of 

varenicline, an a4b2 nicotinic acetylcholine receptor 

partial agonist, vs placebo or sustained-release 

bupropion for smoking cessation. A randomized 


104. Jimenez-Ruiz C, Berlin I, Hering T: Varenicline. 

A novel pharmacotherapy for smoking cessation. 

Drugs 69: 1319, 2009. 

105. Nides M, Oncken C, Gonzales D, et al: Smoking

cessation with varenicline, a selective a4b2 nicotinic 

receptor partial agonist: results from a 7-week, 

randomized, placebo- and bupropion-controlled 

trial with 1-year follow up. Arch Intern Med 166: 

1561, 2006. 

106. Oncken C, Gonzales D, Nides M, et al: Efficacy and 

safety of the novel selective nicotinic acetylcholine 

receptor partial agonist, varenicline, for smoking 

cessation. Arch Intern Med 166: 1571, 2006. 

107. Tonstad S, Tonnesen P, Hajek P, et al: Effect of 

maintenance therapy with varenicline on smoking 

cessation: a randomized controlled trial. JAMA 

296:64, 2006. 

107a. Rigotti NA, Pipe AL, Benowitz NL, et al: Efficacy 

and safety of varenicline for smoking cessation in 

patients with cardiovascular disease. A randomized 

trial. Circulation 121: 221, 2010. 

108. Kuehn BM: Studies linking smoking-cessation 

drug with suicide risk spark concerns. JAMA 301: 

1007, 2009. 

109. Safety of smoking cessation drugs. The Medical Letter 

51(Issue 1319); 65, 2009. 

110. Dierker L, Donny E: The role of psychiatric disorders 

in the relationship between cigarette smoking 

and DSM-IV nicotine dependence among young 

adults. Nicotine Tob Res 10:439, 2008. 

111. Breslau N, Schulz LR, Johnson EO, et al: Smoking 

and the risk of suicidal behavior: a prospective 

study of a community sample. Arch Gen Psychiatry 

62: 328, 2005. 

112. Goodwin RD, Zvolensky MJ, Keyes KM: Nicotine 

dependence and mental disorders among adults in 

the USA: evaluating the role of the mode of administration. 

Psychol Med 38: 1277, 2008. 

113. Miller M, Hemenway D, Rimm E: Cigarettes and 

suicide: a prospective study of 50,000 men. Am J 

Public Health 90: 768, 2000. 

114. Anonymous: Varenicline (Chantix) warnings: risk 

versus benefit. The Medical Letter 50 (Issue 1290) 

July 14: 53. 

115. Hays TJ, Ebbert JO. Bupropion sustained release 

for treatment of tobacco dependence. Mayo Clinic 

Proceed. 78:1020, 2003. 

116. Patterson F, Schnoll RA, Wileyto EP, et al: Toward 

personalized therapy for smoking cessation: a randomized 

placebo-controlled trial of bupropion. 

Nature 84: 320, 2008. 

117. Colby SM, Gwaltney CJ: Pharmacotherapy of adolescent 

smoking cessation (commentary). JAMA 

298: 2182, 2007. 

118. Fossati R, Apolone G, Negri E, et al: A doubleblind, 

placebo-controlled, randomized trial of 

bupropion for smoking cessation in primary care. 



119. Ahluwalia JS, Harris KJ, Catley D, et al: Sustainedrelease 

bupropion for smoking cessation in African 

Americans: A randomized controlled trial. JAMA 

288:468, 2002. 

120. Jorenby D: Clinical efficacy of bupropion in the 

management of smoking cessation. Drugs 62(Suppl 

2):25, 2002. 

121. Hatsukami DK, Rennard S, Patel MK, et al. Effects 

of sustained-release bupropion among persons interested 

in reducing but not quitting smoking. Am 

J Med 116:151, 2004. 

122. Jorenby DE, Leischow SJ, Nides MA, et al: A controlled 

trial of sutained release uproprion, a nicotine 

patch, or both for smoking cessation. N Engl J 

Med 340: 685, 1999. 

123. Hurt RD, Sachs DPL, Glover ED, et al: A comparison 

of sustained release bupropion and placebo for 

smoking cessation. N Engl J Med 337:1195, 1997. 

124. Hayford KE, Patten CA, Rummans TA, et al: Efficacy 

of bupropion for smoking cessation in smokers 

with a former history of major depression or 

alcoholism. Br J Psychiatry 174:173, 1999. 

125. Swan GE, McAfee T, Curry SJ, et al. Effectiveness of 

bupropion sustained release for smoking cessation 

in a health care setting. Arch Intern Med 163: 2337, 

2003. 

126. Tonstad S, Farsang C, Klaene G, et al. Bupropion 

SR for smoking cessation in smokers with cardiovascular 

disease: A multicenter randomized study. 

Eur Heart J. 24:946, 2003. 

127. Aubin H-J: Tolerability and safety of sustainedrelease 

bupropion in the management of smoking 

cessation. Drugs 62(Suppl 2):45, 2002. 

128. Prochazka A: New developments in smoking cessation. 

Chest 117(4 Suppl 1): 169S, 2000. 

129. Steinberg MB, Greenhaus S, Schemlzer AC, et al: 

Triple-combination pharmacotherapy for medically 

ill smokers. A randomized trial. Ann Intern 

Med 150: 447, 2009. 

130. Sandyk R, Gillman MA, Iacono RP, Bamford CR: 

Clonidine in neuropsychiatric disorders: a review. 

Intl J Neurosci 35: 205, 1987. 

131. Covey LS, Glassman AH: A meta-analysis of double-blind 

placebo controlled trials of clonidine for 

smoking cessation. Br J Addict 86:991, 1991. 

132. Prichard BN: Drug treatment of hypertension. 

Drugs 35 (Suppl 6): 40, 1988. 

133. Hall SM, Reus VI, Munoz RF, et al: Nortriptyline 

and cognitive-behavioral therapy in the treatment 

of cigarette smoking. Arch Gen Psychiatry 55:683, 

1998. 

134. da Costa CL, Younes RN, Lourenco MT. Stopping 

smoking: a prospective, randomized, double-blind 

study comparing nortriptyline to placebo. Chest.


122:403, 2002. 

135. Kahan M: Treatment: nortriptyline was associated 

with an increased rate of 6 month smoking cessation. 

Evid Based Cardiovasc Med 3: 15, 1999. 

136. Prochazka AV, Kick S, Steinbrunn C, et al: A randomized 

trial of nortriptyline combined with 

transdermal nicotine for smoking cessation. Arch 

Intern Med 164: 2229, 2004. 

137. Cook JW, Spring B, McChargue DE, et al. Influence 

of fluoxetine on positive and negative affect in a 

clinic-based smoking cessation trial. Psychopharmacol 

(Berl). 173(1-2):153, 2004. 

138. Murphy JK, Edwards NB, Downs AD, et al. Effects 

of doxepin on withdrawal symptoms in smoking 

cessation. Am J Psychiatry147:1353, 1990. 

139. Hughes JR, Stead LF, Lancaster T. Antidepressants 

for smoking cessation. Cochrane Database of Systematic 

Reviews. 2004, Issue 2, CD 000031, pub 2. 

140. Fowler JS, Logan J, Wang GJ, Volkow ND: Monoamine 

oxidase and cigarette smoking. Neurotoxicol 

24: 75, 2003. 

141. George TP, Vessicchio J, Termine A, et al: A preliminary 

placebo-controlled trial of selegiline hydrochloride 

for smoking cessation. Biol Psychiatry 

53: 136, 2003. 

142. Zickler P. Manipulating dopamine levels changes 

smoking behavior. Natl Institute on Drug Abuse 

Notes, Research Findings, June 2003; 18(1). Accessed 

10/27/04. 

143. Foulds J, Burke M, Steinberg M, et al. Advances in 

pharmacotherapy for tobacco dependence. Expert 

Opin Emerg Drugs 2004; 9(1): 39, 2004. 

144. Murphy M, Hey K, Johnstone E, et al. Bromocriptine 

use is associated with decreased smoking rates. 

Addict Biol 7: 325, 2002. 

145. Zickler P (Staff Writer). Hard-to-treat smokers 

may benefit from medication that acts on dopamine. 

Natl Institute on Drug Abuse Notes, Research 

Findings, December 2003; 18(5). Accessed 

8/16/06. 

146. Lauro S, Paxeras JA. Update on the treatment of 

smoking dependence. Arch Bronconeumol 40: 

123, 2004. 

147. Sellers EM, Ramamoorthy Y, Zeman MV, et 

al: The effect of methoxsalen on nicotine and 

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 

(NNI) metabolism in vivo. Nicotine Tob Res 5: 891, 

2003. 




149. Malin DH, Alvarado CL, Woodhouse KS, et al: 

Passive immunization against nicotine attenuates 

nicotine discrimination. Life Sci70:2793, 2002. 

150. Pentel P, Malin D. A vaccine for nicotine dependence: 

targeting the drug rather than the brain. 

Respiration 69:193, 2002. 

151. Hieda Y, Keyler DE, Van DeVoort JT, et al: Immunization 

of rats reduces nicotine distribution to 

brain. Psychopharmacology (Berl) 143:150, 1999. 

152. Lindblom N, de Villiers SHL, Kalayanov G, et al: 

Active immunization against nicotine prevents reinstatement 

of nicotine-seeking behavior in rats. 

Respiration 69:254, 2002. 

153. de Villiers SHL, Lindblom N, Kalayanov G, et al: 

Active immunization against nicotine suppresses 

nicotine-induced dopamine release in the rat nucleus 

accumbens shell. Respiration 69:247, 2002. 

154. Xenova Group. Antismoking vaccine TA-NIC preliminary 

12 month clinical trial results. Xenova 

Group: Berkshire, 2005. 

155. Celtic Pharma completes rapid enrollment in 

phase IIb study for TA-NIC, the nicotine vaccine 

for smoking cessation. http://www.celticpharma. 

com/news/pr/release_102907.pdf. Accessed April 

22, 2008. 

156. Buchhalter AR, Fant RV, Henningfield JE: Novel 

pharmacological approaches for treating tobacco 

dependence and withdrawal: current status. Drugs 

68: 1067, 2008. 

157. NicVAX³ (nicotine conjugate vaccine). www.Nabi. 

com/pipeline/clinicaltrials.php. Accessed March 

24, 2008. 

158. Nabi Biopharmaceuticals initiates phase IIb “proof 

of concept” study for NicVAX (press release). Boca 

Raton, Fl: Nabi Biopharmaceuticals 2006. 

159. Maurer P, Bachmann MF: Vaccination against 

nicotine: an emerging therapy for tobacco dependence. 

Expert Topic Investig Drug 16: 1775, 2007. 

160. Keyler D, Shoeman D, Lesage M. Maternal vaccination 

against nicotine reduce nicotine distribution 

to fetal brain in rats. JPET 305: 587, 2003. 

161. Hall W. The prospects for immunotherapy in 

smoking cessation. Lancet 360:1089, 2002. 

162. DiMarzo V, Bifulco M, De Petrocellis L. The endocannabinoid 

system and its therapeutic exploitation. 

Nat Rev Drug Discov 3: 771, 2004. 

163. Cohen C, Perrault G, Griebel G, Soubrié P: Nicotine 

associated cues maintain nicotine-seeking 

behavior in rats several weeks after nicotine withdrawal: 

reversal by the cannabinoid (CB1) receptor 

antagonist, rimonabant (SR141716). Neuropsychopharmacol 

30: 145, 2005. 

164. Tonstad S: Rimonabant: A cannabinoid receptor 

blocker for the treatment of metabolic and cardiovascular 

risk factors. Nutr Metab Cardiovasc Dis 

16: 156, 2006. 

165. Nissen SE, Nicholls SJ, Wolski K, et al for the

TRADIVARIUS Investigators: Effect of rimonabant 

on progression of atherosclerosis in patients with 

abdominal obesity and coronary artery disease. 

A STRADIVARIUS randomized controlled trial. 

JAMA 299: 1547, 2008. 

166. Rauhut A, Mullins S, Dwoskin L, Bardo M. Reboxetine: 

Attenuation of intravenous nicotine selfadministration 

in Rats. J Pharm Exp Ther 303: 664, 

2002. 

167. Epstein A, King A. Naltrexone attenuates acute 

cigarette smoking behavior. Pharmacol Biochem 

Behav. 77:29, 2004. 

168. Krishman-Sarin S, Meandzija B, O’Malley S. Naltrexone 

and nicotine patch smoking cessation: 

a preliminary study. Nicotine Tob Res. 5(6): 851, 

2003. 

169. Botteri E, Iodice S, Bagnardi V, et al. Smoking and 

colorectal cancer. A meta-analysis. JAMA 300: 

2765, 2008. 

170. Kenfield SA, Stampfer MJ, Rosner BA, Colditz GA: 

Smoking and smoking cessation in relation to mortality 

in women. JAMA 299: 2037, 2008. 

171. Strandberg AY, Strandberg TE, Pitkala K, et al: The 

effect of smoking in midlife on health-related quality 

of life in old age. Arch Intern Med 168: 1968, 

2008. 

172. Cesaroni G, Forastiere F, Agabiti N, et al: Effect 

of the Italian smoking ban on population rates in 

acute coronary events. Circulation 117: 1183, 2008. 

173. Van Domburg RT, Scholte op Reimer W, Hoeks SE, 

et al: Three life-years gained from smoking cessation 

after coronary artery bypass surgery: a 30-year 

follow up study. Am Heart J 156: 473, 2008. 

174. Lerman C, Niaura R: Applying genetic approaches 

to the treatment of nicotine dependence. Oncogene 

21:7412, 2002. 

175. Keenan PS: Smoking and weight change after new 

health diagnoses in older adults. Arch Intern Med 

169: 237, 2009. 

176. Salize HJ, Merkel S, Reinhard I, et al: Cost-effective 

primary care-based strategies to improve smoking 

cessation. More value for money. Arch Intern Med 

169: 230, 2009. 

177. Burke MV, Ebbert JO, Hays JT: Treatment of tobacco 

dependence. Mayo Clin Proc 83: 479, 2004. 

178. Christakis NA, Fowler JH: The collective dynamics 

of smoking in a large social network. N Engl J Med 

358: 2249, 2008. 

179. Dawood N, Vaccarino V, Reid KJ, et al for the PRE- 

MIER Registry Investigators: Predictors of smoking 

cessation after a myocardial infarction. The role 

of institutional smoking cessation programs in improving 

success. Arch Intern Med 168: 1961, 2008. 

180. Fiore MC, Jaén CR: A clinical blueprint to acceler- 


ate the elimination of tobacco use (commentary). 

JAMA 299: 2083, 2008. 

181. Rigotti NA, Munafo MR, Stead LF: Smoking cessation 

interventions for hospitalized smokers. A 

systematic review. Arch Intern Med 168: 1950, 2008. 

182. Sabia S, Marmot M, Dufouil C, Singh-Manoux A: 

Smoking history and cognitive function in middle 

age from the Whitehall II study. Arch Intern Med 

2008; 168: 1165, 2008. 

183. Steinberg MB, Schmelzer AC, Richardson DL, 

Foulds J: The case for treating tobacco dependence 

as a chronic disease. Ann Intern Med 148: 554, 

2008. 

184. Thorndike AN, Regan S, McKool K, et al: Depressive 

symptoms and smoking cessation after hospitalization 

for cardiovascular disease. Arch Intern 

Med 168: 186, 2008. 

185. Gostin LO: Global regulatory strategies for tobacco 

control (commentary). JAMA 299: 763, 2008. 

186. Epstein RS: What’s needed for personalized therapy 

in smoking cessation. Clin Pharm Therap 84: 

309, 2008. 

187. Frishman WH: Smoking cessation pharmacotherapy: 

nicotine and non-nicotine preparations. Prevent 

Cardiol Spring: 10, 2007. 

188. Frishman WH, Mitta W, Kupersmith A, Ky T: Nicotine 

and non-nicotine smoking cessation pharmacotherapies. 


189. Kendler KS, Neale MC, Sullivan P, et al: A population-based 

twin study in women of smoking initiation 

and nicotine dependence. Psychol Med 29: 299, 

1999. 

190. Shields AE, Blumenthal D, Weiss KB, et al C: Barriers 

to translating emerging genetic research on 

smoking into clinical practice. Perspectives of primary 

care physicians. J Gen Intern Med 20:131, 

2005. 

191. Glantz LH, Annas GJ: Tobacco, the Food and 

Drug Administration, and Congress. N Engl J Med 

343:1802, 2000. 

192. True WR, Xian H, Scherrer JF, et al: Common genetic 

vulnerability for nicotine and alcohol dependence 

in men. Arch Gen Psychiatry 56; 655, 1999. 

192a. Chandler MA, Rennard SI: Smoking cessation. 

Chest 137: 428, 2010. 

193. Rosner SA, Stampfer MJ: The heart-breaking news 

about tobacco: it’s all bad. Lancet 368: 621, 2006. 

194. Kessler D. A Question of Intent: A Great American 

Battle with a Deadly Industry. New York: Public Affairs, 

2001. 

195. Curfman GD, Morrissey S, Drazen JM: Tobacco, 

public health, and the FDA. N Engl J Med 361: 402, 

2009. 

196. Leischow SJ: Setting the national tobacco control


agenda. JAMA 301: 1058, 2009. 

197. Bayer R, Kelly M: Tobacco control and free 

speech—an American dilemma. N Engl J Med 362: 

281, 2010. 

198. Gostin LO: FDA regulation of tobacco. Politics, 

law, and the public’s health. JAMA 302: 1459, 2009.


Pharmacotherapy of Obesity 


Harriette R. Mogul, MD, MPH 

Stephen J. Peterson, MD 

1. Ogden CL, Carroll MD, Curtin LR, et al: Prevalence 

of overweight and obesity in the United 

States, 1999-2004. JAMA 295:1549,2006. 

2. National Task Force on the Prevention and Treatment 

of Obesity. Overweight, obesity, and health 

risk. Arch Intern Med 160: 898,2000. 

3. Parikh NI, Pencina MJ, Wang TJ, et al: Increasing 

trends in incidence of overweight and obesity over 

5 decades. Am J Med 120:242,2007. 

4. Hedley AA, Ogden CL, Johnson CL, et al: Prevalence 

of overweight and obesity among US children, 

adolescents, and adults, 1999-2002. JAMA 

291: 2847, 2004. 

5. Flegal KM. Epidemiologic aspects of overweight 

and obesity in the United States. Physiol Behav 

86:599,2005. 

6. Flegal KM, Carroll MD, Ogden CL, Johnson CL. 

Prevalence and trends in obesity among US adults, 

1999-2000. JAMA 288:1723,2002. 

7. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson 

CL: Overweight and obesity in the United States: 

prevalence and trends, 1960-1994. Int J Obes Relat 

Metab Disord 22:39,1998. 

8. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson 

CL: Increasing prevalence of overweight among US 

adults. The National Health and Nutrition Examination 

Surveys, 1960 to 1991. JAMA 272:205,1994. 

9. Supt. of Documents: Healthy People 2000. 017- 

001-00474-0, 1990. Washington, DC 20402-9325, 

Government Printing Office. 

10. Supt of Documents: Healthy People 2010. 017-001- 

00547-9, 2000. Washington, DC 20402-9325. Government 

Printing Office. 

11. Visser M, Bouter LM, McQuillan GM, et al: Elevated 

C-reactive protein levels in overweight and 

obese adults. JAMA 282: 2131,1999. 

12. Rea TD, Heckbert SR, Kaplan RC, et al: Body mass 

index and the risk of recurrent coronary events following 

acute myocardial infarction. Am J Cardiol 

88: 467,2001. 

13. Pickering TG: Obesity and hypertension: a growing 

problem. J Clin Hypertens 3: 252,2001. 

14. Stevens V, Obarzanek E, Cook N, et al: Long-term 

weight loss and changes in blood pressure: results 

of the Trials of Hypertension Prevention, Phase II. 

Ann Intern Med 134:1,2001. 

15. Liu S, Manson JE: Dietary carbohydrates, physical 

inactivity, obesity, and the “metabolic syndrome” 

as predictors of coronary heart disease. Curr Opin 

Lipidol 12: 395, 2001. 

16. Field AE, Coakley EH, Must A, et al: Impact of 

overweight on the risk of developing common 

chronic diseases during a 10-year period. Arch Intern 

Med 161: 1581,2001. 

17. Stein PD, Beemath A, Olson RE: Obesity as a risk 

factor in venous thromboembolism. Am J Med 118: 

978,2005. 

18. Hayashi T, Boyko EJ, Leonetti DL, et al: Visceral 

adiposity is an independent predictor of incident 

hypertension in Japanese Americans. Ann Intern 

Med 140: 992,2004. 

19. Chinali M, deSimone G, Roman MJ, et al: Impact 

of obesity on cardiac geometry and function in a 

population of adolescents. J Am Coll Cardiol 47: 

2267,2006. 

20. Dorbala S, Crugnale S, Yang D, DiCarli MF: Effect 

of body mass index on left ventricular cavity size 

and ejection fraction. Am J Cardiol 97: 725,2006. 

21. Avelar E, Cloward TV, Walker JM, et al: Left ventricular 

hypertrophy in severe obesity. Interactions 

among blood pressure, nocturnal hypoxemia and 

body mass. Hypertension 49: 34, 2007. 



23-1


22. Canoy D, Boekholdt SM, Wareham N, et al: Body 

fat distribution and risk of coronary heart disease 

in men and women in the European Prospective 

Investigation into Cancer and Nutrition in Norfolk 

Cohort. A population-based prospective study. 

Circulation 116: 2933, 2007. 

23. Bogers RP, Bemelmans WJE, Hoogenveen RT, et 

al for the BMI-CHD Collaboration Investigators: 

Association of overweight with increased risk of 

coronary heart disease partly independent of blood 

pressure and cholesterol levels. A meta-analysis of 

21 cohort studies including more than 300,000 persons. 


24. Wilson PWF, Bozeman SR, Burton TM, et al: Prediction 

of first events of coronary heart disease and 

stroke with consideration of adiposity. Circulation 

118: 124, 2008. 

25. Harmancey R, Wilson CR, Taegtmeyer H: Adaptation 

and maladaptation of the heart in obesity. Hypertension 

52: 181, 2008. 

25a. Sui X, LaMonte MJ, Laditka JN, et al: Cardiorespiratory 

fitness and adiposity as mortality predictors 

in older adults. JAMA 298: 2507, 2007. 

26. Zhang C, Rexrode KM, van Dam RM, et al: Abdominal 

obesity and the risk of all-cause, cardiovascular, 

and cancer mortality. Sixteen years of 

follow-up in US women. Circulation 117: 1658, 

2008. 

27. Burke GL, Bertoni AG, Shea S, et al: The impact of 

obesity on cardiovascular disease risk factors and 

subclinical vascular disease. Arch Intern Med 168: 

928, 2008. 

27a. Berrington de Gonzalez A, Hartge P, Cerhan JR, 

et al: Body-mass index and mortality among 1.46 

million white adults. N Engl J Med 363: 2211, 2010. 

28. Hill JO, Wyatt HR, Reed GW, Peters JC: Obesity 

and the environment. Where do we go from here? 

Science 301: 598, 2003. 

29. Alley DE, Chang VW: The chancing relationship 

of obesity and disability, 1988-2004. JAMA 298: 

2020,2007. 

30. Bloomgarden ZT: Diabetes and obesity. Diabetes 

Care 31: 176,2008. 

31. National Institutes of Health, Clinical Guidelines 

on the Identification, Evaluation, and Treatment of 

Overweight and Obesity in Adults: The Evidence 

Report. Obes Res 6(Suppl 2): 51,1998. 

32. Douketis JD, Feightner JW, Attia J, Feldman WF: 

Periodic health examination, 1999 update: 1. Detection, 

prevention and treatment of obesity. Canadian 

Task Force on Preventive Health Care. Canad 

Med Assn J 160:513,1999. 

33. Aronne LJ: Obesity. Med Clin North Am 

82:161,1998. 

34. Mango V, Frishman WH: Physiologic, psychologic, 

and metabolic consequences of bariatric surgery. 

Cardiol in Rev 14: 232,2006. 

35. Stunkard AJ: Current views on obesity. Am J Med 

100:230,1996. 

36. Manson JE, Faich GA: Pharmacotherapy for obesity 

— do the benefits outweigh the risks? [editorial]. 

N Engl J Med 1996; 335:1996. 

37. Bray GA: Evaluation of drugs for treating obesity. 

Obes Res 3 Suppl 4: 425,1995. 

38. Wadden TA, Berkowitz RI, Sarwer DB, et al: Benefits 

of lifestyle modification in the pharmacologic 

treatment of obesity. A randomized trial. Arch Intern 

Med 161: 218,2001. 

39. Glazer G: Long-term pharmacotherapy of obesity 

2000. A review of efficacy and safety. Arch Intern 

Med 161: 1814,2001. 

40. Andres R, Muller DC, Sorkin JD: Long-term effects 

of change in body weight on all-cause mortality. A 

review. Ann Intern Med 119(7 Pt 2):737,1993. 

41. Freedman DS, Dietz WH, Srinivasan SR, Berenson 

GS: The relation of overweight to cardiovascular 

risk factors among children and adolescents: 

the Bogalusa Heart Study. Pediatrics 103(6 Pt 

1):1175,1999. 

42. Pi-Sunyer FX: Medical hazards of obesity. Ann Intern 

Med 119(7 Pt 2):655,1993. 

43. Poirier P, Giles TD, Bray GA, et al: Obesity and cardiovascular 

disease: pathophysiology, evaluation, 

and effect of weight loss. An update of the 1997 

American Heart Association Scientific Statement 

on Obesity and Heart Disease from the Obesity 

Committee of the Council on Nutrition, Physical 

Activity, and Metabolism. Circulation 113: 898, 

2006. 

44. Wong CY, O’Moore-Sullivan T, Leano R, et al: Association 

of subclinical right ventricular dysfunction 

with obesity. J Am Coll Cardiol 47: 611,2006. 

45. Litwin SE: The growing problem of obesity and the 

heart. The plot “thickens”. Editorial comment. J Am 

Coll Cardiol 47: 617,2006. 

46. Kannel WB, D’Agostino RB, Cobb JL: Effect of 

weight on cardiovascular disease. Am J Clin Nutr 

63(3 Suppl):419,1996. 

47. Manson JE, Colditz GA, Stampfer MJ et al: A prospective 

study of obesity and risk of coronary heart 

disease in women. N Engl J Med 322(13):882,1990. 

48. Manson JE, Willett WC, Stampfer MJ et al: Body 

weight and mortality among women. N Engl J Med 

333:677,1995. 

49. Lee IM, Paffenbarger-RS J: Change in body weight 

and longevity. JAMA 268:2045,1992. 

50. Lee IM, Manson JE, Hennekens CH, Paffenbarger- 

RS J: Body weight and mortality. A 27-year follow-

up of middle-aged men. JAMA 270:2823,1993. 

51. Colditz GA, Willett WC, Rotnitzky A, Manson JE: 

Weight gain as a risk factor for clinical diabetes 

mellitus in women. Ann Intern Med 122:481,1995. 

52. Stamler R, Stamler J, Riedlinger WF et al: Weight 

and blood pressure. Findings in hypertension 

screening of 1 million Americans. JAMA 

240:1607,1978. 

53. Najarian R, Sullivan L, Kannel W, et al: Metabolic 

syndrome compared with type 2 diabetes mellitus 

as a risk factor for stroke. Arch Intern Med. 

166:106,2006. 

54. Executive Summary of the Third Report of the 

National Cholesterol Education Program (NCEP) 

Expert Panel on Detection, Evaluation, and Treatment 

of High Blood Cholesterol in Adults (Adult 

Treatment Panel III). JAMA. 285:2486,2001. 

55. Lee IM, Paffenbarger-RS J: Quetelet’s index and 

risk of colon cancer in college alumni. J Natl Cancer 

Inst 1992; 84:1326,1992. 

56. Wadden TA, Berkowitz RI, Womble LG, et al: Randomized 

trial of lifestyle modification and pharmacotherapy 

for obesity. N Engl J Med 353: 2111,2006. 

57. Berenson A: A ray of hope for diabetics. This drug 

helps shed pounds. New York Times Business Day, 

March 2, 2006, C1. 

58. Thompson WG, Cook DA, Clark MM, et al: Treatment 

of obesity. Mayo Clin Proc 82: 93, 2007. 

59. Padwal RS, Majumdar SR: Drug treatments for 

obesity: orlistat, sibutramine and rimonabant. Lancet 

369: 71, 2007. 

60. Neff LM, Aronne LJ: Pharmacotherapy for obesity. 

Curr Atheroscler Rep 9: 454, 2007. 

60a. Bray GA: Medical therapy for obesity. Mt. Sinai J 

Med 77: 407, 2010. 

61. Blanck HM, Khan LK, Serdula MK: Prescription 

weight loss pill use among Americans: patterns 

of pill use and lessons learned from the fen-phen 

market withdrawal. Prev Med 39: 1243, 2004. 

62. Ioannides-Demos L, Proietto J, McNeil J. Pharmacotherapy 

for obesity. Drugs 65:1391,2005. 

63. Carek PJ, Dickerson LM: Current concepts in the 

pharmacological management of obesity. Drugs 57: 

883,1999. 

64. Colman, E. Anorectics on trial: A half century of 

federal regulation of prescription appetite suppressants. 

Ann Intern Med 143:380,2005. 

65. Li Z, Maglione M, Tu W, et al. Meta-analysis: 

Pharmacologic treatment of obesity. Ann Intern 

Med.142: 532,2005. 

66. Lesses NF, Myerson A: Human autonomic pharmacology: 

XVI: Benzedrine sulphate as an aid in 

treatment of obesity. Obes Res 2: 286,1994. 

67. Nathanson MH: The central action of beta-amino 


propylbenzene (Benzedrine): Clinical observations. 

JAMA 108:528,1939. 

68. Frishman WH, Weiser M, Michaelson MD. The 

pharmacologic approach to the treatment of obesity: 

past, present and future. In: Frishman WH, 

Sonnenblick EH (eds). Cardiovascular Pharmacotherapeutics. 

New York: McGraw Hill, 1997: 

1093-1114. 

69. Fernandez-Soto ML, Gonzalez-Jimenez A, Barredo-Acedo 

F et al: Comparison of fluoxetine and 

placebo in the treatment of obesity. Ann Nutr 

Metab 39:159, 1995. 

70. Sayler ME, Goldstein DJ, Roback PJ, Atkinson 

RL: Evaluating success of weight loss programs, 

with an application to fluoxetine weight reduction 

clinical trial data. Int J Obes Relat Metab Disord 

18:742,1994. 

71. Goldstein DJ, Rampey-AH J, Enas GG et al: Fluoxetine: 

a randomized clinical trial in the treatment of 

obesity. Int J Obes Relat Metab Disord 18:129,1994. 

72. Hudson JI, McElroy SL, Raymond NC et al: Fluvoxamine 

in the treatment of binge-eating disorder: a 

multicenter placebo-controlled, double-blind trial. 

Am J Psychiatry 1998; 155:1756-62. 

73. Bray GA, Ryan DH, Gordon D et al: A double-blind 

randomized placebo-controlled trial of sibutramine. 

Obes Res 4:263,1996. 

74. Weintraub M, Rubio A, Golik A et al: Sibutramine 

in weight control: a dose-ranging, efficacy study. 

Clin Pharmacol Ther 50:330,1991. 

75. Shechter M, Beigel R, Freimark D, et al: Short-term 

sibutramine therapy is associated with weight loss 

and improved endothelial function in obese patients 

with coronary artery disease. Am J Cardiol 

97: 1650, 2006. 

76. Heusser K, Tank J, Diedrich A, et al: Influence of 

sibutramine treatment on sympathetic vasomotor 

tone in obese subjects. Clin Pharmacol Ther 79: 

500, 2006. 

77. Apfelbaum M, Vague P, Ziegler O et al: Long-term 

maintenance of weight loss after a very-low-calorie 

diet: a randomized blinded trial of the efficacy and 

tolerability of sibutramine. Am J Med 106:179,1999. 

78. Kaplan L. Pharmacological therapies for obesity. 

Gastroenterol Clin N Am 34:91,2005. 

79. Hauner H, Meier M, Jockel KH, et al: Prediction 

of successful weight reduction under sibutramine 

therapy through genotyping of the G-protein 

b3-subunit gene (GNB3) C825T polymorphism. 

Phartmacogenetics 13: 453,2003. 

80. Wirth A, Krause J: Long-term weight loss with 

sibutramine: a randomized controlled trial. JAMA 

286: 1331,2001. 

81. James WPT, Astrup A, Finer N, et al: Effect of


sibutramine on weight maintenance after weight 

loss: a randomised trial. Lancet 356: 2119,2000. 

82. Dujovne CA, Zavoral JH, Rowe E, et al: Effects 

of sibutramine on body weight and serum lipids: 

a double-blind, randomized, placebo-controlled 

study in 322 overweight and obese patients with 

dyslipidemia. Am Heart J 142: 489,2001. 

83. Sánchez-Reyes L, Fanghänel D, Yamamoto J, et al. 

Use of sibutramine in overweight adult hispanic 

patients with type 2 diabetes mellitus: a 12-month, 

randomized, double-blind, placebo-controlled 

clinical trial. Clin Therap 26:1427,2004. 

84. Van Gaal LF, Caterson ID, Coutinho W, et al on 

behalf of the SCOUT Investigators: Weight and 

blood pressure response to weight management 

and sibutramine in diabetic and non-diabetic highrisk 

patients: an analysis from the 6-week lead-in 

period of the sibutramine cardiovascular outcomes 

(SCOUT) trial. Diabetes Obes Metab September 16, 

2009 (epub ahead of print). 

84a. James WPT, Caterson ID, Coutinho W, et al for 

the SCOUT Investigators: Effect of sibutramine on 

cardiovascular outcomes in overweight and obese 

subjects. N Engl J Med 363: 905, 2010. 

84b. Sibutramine (Meridia) withdrawn. The Medical Ltr 

52: 88, 2010. 

85. Scholze J, Grimm E, Herrmann D, et al: Optimal 

treatment of obesity-related hypertension. The 

Hypertension-Obesity-Sibutramine (HOS) Study. 

Circulation 115: 1991, 2007. 

86. Davidson MH, Hauptman J, DiGirolamo M et al: 

Weight control and risk factor reduction in obese 

subjects treated for 2 years with orlistat: a randomized 

controlled trial. JAMA 1999; 281: 235-42 [published 

in erratum 281:235,1999. 

87. Richelsen B, Tonstad S, Rössner S, et al: Effect of 

orlistat on weight regain and cardiovascular risk 

factors following a very-low-energy diet in abdominally 

obese patients. A 3-year randomized, placebo-controlled 

trial. Diabetes Care 30: 27, 2007. 

88. Heymsfield SB, Segal KR, Hauptman J, et al: Effects 

of weight loss with orlistat on glucose tolerance and 

progression to type 2 diabetes in obese adults. Arch 

Intern Med 160: 1321,2000. 

89. Lindgärde F. The effect of orlistat on body weight 

and coronary heart disease risk profile in obese patients: 

the Swedish Multi-morbidity Study. J Intern 

Med 248: 245,2000. 

90. Swinburn B, Carey D, Hills A, et al. Effect of orlistat 

on cardiovascular disease risk in obese adults. Diabetes 

Obese Meabt. 7:254,2004. 

91. Ault A: Orlistat gains OTC approval for weight 

loss. www.cardiologynews.com, March 2007: 7. 

92. Giacobino JP: Beta 3-adrenoceptor: an update. Eur 

J Endocrinol 132:377,1995. 

93. Weyer C, Gautier JF, Danforth E: Development of 

beta 3-adrenoceptor agonists for the treatment of 

obesity and diabetes—an update. Diabetes Metab 

25:11,1999. 

94. Kordik CP, Reitz AB: Pharmacological treatment 

of obesity: therapeutic strategies. J Med Chem 

42:181,1999. 

95. Arner P: The beta 3-adrenergic receptor—a cause 

and cure of obesity? [editorial comment]. N Engl J 

Med 333: 382,1995. 

96. van Marken Lichtenbelt WD, Vanhommerig JW, 

Smulders NM, et al: Cold-activated brown adipose 

tissue in healthy men. N Engl J Med 360: 1500,2009. 

97. Cypess AM, Lehman S, Williams G, et al: Identification 

and importance of brown adipose tissue in 

adult humans. N Engl J Med 360: 1509, 2009. 

98. Virtanen KA, Lidell ME, Orava J, et al: Functional 

brown adipose tissue in healthy adults. N Engl J 

Med 360: 1518, 2009. 

99. Langin D: Recruitment of brown fat and conversion 

of white into brown adipocytes: strategies to 

fight the metabolic complications of obesity? Biochim 

Biophys Acta September 24, 2009 epub ahead 

of print. 

100. Strosberg AD: Structure and function of the beta 

3-adrenergic receptor. Annu Rev Pharmacol Toxicol 

37:421,1997. 

101. Goldberg DE, Frishman WH. β 3 -Adrenergic Agonism: 

A New Concept in Human Pharmacotherapy. 

New York: Futura, 1995. 

102. Widen E, Lehto M, Kanninen T et al: Association 

of a polymorphism in the beta 3-adrenergic-receptor 

gene with features of the insulin resistance syndrome 

in Finns. N Engl J Med 333: 348,1995. 

103. Clement K, Vaisse C, Manning BS et al: Genetic 

variation in the beta 3-adrenergic receptor and an 

increased capacity to gain weight in patients with 

morbid obesity. N Engl J Med 333: 352,1995. 

104. Walston J, Silver K, Bogardus C et al: Time of onset 

of non-insulin-dependent diabetes mellitus and 

genetic variation in the beta 3-adrenergic-receptor 

gene. N Engl J Med 333: 343,1995. 

105. Mitchell BD, Blangero J, Comuzzie AG et al: A 

paired sibling analysis of the beta-3 adrenergic receptor 

and obesity in Mexican Americans. J Clin 

Invest 101:584,1998. 

106. Hsueh W-C, Cole SA, Shuldiner AR, et al: Interactions 

between variants in the b 3 -adrenergic 

receptor and peroxisome proliferator-activated 

receptor-g2 genes and obesity. Diabetes Care 24: 

672,2001. 

107. Mantzoros CS: The role of leptin in human obesity 

and disease: A review of current evidence. Ann In-

tern Med 130:671,1999. 

108. Bray GA, York DA: Clinical review 90: Leptin and 

clinical medicine: a new piece in the puzzle of obesity. 

J Clin Endocrinol Metab 1997; 82:2771-76 [erratum 

published 82: 2771,1997. 

109. Levin B. Factors promoting and ameliorating the 

development of obesity. Physiol Behav 86: 633,2005. 

110. Jackson M, Ahima R. Neuroendocrine and metabolic 

effects of adipocyte-derived hormones. Clin 

Sci 110: 143,2006. 

111. Farooqi IS, Jebb SA, Langmack G et al: Effects of 

recombinant leptin therapy in a child with congenital 

leptin deficiency. N Engl J Med 341:879,1999. 

112. Heymsfield SB, Greenberg AS, Fujioka K et al: Recombinant 

leptin for weight loss in obese and lean 

adults: a randomized, controlled, dose-escalation 

trial. JAMA 282:1568,1999. 

113. Wang MY, Orci L, Ravazzola M, Unger RH. Fat 

storage in adipocytes requires inactivation of 

leptin’s paracrine activity: Implications for treatment 

of human obesity. Proc Natl Acad Sci 102: 

18011,2005. 

114. Dotsch J, Rascher W, Meissner U. New insights into 

leptin resistance by modifying cytokine receptor 

signal transduction. Eur J Endocrinol. 152:333,2005. 

115. Howard JK, Cave BJ, Oksanen LJ, et al. Enhanced 

leptin sensitivity and attenuation of diet-induced 

obesity in mice with haploinsufficiency of Socs3. 

Nature Med. 10:734,2004. 

116. Mori H, Hanada R, Hanada T, et al. Socs3 deficiency 

in the brain elevates leptin sensitivity and 

confers resistance to diet-induced obesity. Nature 

Medicine. 10:739,2004. 

117. Gadde KM, Allison DB: Cannabinoid-1 receptor 

antagonist, rimonabant, for management of obesity 

and related risks. Circulation 114: 974, 2006. 

118. Korner J, Aronne L. Pharmacological approaches 

to weight reduction: Therapeutictargets. J Clin Endocrinol 

Metab 89: 2616,2004. 

119. Després J, Golay A, Sjöström L. Effects of 

rimonabant on metabolic risk factors in overweight 

patients with dyslipidemia. N Engl J Med. 

353: 2121,2005. 

120. Van Gaal L, Rissanen A, Scheen A, et al. Effects of 

the cannabinoid-1 receptor blocker rimonabant on 

weight reduction and cardiovascular risk factors 

in overweight patients: 1-year experience from the 

RIO-Europe study. Lancet 365: 1389, 2005. 

121. Wilding J. Clinical evaluation of anti-obesity drugs. 

Curr Drug Targets. 5: 325,2005. 

122. Carai M, Colombo G, Gessa G. Rimonabant: The 

first therapeutically relevant cannabinoid antagonist. 

Life Sci 77:2339,2005. 

123. Jbilo O, Ravinet-Trillou C, Arnone M, et al. The 


CB1 receptor antagonist rimonabant reverses the 

diet-induced obesity phenotype through the regulation 

of lipolysis and energy balance. FASEB J. 19: 

1567,2005. 

124. Gelfand EV, Cannon CP: Rimonabant: a cannabinoid 

receptor type 1 blocker for management of 

multiple cardiometabolic risk factors. J Am Coll 

Cardiol 47: 1919,2006. 

125. Bays H. Current and investigational antiobesity 

agents and obesity therapeutic treatment targets. 

Obes Res. 12: 1197, 2004. 

126. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al for 

the RIO-North America Study Group: Effect of 

rimonabant, a cannabinoid-1 receptor blocker, on 

weight and cardiometabolic risk factors in overweight 

or obese patients. RIO-North America: a 

randomized controlled trial. JAMA 295: 761,2006. 

127. Wadman M. Rimonabant adds appetizing choice to 

slim obesity market. Nature Med 12: 27, 2006. 

127a. Smith SR, Weissman NJ, Anderson CM, et al: Multicenter, 

placebo-controlled trial of lorcaserin for 

weight management. N Engl J Med 363: 245, 2010. 

128. Davidson MB, Peters AL: An overview of metformin 

in the treatment of type 2 diabetes mellitus. 

Am J Med 102: 99,1997. 

129. Garber AJ, Duncan TG, Goodman AM et al: Efficacy 

of metformin in type II diabetes: results of 

a double-blind, placebo-controlled, dose-response 

trial. Am J Med 103:491,1997. 

130. Turner RC, Cull CA, Frighi V, Holman RR: Glycemic 

control with diet, sulfonylurea, metformin, 

or insulin in patients with type 2 diabetes mellitus: 

progressive requirement for multiple therapies 

(UKPDS 49). UK Prospective Diabetes Study (UK- 

PDS) Group. JAMA 281:2005,1999. 

131. Inzucchi SE, Maggs DG, Spollett GR et al: Efficacy 

and metabolic effects of metformin and troglitazone 

in type II diabetes mellitus. N Engl J Med 

338:867,1998. 

132. Lee A, Morley JE: Metformin decreases food consumption 

and induces weight loss in subjects with 

obesity with type II non-insulin-dependent diabetes. 

Obes Res 6:47,1998. 

133. Hoffmann J, Spengler M: Efficacy of 24-week 

monotherapy with acarbose, metformin, or placebo 

in dietary-treated NIDDM patients: the Essen- 

II Study. Am J Med 103: 483,1997. 

134. Giugliano D, De-Rosa N, Di-Maro G et al: Metformin 

improves glucose, lipid metabolism, and 

reduces blood pressure in hypertensive, obese 

women. Diabetes Care 16:1387,1993. 

135. Campbell IW, Menzies DG, Chalmers J et al: One 

year comparative trial of metformin and glipizide 

in type 2 diabetes mellitus. Diabete Metab


20:394,1994. 

136. Wu R-R, Zhao J-P, Jin H, et al: Lifestyle intervention 

and metformin for treatment of anti-psychotic-induced 

weight gain. A randomized controlled 

trial. JAMA 299:185,2008. 

137. Mogul HR, Peterson SJ, Weinstein BI, et al: Metformin 

and carbohydrate-modified diet, a novel obesity 

treatment protocol: preliminary findings from 

a case series of non-diabetic women with midlife 

weight gain and hyperinsulinemia. Heart Dis 3: 

285, 2001. 

138. Munro JF, MacCuish AC, Marshall A et al: Weightreducing 

effect of diguanides in obese non-diabetic 

women. Br Med J 2: 13,1969. 

139. Fontbonne A, Charles MA, Juhan Vague I et al: The 

effect of metformin on the metabolic abnormalities 

associated with upper-body fat distribution. BIG- 

PRO Study Group. Diabetes Care 19:920,1996. 

140. Mogul HR, Peterson SJ, Weinstein BI, et al: Longterm 

(2-4 year) weight reduction with metformin 

plus carbohydrate-modified diet in euglycemic, 

hyperinsulinemic, midlife women (Syndrome W). 

Heart Dis 5: 384,2003. 

141. Freemark M, Bursey D: The effects of metformin 

on Body Mass Index and glucose tolerance in 

obese adolescents with fasting hyperinsulinemia 

and a family history of type 2 diabetes. Pediatrics 

107(4):e55,2001. 

142. Hadigan C, Corcoran C, Basgoz N et al: Metformin 

in the treatment of HIV lipodystrophy syndrome: A 

randomized controlled trial. JAMA 284:472,2000. 

143. Crave JC, Fimbel S, Lejeune H et al: Effects of diet 

and metformin administration on sex hormonebinding 

globulin, androgens, and insulin in hirsute 

and obese women. J Clin Endocrinol Metab 

80:2057,1995. 

144. Glueck CJ, Wang P, Fontaine R et al: Metformininduced 

resumption of normal menses in 39 of 

43 (91%) previously amenorrheic women with 

the polycystic ovary syndrome. Metabolism 

48:511,1999. 

145. Casimirri F, Biscotti M, Gambineri A: Metformin 

improves insulin, body fat distribution, and 

androgens in obese women with and without the 

polycystic ovary syndrome (abstract). Int J Obes 

21:S61,1997. 

146. Nestler JE, Jakubowicz DJ: Decreases in ovarian 

cytochrome P450c17 alpha activity and serum 

free testosterone after reduction of insulin secretion 

in polycystic ovary syndrome. N Engl J Med 

335:617,1996. 

147. Moghetti P, Castello R, Negri C et al: Metformin effects 

on clinical features, endocrine and metabolic 

profiles, and insulin sensitivity in polycystic ovary 

syndrome: a randomized, double -blind, placebocontrolled 

6-month trial, followed by open, longterm 

clinical evaluation. J Clin Endocrinol Metab 

85:139,2000. 

148. Arslanian SA, Lewy V, Danadian K, Saad R: Metformin 

therapy in obese adolescents with polycystic 

ovary syndrome and impaired glucose 

tolerance: amelioration of exaggerated adrenal response 

to adrenocorticotropin with reduction of 

insulinemia/insulin resistance. J Clin Endocrinol 

Metab 87: 1555,2002. 

149. Glueck CJ, Goldenberg N, Wang P, et al: Metformin 

during pregnancy reduces insulin, insulin resistance, 

insulin secretion, weight, testosterone and 

development of gestational diabetes: prospective 

longitudinal assessment of women with polycystic 

ovary syndrome from preconception throughout 

pregnancy. Human Reprod 19: 510,2004. 

150. Harborne LR, Sattar N, Norman JE, Fleming R: 

Metformin and weight loss in obese women with 

polycystic ovary syndrome: comparison of doses. J 

Clin endocrinol Metab 90: 4593,2005. 

151. Ibanez L, Lopez-Bermejo A, Diaz M, et al: Metformin 

treatment for four years to reduce total and 

visceral fat in low birth weight girls with precocious 

pubarche. J Clin Endocrinol Metab 93: 1841, 

2008. 

152. Dunn CJ, Peters DH: Metformin. A review of its 

pharmacological properties and therapeutic use in 

non-insulin-dependent diabetes mellitus. Drugs 

49:721,1995. 

153. Paolisso G, Amato L, Eccellente R et al: Effect of 

metformin on food intake in obese subjects. Eur J 

Clin Invest 28:441,1998. 

154. Boden G, Chen X, Ruiz J et al: Mechanisms of fatty 

acid-induced inhibition of glucose uptake. J Clin 

Invest 93:2438,1994. 

155. Abbasi F, Kamath V, Rizvi AA et al: Results of a 

placebo-controlled study of the metabolic effects of 

the addition of metformin to sulfonylurea-treated 

patients. Evidence for a central role of adipose tissue. 

Diabetes Care 20:1863,1997. 

156. Boden G, Chen X, Iqbal N: Acute lowering of 

plasma fatty acids lowers basal insulin secretion 

in diabetic and nondiabetic subjects. Diabetes 

47:1609,1998. 

157. Boden G, Chen X: Effects of fatty acids and ketone 

bodies on basal insulin secretion in type 2 diabetes. 

Diabetes 48:577,1999. 

158. Lee ZSK, Chan JCN, Yeung VT et al: Plasma insulin, 

growth hormone, cortisol, and central obesity 

among young Chinese Type 2 diabetic patients. 

Diabetes Care 22:1450,1999. 

159. Mather KJ, Verma S, Anderson TJ: Improved endo-

thelial function with metformin in type 2 diabetes 

mellitus. J Am Coll Cardiol 37:1344,2001. 

160. Charles MA, Morange P, Eschwege E et al: Effect of 

weight change and metformin on fibrinolysis and 

the von Willebrand factor in obese nondiabetic 

subjects: the BIGPRO1 Study. Biguanides and the 

Prevention of the Risk of Obesity. Diabetes Care 

21:1967,1998. 

161. DeFronzo RA, Ratner RE, Han J, et al: Effects of 

exenatide (exendin-4) on glycemic control and 

weight over 30 weeks in metformin-treated patients 

with type 2 diabetes. Diabetes Care 28: 1092,2005. 

162. Exenatide (Byetta) for type 2 diabetes. The Medical 

Letter 47: 45,2005. 

163. Lam S, See S: Exenatide. A novel incretin mimetic 

agent for treating type 2 diabetes mellitus. Cardiol 

in Rev 14: 205,2006. 

163a. Astrup A, Rössner S, Van Gaal L, et al: Effects of liraglutide 

in the treatment of obesity: a randomised, 

double-blind, placebo-controlled study. Lancet 

374: 1606, 2009. 

164. Whitehouse F, Kruger DF, Fineman M, et al: A randomized 

study and open-label extension evaluating 

the long-term efficacy of pramlintide as an adjunct 

to insulin therapy in type 1 diabetes. Diabetes Care 

24: 724,2002. 

165. Hollander PA, Levy P, Fineman MS, et al: Pramlintide 

as an adjunct to insulin therapy improves longterm 

glycemic and weight control in patients with 

type 2 diabetes: a 1-year randomized controlled 

trial. Diabetes Care 26: 784,2003. 

166. Ratner RE, Dickey R, Fineman M, et al: Amylin 

replacement with pramlintide as an adjunct to 

insulin therapy improves long-term glycemic and 

weight control in type 1 diabetes mellitus: a one 

year randomized controlled trial. Diabetes Med 21: 

1204,2004. 

167. Hollander PA, Maggs DG, Ruggles JA, et al: Effect 

of pramlintide on weight in overweight and obese 

insulin-treated type 2 diabetes patients. Obes Res 

12: 661,2004. 

168. Gordon A, Price LH: Mood stabilization and weight 

loss with topiramate. Am J Psychiatry 156:968,1999. 

169. Ben-Menachem E, Axelsen M, Johanson EH, et al. 

Predictors of weight loss in adults with topiramatetreated 

epilepsy. Obes Res. 11: 556,2003. 

170. Astrup A, Toubro S. Topiramate: a new potential 

pharmacological treatment for obesity. Obes. Res. 

12(12) Suppl: 167S,2004. 

171. Bray GA, Hollander P, Klein S, et al. A 6-month 

randomized, placebo-controlled, dose-ranging trial 

of topiramate for weight loss in obesity. Obes Res. 

11:722,2003. 

172. Astrup A, Caterson I, Zelissen P, et al. Topiramate: 


Long-term maintenance of weight loss induced by 

a low-calorie diet in obese subjects. Obes. Res. 12: 

1658,2004. 

173. Wilding J, Van Gaal L, Rissanen A, et al. A randomized 

double-blind placebo-controlled study of 

the long-term efficacy and safety of topiramate in 

the treatment of obese subjects. Intl J Obesity 28: 

1399,2004. 

174. Gadde KM, Franciscy DM, Wagner HR 2nd, 

Krishman KR. Zonisamide for weight loss in 

obese adults: a randomized controlled trial. JAMA. 

289:1820,2003. 

175. Appolinario J, Bueno J, Coutinho W. Psychotropic 

drugs in the treatment of obesity - What promise? 

CNS Drugs 18: 629,2004. 

176. Gadde KM, Parker CB, Maner LG, et al. Bupropion 

for weight loss: an investigation of efficacy and tolerability 

in overweight and obese women. Obes Res 

9: 544,2001. 

177. Anderson JW, Greenway FL, Fujioka K, et al. Bupropion 

SR enhances weight loss: a 48-week double-blind, 

placebo-controlled trial. Obes Res 10: 

633, 2002. 

177a. Greenway FL, Fujioka K, Plodkowski RA, et al: Effect 

of naltrexone plus bupropion on weight loss in 

overweight and obese adults (COR-I): a multicentre, 

randomised, double-blind, placebo-controlled, 

phase 3 trial. Lancet 376: 595, 2010. 

177b. Pollack A: F.D.A. panel backs drug to treat obesity. 

NY Times December 8, 2010. 

178. Cuneo RC, Judd S, Wallace JD et al: The Australian 

Multicenter Trial of Growth Hormone (GH) Treatment 

in GH-Deficient Adults. J Clin Endocrinol 

Metab 83:107,1998. 

179. Gura T: Uncoupling proteins provide new clue to 

obesity’s causes [news]. Science 280:1369, 1998. 

180. Gimeno RE, Dembski M, Weng X et al: Cloning 

and characterization of an uncoupling protein homolog: 

a potential molecular mediator of human 

thermogenesis. Diabetes 46:900,1997. 

181. Gong DW, He Y, Karas M, Reitman M: Uncoupling 

protein-3 is a mediator of thermogenesis regulated 

by thyroid hormone, beta3-adrenergic agonists, 

and leptin. J Biol Chem 272: 24129,1997. 

182. Fleury C, Neverova M, Collins S et al: Uncoupling 

protein-2: a novel gene linked to obesity and hyperinsulinemia. 

Nat Genet 15:269,1997. 

183. Gura T: Enzyme blocker prompts mice to shed 

weight. Science 288: 2299,2000. 

184. Bouchard C: Inhibition of food intake by inhibitors 

of fatty acid synthase. N Engl J Med 343: 1888, 2000. 

185. Kuhajdaa F, Landreed L, Ronnettd G. The connections 

between C75 and obesity drug-target pathways. 

Trends in Pharmacol Sci. 26:541,2005.


186. Leonhardt M, Hrupka B, Langhans W: New approaches 

in the pharmacological treatment of obesity. 

Eur J Nutri 38:1,1999. 

187. Campfield LA, Smith FJ, Burn P: Strategies and potential 

molecular targets for obesity treatment. Science 

280:1383,1998. 

188. Chaudhri OB, Wynne K, Bloom SR: Can gut hormones 

control appetite and prevent obesity? Diabetes 

Care 31(Suppl 2): S284,2008. 

189. Zimanyi IA, Fathi Z, Poindexter GS: Central control 

of feeding behavior by neuropeptide Y. Curr 

Pharm Des 4:349,1998. 

190. Borowsky B, Walker MW, Bard J et al: Molecular 

biology and pharmacology of multiple NPY Y5 receptor 

species homologs. Regul Pept 75-76:45,1998. 

191. Wisse BE, Schwartz MW: Role of melanocortins in 

control of obesity. Lancet 358: 857,2001. 

192. Balasubramaniam A. Clinical potentials of neuropeptide 

Y family of hormones. Am J Surg. 4: 

430,2002. 

193. Wieland HA, Hamilton BS, Drist B, Doods HN. The 

role of NPY in metabolic homeostasis: implications 

for obesity therapy. Invest Drugs. 9: 1327,2000. 

194. Sherman CB, Peterson SJ, Frishman WH: Apolipoprotein 

A-I mimetic peptides: a potential new therapy 

for the prevention of atherosclerosis. Cardiol in 

Rev 18: 141, 2010. 

195. Hallschmida M, Benedicta C, Borna J, et al. Manipulating 

central nervous mechanisms of food intake 

and body weight regulation by intranasal administration 

of neuropeptides in man. Physiol Behav 

83:55,2004. 

196. Blüher S, Ziotopoulou M, Bullen J, et al. Responsiveness 

to peripherally administered melanocortins 

in lean and obese mice. Diabetes 53:82,2004. 

197. Batterham RL, Cowley MA, Small CJ, et al. Gut 

hormone PYY 3–36 physiologically inhibits food 

intake. Nature 418:650,2002. 

198. Batterham RL, Cohen MA, Ellis SM, et al. Inhibition 

of food intake in obese subjects by peptide 

YY3–36. N Engl J Med 349:941,2003. 

199. Hansen TK, Dall R, Hosoda H, et al. Weight loss 

increases circulating levels of ghrelin in human 

obesity. Clin Endocrinol 56:203,2002. 

200. Cummings DE, Weigle DS, Frayo RS, et al. Plasma 

ghrelin levels after diet-induced weight loss or gastric 

bypass surgery. N Engl J Med 346:1623,2002. 

201. Christophe J: Is there appetite after GLP-1 and PA- 

CAP? Ann N Y Acad Sci 865:323,1998. 

202. Nakazato M, Murakami N, Date Y et al: A role for 

ghrelin in the central regulation of feeding. Nature 

409:194,2001. 

203. Shintani M, Ogawa Y, Ebihara K et al: Ghrelin, an 

endogenous growth hormone secretagogue, is a 

novel orexigenic peptide that antagonizes leptin 

action through the activation of hypothalamic 

neuropeptide Y/Y1 receptor pathway. Diabetes 

50:227,2001. 

204. Cummings DE, Purnell JQ, Frayo RS et al: A preprandial 

rise in plasma ghrelin levels suggests 

a role in meal initiation in humans. Diabetes 

50:1714,2001. 




206. Lambert PD, Anderson KD, Sleeman MW et al: 

Ciliary neurotrophic factor activates leptin-like 

pathways and reduces body fat, without cachexia 

or rebound weight gain, even in leptin- resistant 

obesity. Proc Natl Acad Sci U S A 98:4652,2001. 

207. Ettinger MP, Littlejohn TW, Schwartz SL, et al. Recombinant 

ciliary neurotrophic factor for weight 

loss in obese adults: a randomized dose-ranging 

study. JAMA 289:1826,2003. 

208. Coffin S, Konduru C, Schwarcz M, Frishman WH: 

Surgical approaches for the prevention and treatment 

of type 2 diabetes mellitus. Cardiol in Rev 17: 

275, 2009. 

209. Palamara KL, Mogul HR, Peterson SJ, Frishman 

WH: Obesity: new perspectives and pharmacotherapies. 


210. McNeely W, Goa KL. Better Than Slim Chances for 

Orlistat and Sibutramine to Promote Weight Loss. 

Drugs & Therapy Perspectives. 2000;15(12):1-6; 4.


Heart Disease and Treatment 

of Diabetes Mellitus 

Irene A. Weiss, MD 

Guy Valiquette, MD 

Monica D. Schwarcz, MD 


1. 2007 National Diabetes Fact Sheet. [CDC Website] 

Available at: http://apps.nccd.cdc.gov/DDTSTRS/ 

default.aspx.Accessed February 26, 2009. 

2. Haffner SM, Lehto S, Ronnemaa T, et al: Mortality 

from coronary heart disease in subjects with type 

2 diabetes and in nondiabetic subjects with and 

without prior myocardial infarction. N Engl J Med. 

339:229, 1998. 

2a. Gerstein HC: More insights on the dysglycaemiacardiovascular 

connection. Lancet 375: 2195, 2010. 

3. Fox CS, Coady S, Sorlie PD, et al: Trends in cardiovascular 

complications of diabetes. JAMA. 

292:2495, 2004. 

3a. Laakso M: Cardiovascular disease in type 2 diabetes 

from population to man to mechanisms. The 

Kelly West Award Lecture 2008. Diabetes Care 33: 

442, 2010. 

3b. Selvin E, Steffes MW, Zhu H, et al: Glycated hemoglobin, 

diabetes, and cardiovascular risk in nondiabetic 

adults. N Engl J Med 362: 800, 2010. 

4. Selvin E, Marinopoulos S, Berkenblit G, et al: Meta-analysis: 

Glycosylated hemoglobin and cardiovascular 

disease in diabetes mellitus. Ann Intern 

Med. 141:421, 2004. 

5. Khaw KT, Wareham N, Bingham S, et al: Association 

of hemoglobin A1c with cardiovascular 

disease and mortality in adults: The European prospective 

investigation into cancer in Norfolk. Ann 

Intern Med. 141:413, 2004. 

6. Selvin E, Coresh J, Golden SH, et al: Glycemic 

control and coronary heart disease risk in persons 

with and without diabetes: The atherosclerosis risk 

in communities study. Arch Intern Med. 165:1910, 

2005. 

7. Selvin E, Coresh J, Golden SH, et al: Glycemic control, 

atherosclerosis, and risk factors for cardio- 

vascular disease in individuals with diabetes: The 

atherosclerosis risk in communities study. Diabetes 

Care. 28:1965, 2005. 

8. Ravipati G, Aronow WS, Ahn C, et al: Association 

of diet alone, insulin, sulfonylureas, metformin, 

and thiazolidinediones with the severity of coronary 

artery disease in patients with diabetes mellitus. 

Am J Ther. 13:400, 2006. 

9. Loubatieres A:The mechanism of action of the hypoglycemic 

sulfonamides; a concept based on investigations 

in animals and in man. Diabetes. 6:408, 

1957. 

10. Siconolfi-Baez L, Banerji MA, Lebovitz HE: Characterization 

and significance of sulfonylurea receptors. 

Diabetes Care. 13 Suppl 3:2, 1990. 

11. Aguilar-Bryan L, Nichols CG, Wechsler SW, et al: 

Cloning of the beta cell high-affinity sulfonylurea 

receptor: A regulator of insulin secretion. Science 

268:423, 1995. 

12. Groop L, Groop PH, Stenman S, et al: Comparison 

of pharmacokinetics, metabolic effects and mechanisms 

of action of glyburide and glipizide during 

long-term treatment. Diabetes Care 10:71, 1987. 

13. Simonson DC, Kourides IA, Feinglos M, et al: Efficacy, 

safety, and dose-response characteristics of 

glipizide gastrointestinal therapeutic system on 

glycemic control and insulin secretion in NIDDM. 

results of two multicenter, randomized, placebocontrolled 

clinical trials. the glipizide gastrointestinal 

therapeutic system study group. Diabetes Care 

20:597, 1997. 

14. Shorr RI, Ray WA, Daugherty JR, et al: Individual 

sulfonylureas and serious hypoglycemia in older 

people. J Am Geriatr Soc 44:751, 1996. 

15. Meinert CL, Knatterud GL, Prout TE, et al: A study 

of the effects of hypoglycemic agents on vascular 



24-1


complications in patients with adult-onset diabetes. 

II. mortality results. Diabetes 19:Suppl:789, 

1970. 

16. Garratt KN, Brady PA, Hassinger NL, et al: Sulfonylurea 

drugs increase early mortality in patients 

with diabetes mellitus after direct angioplasty for 

acute myocardial infarction. J Am Coll Cardiol 

33:119, 1999. 

17. Huizar JF, Gonzalez LA, Alderman J, et al: Sulfonylureas 

attenuate electrocardiographic ST-segment 

elevation during an acute myocardial infarction in 

diabetics. J Am Coll Cardiol 42:1017, 2003. 

18. Simpson SH, Majumdar SR, Tsuyuki RT, et al: 

Dose-response relation between sulfonylurea 

drugs and mortality in type 2 diabetes mellitus: 

A population-based cohort study. CMAJ 174:169, 

2006. 19. Brady PA, Terzic A: The sulfonylurea 

controversy: More questions from the heart. J Am 


20. Bell DS: Do sulfonylurea drugs increase the risk of 

cardiac events? CMAJ 174:185, 2006. 

21. Intensive blood-glucose control with sulphonylureas 

or insulin compared with conventional treatment 

and risk of complications in patients with 

type 2 diabetes (UKPDS 33). UK prospective diabetes 

study (UKPDS) group. Lancet 352:837, 1998. 

22. Selvin E, Bolen S, Yeh HC, et al: Cardiovascular 

outcomes in trials of oral diabetes medications: A 

systematic review. Arch Intern Med 168:2070, 2008. 

23. Dornhorst A: Insulinotropic meglitinide analogues. 

Lancet 358:1709, 2001. 

24. Sunaga Y, Gonoi T, Shibasaki T, et al: The effects of 

mitiglinide (KAD-1229), a new anti-diabetic drug, 

on ATP-sensitive K+ channels and insulin secretion: 

Comparison with the sulfonylureas and nateglinide. 

Eur J Pharmacol 431:119, 2001. 

25. Black C, Donnelly P, McIntyre L et al: Meglitinide 

Analogues for Type 2 Diabetes Mellitus. Cochrane 

database Syst Rev April 18, 2007. 

26. Esposito K, Giugliano D, Nappo F, et al: Regression 

of carotid atherosclerosis by control of postprandial 

hyperglycemia in type 2 diabetes mellitus. Circulation. 

110:214, 2004. 

27. Rizzo MR, Barbieri M, Grella R, et al: Repaglinide 

has more beneficial effect on cardiovascular risk 

factors than glimepiride: Data from meal-test 

study. Diabetes Metab 31:255,2005. 

27a. The NAVIGATOR Study Group: Effect of nateglinide 

on the incidence of diabetes and cardiovascular 

events. N Engl J Med 362: 1463, 2010. 

27b. Nathan DM: Navigating the choices for diabetes 

prevention. N Engl J Med 362: 1533, 2010. 

28. Kawamori R, Tajima A, Iwamoto Y, et al: Voglibose 

for prevention of type 2 diabetes mellitus: a ran- 

domised, double-blind trial in Japanese individuals 

with impaired glucose tolerance. Lancet 373: 1607, 

2009. 

29. Inzucchi SE: Oral antihyperglycemic therapy for 

type 2 diabetes: Scientific review. JAMA 287:360, 

2002. 

30. Chiasson JL, Josse RG, Gomis R, et al: Acarbose for 

prevention of type 2 diabetes mellitus: The STOP- 

NIDDM randomised trial. Lancet 359:2072, 2002. 

31. Chiasson JL, Josse RG, Gomis R, et al: Acarbose for 

the prevention of type 2 diabetes, hypertension and 

cardiovascular disease in subjects with impaired 

glucose tolerance: Facts and interpretations concerning 

the critical analysis of the STOP-NIDDM 

trial data. Diabetologia 47:969, 2004; discussion 

976-7. 

32. Hanefeld M, Chiasson JL, Koehler C, et al: Acarbose 

slows progression of intima-media thickness 

of the carotid arteries in subjects with impaired 

glucose tolerance. Stroke 35:1073, 2004. 

33. Van de Laar FA, Lucassen PL, Akkermans RP, et al: 

Alpha-glucosidase inhibitors for patients with type 

2 diabetes: Results from a Cochrane systematic 

review and meta-analysis. Diabetes Care 28:154,2 

005. 

34. Scheen AJ: Clinical efficacy of acarbose in diabetes 

mellitus: A critical review of controlled trials. Diabetes 

Metab 24:311,1998. 

35. Nathan DM, Buse JB, Davidson MB, et al: Management 

of hyperglycemia in type 2 diabetes: A 

consensus algorithm for the initiation and adjustment 

of therapy: A consensus statement from the 

American Diabetes Association and the European 

Association for the Study of Diabetes. Diabetes 

Care 29:1963, 2006. 

36. Cusi K, Consoli A, DeFronzo RA: Metabolic effects 

of metformin on glucose and lactate metabolism in 

noninsulin-dependent diabetes mellitus. J Clin Endocrinol 

Metab 81:4059, 1996. 

37. Hundal RS, Krssak M, Dufour S, et al: Mechanism 

by which metformin reduces glucose production in 

type 2 diabetes. Diabetes 49:2063, 2000. 

38. Johnson AB, Webster JM, Sum CF, et al: The impact 

of metformin therapy on hepatic glucose production 

and skeletal muscle glycogen synthase activity 

in overweight type II diabetic patients. Metabolism 

42:1217, 1993. 

39. Razani B, Chakravarthy MV, Semenkovich CF: 

Insulin resistance and atherosclerosis. Endocrinol 

Metab Clin North Am 37:603, 2008. 

40. Nagi DK, Yudkin JS: Effects of metformin on insulin 

resistance, risk factors for cardiovascular 

disease, and plasminogen activator inhibitor in NI- 

DDM subjects. A study of two ethnic groups. Dia-

etes Care 16:621, 1992. 

41. Mather KJ, Verma S, Anderson TJ: Improved endothelial 

function with metformin in type 2 diabetes 

mellitus. J Am Coll Cardiol 37:1344, 2001. 

42. Jadhav S, Ferrell W, Greer IA, et al: Effects of metformin 

on microvascular function and exercise tolerance 

in women with angina and normal coronary 

arteries: A randomized, double-blind, placebocontrolled 


43. Golay A: Metformin and body weight. Int J Obes 

(Lond). 32:61, 2008. 

44. Garber AJ, Duncan TG, Goodman AM, et al: Efficacy 

of metformin in type II diabetes: Results of 

a double-blind, placebo-controlled, dose-response 

trial. Am J Med. 103:491, 1997. 

45. Bailey CJ, Turner RC: Metformin. N Engl J Med 

334:574, 1996. 

46. Masoudi FA, Inzucchi SE, Wang Y, et al: Thiazolidinediones, 

metformin, and outcomes in older 

patients with diabetes and heart failure: An observational 


47. Eurich DT, Majumdar SR, McAlister FA, et al: 

Improved clinical outcomes associated with metformin 

in patients with diabetes and heart failure. 


48. Tahrani AA, Varughese GI, Scarpello JH, et al: Metformin, 

heart failure, and lactic acidosis: Is metformin 

absolutely contraindicated? BMJ 335:508, 

2007. 

49. McCormack J, Johns K, Tildesley H: Metformin’s 

contraindications should be contraindicated. 

CMAJ 173:502, 2005. 

50. Fantus IG: Metformin’s contraindications: Needed 

for now. CMAJ 173:505, 2005. 

51. Holstein A, Stumvoll M: Contraindications can 

damage your health—is metformin a case in point? 

Diabetologia 48:2454, 2005. 

52. Bodmer M, Meier C, Krahenbuhl S, et al: Metformin, 

sulfonylureas, or other antidiabetes drugs and 

the risk of lactic acidosis or hypoglycemia: A nested 

case-control analysis. Diabetes Care 31:2086, 2008. 

53. Rachmani R, Slavachevski I, Levi Z, et al: Metformin 

in patients with type 2 diabetes mellitus: Reconsideration 

of traditional contraindications. Eur 

J Intern Med. 13:428, 2002. 

54. Effect of intensive blood-glucose control with 

metformin on complications in overweight patients 

with type 2 diabetes (UKPDS 34). UK prospective 

diabetes study (UKPDS) group. Lancet 

352:854,1998. 

55. vans JM, Ogston SA, Emslie-Smith A, et al: Risk of 

mortality and adverse cardiovascular outcomes in 

type 2 diabetes: A comparison of patients treated 

with sulfonylureas and metformin. Diabetologia 


49:930,2006. 

56. Johnson JA, Majumdar SR, Simpson SH, et al: Decreased 

mortality associated with the use of metformin 

compared with sulfonylurea monotherapy 

in type 2 diabetes. Diabetes Care 25:2244,2002. 

57. Chiarelli F, Di Marzio D: Peroxisome proliferatoractivated 

receptor-gamma agonists and diabetes: 

Current evidence and future perspectives. Vasc 

Health Risk Mgmt 4:297,2008. 

58. Yki-Jarvinen H: Thiazolidinediones. N Engl J Med 

351:1106,2004. 

59. McGuire DK, Inzucchi SE: New drugs for the treatment 

of diabetes mellitus. Part I: Thiazolidinediones 

and their evolving cardiovascular implications. 

Circulation 117: 440, 2008. 

60. Deeks ED, Keam SJ: Rosiglitazone. A review of 

its use in type 2 diabetes mellitus. Drugs 67: 2747, 

2007. 

61. Nakamura T, Funahashi T, Yamashita S, et al: Thiazolidinedione 

derivative improves fat distribution 

and multiple risk factors in subjects with visceral 

fat accumulation—double-blind placebo-controlled 

trial. Diabetes Res Clin Pract 54:181,2001. 

62. Mayerson AB, Hundal RS, Dufour S, et al: The effects 

of rosiglitazone on insulin sensitivity, lipolysis, 

and hepatic and skeletal muscle triglyceride 

content in patients with type 2 diabetes. Diabetes 

51:797,2002. 

63. Bajaj M, Suraamornkul S, Pratipanawatr T, et al: 

Pioglitazone reduces hepatic fat content and augments 

splanchnic glucose uptake in patients with 

type 2 diabetes. Diabetes 52:1364,2003. 

64. Lebovitz HE, Kreider M, Freed MI: Evaluation 

of liver function in type 2 diabetic patients during 

clinical trials: Evidence that rosiglitazone 

does not cause hepatic dysfunction. Diabetes Care 

25:815,2002. 

65. Ali AA, Weinstein RS, Stewart SA, et al: Rosiglitazone 

causes bone loss in mice by suppressing 

osteoblast differentiation and bone formation. Endocrinology 

146:1226,2005. 

66. Schwartz AV, Sellmeyer DE, Vittinghoff E, et al: 

Thiazolidinedione use and bone loss in older diabetic 

adults. J Clin Endocrinol Metab 91:3349,2006. 

67. Yaturu S, Bryant B, Jain SK: Thiazolidinedione 

treatment decreases bone mineral density in type 2 

diabetic men. Diabetes Care 30:1574,2007. 

68. Grey A, Bolland M, Gamble G, et al: The peroxisome 

proliferator-activated receptor-gamma agonist 

rosiglitazone decreases bone formation and 

bone mineral density in healthy postmenopausal 

women: A randomized, controlled trial. J Clin Endocrinol 

Metab 92:1305,2007. 

69. Guan Y, Hao C, Cha DR, et al: Thiazolidinediones


expand body fluid volume through PPAR gamma 

stimulation of ENaC-mediated renal salt absorption. 

Nat Med 11:861, 2005. 

70. Delea TE, Edelsberg JS, Hagiwara M, et al: Use 

of thiazolidinediones and risk of heart failure in 

people with type 2 diabetes: A retrospective cohort 

study. Diabetes Care 26:2983,2003. 

71. Inzucchi SE, Masoudi FA, Wang Y, et al: Insulinsensitizing 

antihyperglycemic drugs and mortality 

after acute myocardial infarction: Insights from 

the National Heart Care Project. Diabetes Care 

28:1680,2005. 

72. Home PD, Pocock SJ, Beck-Nielsen H, et al: Rosiglitazone 

evaluated for cardiovascular outcomes—an 

interim analysis. N Engl J Med 357:28,2007. 

73. Home PD, Pocock SJ, Beck-Nielsen H, et al for the 

RECORD Study Team: Rosiglitazone evaluated for 

cardiovascular outcomes in oral agent combination 

therapy for type 2 diabetes (RECORD): a multicentre, 

randomised, open-label trial. Lancet 373: 2125, 

2009. 

74. Lago RM, Singh PP, Nesto RW: Congestive heart 

failure and cardiovascular death in patients with 

prediabetes and type 2 diabetes given thiazolidinediones: 

A meta-analysis of randomised clinical 

trials. Lancet 370:1129, 2007. 

75. Singh S, Loke YK, Furberg CD: Long-term risk of 

cardiovascular events with rosiglitazone: A metaanalysis. 

JAMA 298:1189,2007. 

76. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE: 

Pioglitazone and risk of cardiovascular events in 

patients with type 2 diabetes mellitus. A meta-analysis 

of randomized trials. JAMA 298; 1180, 2007. 

77. Dargie HJ, Hildebrandt PR, Riegger GA, et al: A 

randomized, placebo-controlled trial assessing the 

effects of rosiglitazone on echocardiographic function 

and cardiac status in type 2 diabetic patients 

with New York Heart Association functional class I 

or II heart failure. J Am Coll Cardiol 49:1696.2007. 

78. Manufacturers of some diabetes drugs to strengthen 

warning on heart failure risk. [FDA NEWS website] 

August 14, 2007Available at: http://www.fda. 

gov/bbs/topics/NEWS/2007/NEW01683.html Accessed 


79. Nissen SE, Wolski K:Effect of rosiglitazone on the 

risk of myocardial infarction and death from cardiovascular 

causes. N Engl J Med 356:2457,2007. 

80. Diamond GA, Bax L, Kaul S: Uncertain effects of 

rosiglitazone on the risk for myocardial infarction 

and cardiovascular death. Ann Intern Med 

147:578,2007. 

81. Lipscombe LL, Gomes T, Levesque LE, et al: Thiazolidinediones 

and cardiovascular outcomes in 

older patients with diabetes. JAMA 298:2634,2007. 

82. BARI 2D Study Group: A randomized trial of therapies 

for type 2 diabetes and coronary artery disease. 

N Engl J Med 360: 2503, 2009. 

83. Pop-Busui R, Lombardero M, Lavis V, et al and the 

BARI 2D Study Group: Relation of severe coronary 

artery narrowing to insulin or thiazolidinedione 

use in patients with type 2 diabetes mellitus 

(from the Bypass Angioplasty Revascularization 

Investigation 2 Diabetes Study). Am J Cardiol 104: 

52,2009. 

83a. Rosiglitazone (Avandia) revisited. The Medical Ltr 

52: 17, 2010. 

83b. Nissen SE, Wolski K: Rosiglitazone revisited. An 

updated meta-analysis of risk for myocardial infarction 

and cardiovascular mortality. Arch Intern 

Med 170: 1191, 2010. 

83c. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, 

et al: Risk of acute myocardial infarction, stroke, 

heart failure, and death in elderly Medicare patients 

treated with rosiglitazone or pioglitazone. 

JAMA 304: 411, 2010. 

84. Ratner RE, Cannon CP, Gerstein HC, et al: Assessment 

on the prevention of progression by rosiglitazone 

on atherosclerosis in diabetes patients with 

cardiovascular history (APPROACH): Study design 

and baseline characteristics. Am Heart J 156: 

1074, 2008. 

85. Van der Meer RW, Rijzewijk LJ, de Jong HWAM, 

et al: Pioglitazone improves cardiac function and 

alters myocardial substrate metabolism without 

affecting cardiac triglyceride accumulation and 

high-energy phosphate metabolism in patients 

with well-controlled type 2 diabetes mellitus. Circulation 

119: 2069, 2009. 

86. Nissen SE, Nicholls SJ, Wolski K, et al: Comparison 

of pioglitazone vs glimepiride on progression 

of coronary atherosclerosis in patients with type 2 

diabetes: The PERISCOPE randomized controlled 

trial. JAMA 299:1561, 2008. 

87. Goldberg RB, Kendall DM, Deeg MA, et al: A comparison 

of lipid and glycemic effects of pioglitazone 

and rosiglitazone in patients with type 2 diabetes 

and dyslipidemia. Diabetes Care 28:1547, 2005. 

88. Dormandy JA, Charbonnel B, Eckland DJ, et al: 

Secondary prevention of macrovascular events 

in patients with type 2 diabetes in the PROactive 

study (PROspective pioglitAzone clinical trial in 

macroVascular events): A randomised controlled 

trial. Lancet 366:1279, 2005. 

89. Wilcox R, Kupfer S, Erdmann E, et al: Effects of pioglitazone 

on major adverse cardiovascular events 

in high-risk patients with type 2 diabetes: Results 

from PROspective pioglitAzone clinical trial in 

macro vascular events (PROactive 10). Am Heart J

155:712, 2008. 

90. Erdmann E, Charbonnel B, Wilcox RG, et al: Pioglitazone 

use and heart failure in patients with type 

2 diabetes and preexisting cardiovascular disease: 

Data from the PROactive study (PROactive 08). 


91. Takagi T, Yamamuro A, Tamita K, et al: Pioglitazone 

reduces neointimal tissue proliferation after 

coronary stent implantation in patients with type 

2 diabetes mellitus: An intravascular ultrasound 

scanning study. Am Heart J 146:E5, 2003. 

92. Nishio K, Sakurai M, Kusuyama T, et al: A randomized 

comparison of pioglitazone to inhibit restenosis 

after coronary stenting in patients with type 2 

diabetes. Diabetes Care 29:101,2006. 

93. Elrick H, Srimmler L, Hlad CJ,Jr, et al: Plasma 

insulin response to oral and intravenous glucose 

administration. J Clin Endocrinol Metab 24:1076, 

1964. 

94. Nauck MA, Homberger E, Siegel EG, et al: Incretin 

effects of increasing glucose loads in man 

calculated from venous insulin and C-peptide responses. 

J Clin Endocrinol Metab 63:492,1986. 

94a. Deacon CF: Dipeptidyl peptidase-4 inhibitors in 

the treatment of type 2 diabetes: a comparative review. 

Diabetes, Obesity, Metab 13: 7, 2011. 

95. Scott R, Wu M, Sanchez M, et al: Efficacy and tolerability 

of the dipeptidyl peptidase-4 inhibitor sitagliptin 

as monotherapy over 12 weeks in patients 

with type 2 diabetes. Int J Clin Pract 61:171,2007. 

96. Aschner P, Kipnes MS, Lunceford JK, et al: Effect 

of the dipeptidyl peptidase-4 inhibitor sitagliptin as 

monotherapy on glycemic control in patients with 

type 2 diabetes. Diabetes Care 29:2632,2006. 

96a. Dhillon S: Sitagliptin. A review of its use in the 

management of type 2 diabetes mellitus. Drugs 70: 

489, 2010. 

96b. http://www.fda.gov/safety/medwatch/safetyinformation/ 

safetyalertsforhumanmedicalproducts/ 

ucm183800.htm 

96c. Garg R, Chen W, Pendergrass M: Acute pancreatitis 

in type 2 diabetes treated with exenatide or sitagliptin. 

A retrospective observational pharmacy 

claims analysis. Diabetes Care 33: 2349, 2010. 

97. Vella A, Bock G, Giesler PD, et al: Effects of dipeptidyl 

peptidase-4 inhibition on gastrointestinal 

function, meal appearance, and glucose metabolism 

in type 2 diabetes. Diabetes 56:1475, 2007. 

98. Farilla L, Bulotta A, Hirshberg B, et al: Glucagon-like 

peptide 1 inhibits cell apoptosis and improves glucose 

responsiveness of freshly isolated human islets. 

Endocrinology 144:5149, 2003. 

99. Ban K, Hui S, Drucker DJ, Husain M: Cardiovascu- 


lar consequences of drugs used for the treatment of 

diabetes: potential promise of incretin-based therapies. 

J Am Soc Hypertens 3: 245, 2009. 

100. Chia CW, Egan JM: Incretin-based therapies in 

type 2 diabetes mellitus. J Clin Endocrinol Metab 

93:3703, 2008. 

101. Possibility of pancreatitis in patients taking byetta. 

[FDA Patient Safety News] August 18, 2008. Available 

at: http://www.accessdata.fda.gov/scripts/ 

cdrh/cfdocs/psn/transcript.cfm?show=70 Accessed 


102. Drucker DJ, Buse JB, Taylor K, et al: Exanatide once 

weekly versus twice daily for the treatment of type 

2 diabetes: a randomized, open-label, non-inferiority 

study. Lancet 372: 1240, 2008. 

102a. Bergenstal RM, Wysham C, MacConell L, et al 

for the DURATION-2 Study Group: Efficacy and 

safety of enenatide once weekly versus sitagliptin of 

pioglitazone as an adjunct to metformin for treatment 

of type 2 diabetes (DURATION-2): a randomised 

trial. Lancet 376: 431, 2010. 

102b. Diamant M, Van Gaal L, Stranks S, et al: Once 

wekly exenatide compared with insulin glargine 

titrated to target in patients with type 2 diabetes 

(DURATION-3): an open-label randomised trial. 

Lancet 375: 2234, 2010. 

102c. Liraglutide (Victoza) for type 2 diabetes. The Medical 

Ltr 52: 25, 2010. 

102d. Buse JB, Rosenstock J, Sesti G, et al: Liraglutide 

once a day versus exenatide twice a day for type 

2 diabetes: a 26-week randomised, parallel-group, 

multinational, open-label trial (LEAD-6). LEAD-6 

Study Group. Lancet 374: 39, 2009. 

103. Mafong DD, Henry RR: Exenatide as a treatment 

for diabetes and obesity: Implications for cardiovascular 

risk reduction. Curr Atheroscler Rep 10:55, 

2008. 

104. Blonde L, Klein EJ, Han J, et al: Interim analysis of 

the effects of exenatide treatment on A1C, weight 

and cardiovascular risk factors over 82 weeks in 

314 overweight patients with type 2 diabetes. Diabetes 

Obes Metab 8:436, 2006. 

105. Ray JA, Boye KS, Yurgin N, et al: Exenatide versus 

insulin glargine in patients with type 2 diabetes 

in the UK: A model of long-term clinical and cost 

outcomes. Curr Med Res Opin 23:609, 2007. 

106. Sonne DP, Engstrom T, Treiman M: Protective effects 

of GLP-1 analogues exendin-4 and GLP-1(9- 

36) amide against ischemia-reperfusion injury in 

rat heart. Regul Pept 146:243, 2008. 

107. Zarich SW, Nesto RW: Implications and treatment 

of acute hyperglycemia in the setting of acute myocardial 

infarction. Circulation 115: e436, 2007. 

108. Ceriello A, Zarich SW, Testa R: Lowering glucose


to prevent adverse cardiovascular outcomes in a 

critical care setting. J Am Coll Cardiol 53 (Suppl S): 

S9, 2009. 

109. Van den Berghe G: Does tight blood glucose control 

during cardiac surgery improve patient outcome? 

Editorial. An Intern Med 146: 307, 2007. 

110. Wiener BS, Wiener DC, Larson RJ: Benefits and 

risks of tight glucose control in critically ill adults. 

JAMA 300: 933, 2008. 

111. Van den Berghe G, Schetz M, Vlasselaers D, et al: 

Intensive insulin therapy in critically ill patients: 

NICE-SUGAR or Leuven blood glucose target? J 

Clin Endocrin Metab 94: 3163, 2009. 

112. Hermansen K, Mortensen LS, Hermansen ML: 

Combining insulins with oral antidiabetic agents: 

Effect on hyperglycemic control, markers of cardiovascular 

risk and disease. Vasc Health Risk 

Mgmt.4:561, 2008. 

113. Hermansen K, Davies M, Derezinski T, et al: A 

26-week, randomized, parallel, treat-to-target trial 

comparing insulin detemir with NPH insulin as 

add-on therapy to oral glucose-lowering drugs in 

insulin-naive people with type 2 diabetes. Diabetes 

Care 29:1269, 2006. 

114. Philis-Tsimikas A, Charpentier G, Clauson P, et 

al: Comparison of once-daily insulin detemir with 

NPH insulin added to a regimen of oral antidiabetic 

drugs in poorly controlled type 2 diabetes. Clin 

Ther 28:1569, 2006. 

115. Holman RR, Thorne KI, Farmer AJ, et al: Addition 

of biphasic, prandial, or basal insulin to oral therapy 

in type 2 diabetes. N Engl J Med 357:1716, 2007. 

116. Heine RJ, Van Gaal LF, Johns D, et al: Exenatide 

versus insulin glargine in patients with suboptimally 

controlled type 2 diabetes: A randomized 


117. Roper NA, Bilous RW, Kelly WF, et al: Excess mortality 

in a population with diabetes and the impact 

of material deprivation: Longitudinal, population 

based study. BMJ 322:1389, 2001. 

118. Skyler JS, Bergenstal R, Bonow RO, et al: Intensive 

glycemic control and the prevention of cardiovascular 

events: Implications of the ACCORD, 

ADVANCE, and VA diabetes trials: A position statement 

of the American Diabetes Association and a 

scientific statement of the American College of Cardiology 

Foundation and the American Heart Association. 


119. Dickey RA, Feld S: A new paradigm for control of 

diabetes. Endocr Pract 8:65, 2002. 

120. American Diabetes Association :Standards of medical 

care in diabetes—2009. Diabetes Care 32:S13, 

2009. 

121. Action to Control Cardiovascular Risk in Diabetes 

Study Group, Gerstein HC, Miller ME, et al :Effects 

of intensive glucose lowering in type 2 diabetes. N 

Engl J Med 358:2545, 2008. 

122. Couzin J: Deaths in diabetes trial challenge a longheld 

theory. Science 319: 884, 2008. 

123. ADVANCE Collaborative Group, Patel A, Mac- 

Mahon S, et al:Intensive blood glucose control and 

vascular outcomes in patients with type 2 diabetes. 

N Engl J Med 358:2560, 2008. 

124. Duckworth W, Abraira C, Moritz T, et al:Glucose 

control and vascular complications in veterans with 

type 2 diabetes. N Engl J Med 360:129, 2009. 

124a. Ismail-Beigi F, Craven T, Banerji, MA, et al for 

the ACCORD Trial Group: Effect of intensive 

treatment of hyperglycaemia on microvascular 

outcomes in type 2 diabetes: an analysis of the AC- 

CORD randomised trial. Lancet 376: 419, 2010. 

125. Desouza C, Salazar H, Cheong B, et al:Association 

of hypoglycemia and cardiac ischemia: A study 

based on continuous monitoring. Diabetes Care 

26:1485, 2003. 

126. Kelly TN, Bazzano LA, Fonseca VA, et al: Systematic 

review: glucose control and cardiovascular disease 

in type 2 diabetes. Ann Intern Med 151: 394, 

2009. 

127. Holman RR, Paul SK, Bethel MA, et al: 10-year 

follow-up of intensive glucose control in type 2 

diabetes. N Engl J Med 359:1577, 2008. 

128. Gaede P, Lund-Andersen H, Parving HH, et al: Effect 

of a multifactorial intervention on mortality in 

type 2 diabetes. N Engl J Med 358:580, 2008. 

129. The ACCORD Study Group: Long-term effects of 

intensive glucose lowering on cardiovascular outcomes. 

N Engl J Med 364: 818, 2011.


Prostacyclins, Endothelin Inhibitors, 

and Phosphodiesterase-5 Inhibitors 

in Pulmonary Hypertension 

Warren D. Rosenblum, MD 


1. Proceedings of the 4th World symposium on Pulmonary 

Hypertension. J Am Coll Cardiol Suppl S 

54: 2009. 

2. Rubin LJ: Pathology and pathophysiology of primary 

pulmonary hypertension. Am J Cardiol 74: 

51A, 1995. 

3. Lehrman S, Romano P, Frishman W, et al: Primary 

pulmonary hypertension and cor pulmonale. Cardiol 

in Rev 10: 265, 2002. 

4. Rubin LJ, Barst RJ, Kaiser LR, et al: Primary pulmonary 

hypertension. ACCP Consensus Statement. 

Chest 104: 236, 1993. 

4a. Abe K, Toba M, Alzoubi A, et al: Formation of 

plexiform lesions in experimental severe pulmonary 

arterial hypertension. Circulation 121: 2747, 

2010. 

5. Pietra GG, Edwards WD, Kay JM, Rich S: Histopathology 

of primary pulmonary hypertension: A 

qualitative study of pulmonary blood vessels from 

58 patients in the National Heart Lung and Blood 

Institute primary pulmonary hypertension registry. 

Circulation 80: 1198, 1989. 

6. Humbert M, Sitbon O, Chaovat A, et al: Pulmonary 

hypertension in France. Results from a national 

registry. Am J Respir Crit Care 173: 1023, 2006. 

7. Humbert M, Sitbon O, Simmoneau G: Treatment 

of pulmonary arterial hypertension. N Engl J Med 

351: 1425, 2004. 

7a. Archer SL, Weir K, Wilkins MR: Basic science of 

pulmonary arterial hypertension for clinicians: 

new concepts and experimental therapies. Circulation 

121: 2045, 2010. 

8. Christman BW, McPherson CD, Newman JH, et 

al: An imbalance between the excretion of thromboxane 

and prostacyclin metabolites in pulmonary 

hypertension. N Engl J Med 327:70, 1992. 

9. Giaid A, Yanagisawa M, Langleben D, et al: Expression 

of endothelin-1 in the lungs of patients with 

pulmonary hypertension. N Engl J Med 328:173, 

1993. 

10. Stewart DJ, Levy RD, Cernacek P, Langleben D: 

Increased plasma endothelin-1 in the lungs of patients 

with pulmonary hypertension. N Engl J Med 

114:467, 1991. 

11. Herve P, Launay JM, Scrobohaci ML, et al: Increased 

plasma serotonin in primary pulmonary 

hypertension. Am J Med 99:249, 1995. 

12. Yuan X-J, Wang J, Juhaszova M, et al: Attenuated K + 

channel gene transcription in primary pulmonary 

hypertension. Lancet 352:726, 1998. 

13. Rich S, Dantzker DR, Ayres SM, et al: Primary pulmonary 

hypertension: a national prospective study. 


13a. Almodovar S, Cicalini S, Petrosillo N, Flores SC: 

Pulmonary hypertension associated with HIV infection: 

pulmonary vascular disease: the global 

perspective. Chest 137 Suppl: 6S, 2010 

14. D’Alonzo GE, Barst RJ, Ayres SM, et al: Survival in 

patients with primary pulmonary Hypertension: 

Results from a national prospective registry. Ann 

Intern Med 115:343, 1991. 

15. Rubin LJ: Calcium channel blockers in primary 

pulmonary hypertension. Chest 88:257S, 1985. 

16. Alpert MA, Pressly TA, Mukerji V, et al: Acute and 

long-term effects of nifedipine on pulmonary hypertension 

associated with diffuse systemic sclerosis, 

the CREST syndrome and mixed connective 

tissue diseases. Am J Cardiol 68:1687, 1991. 

17. Fuster V, Steele PM, Edwards WD, et al: Primary 

pulmonary hypertension: natural history and the 

importance of thrombosis. Circulation 70:580, 

1984. 



25-1


18. Dobkin J, Reichel J: Drug treatment of primary 

pulmonary hypertension. In: Frishman WH, Sonnenblick 

EH (eds). Cardiovascular Pharmacotherapeutics. 


19. Rubin LJ: Primary pulmonary hypertension: Practical 

therapeutic recommendations. Drugs 43:37, 

1992. 

20. Rich S: Medical treatment of primary pulmonary 

hypertension: A bridge to transplantation? Am J 

Cardiol 75:63A, 1995. 

21. Pasque MK, Trulock EP, Kaiser LD, Cooper JD: 

Single lung transplantation for pulmonary hypertension: 

Three months hemodynamic follow-up. 


22. Doud JR, McCabe MM, Montoya A, Garrity ER: 

The Loyola University lung transplant experience. 


23. The Task force for the Diagnosis and Treatment of 

Pulmonary Hypertension of the European Society 

of Cardiology (ESC) and the European Respiratory 

Society (ERS) endorsed by the International Society 

of Heart and Lung Transplantation IISHLT). 

Guidelines for the diagnosis and treatment of pulmonary 

hypertension. Eur Heart J 30: 2493, 2009. 

24. McLaughlin W, Archer SL, Badesch DB, et al: ACC/ 

AHA 2009 Expert Consensus Document on Pulmonary 

Hypertension. A report from the American 

College of Cardiology Foundation Task Force 

on Expert Consensus Documents and the American 

Heart Association. Circulation 119: 2250, 2009. 

25. Von Euler US: Zur Kenntnis der pharmakologischen 

Wirkungen von Nativsekreten und Extrakten 

mannlicher accessorisher Geschlectsdrussen. Arch 

Exp Pathol Pharmacol 75:78, 1934. 

26. Moncada S, Gryglewski R, Bunting S, Vane JR: An 

enzyme isolated from the arteries transforms prostaglandin 

endoperoxides to an unstable substance 

that inhibits platelet aggregation. Nature 263:663, 

1976. 

27. Whittaker N, Bunting S, Salmon J, et al: The chemical 

structure of prostaglandin X (prostacyclin). 

Prostaglandins 12:915, 1976. 

28. Bunting S, Gryglewski R, Moncada S, Vane JR: 

Arterial walls generate from prostaglandin endoperoxides 

a substance (prostaglandin X) which relaxes 

strips of mesenteric and coeliac arteries and 

inhibits platelet aggregation. Prostaglandins 12:897, 

1976. 

29. Marcus AJ, Weksler BB, Jaffe EA: Enzymatic conversion 

of prostaglandin endoperoxide H 2 and 

arachidonic acid to PGI 2 by cultured human endothelial 

cells. Biol Chem 253:7138, 1978. 

30. Weksler BB, Marcus AJ, Jaffe EA: Synthesis of 

prostaglandin I 2 (prostacyclin) by cultured human 

bovine endothelial cells. Proc Natl Acad Sci USA 

74:3922, 1977. 

31. MacIntyre DE, Pearson JD, Gordon JL: Localization 

and stimulation of prostacyclin production in 

vascular cells. Nature 271:549, 1978. 

32. Moncada S, Vane JR: Pharmacology and endogenous 

roles of prostaglandin endoperoxides, 

thromboxane A2, and prostacyclin. Pharmacol Rev 

30:293, 1979. 

33. Nakagawa O, Tanaka I, Usui T, et al: Molecular 

cloning of human prostacyclin receptor cDNA and 

its gene expression in the cardiovascular system. 


34. Tateson JE, Moncada S, Vane JR: Effects of prostacyclin 

(PGX) on cyclic AMP concentrations in human 

platelets. Prostaglandins 13:389, 1977. 

35. Higgs EA, Moncada S, Vane JR, et al: Effects of 

prostacyclin (PGI 2 ) on platelet adhesion to rabbit 

arterial subendothelium. Prostaglandins 16:17, 

1978. 

36. Cho MJ, Allen MA: Chemical stability of PGI 2 in 

aqueous solutions. Prostaglandins 15:943, 1978. 

37. Wong PY, Sun FF, McGiff JC: Metabolism of prostacyclin 

in blood vessels. J Biol Chem 253:5555, 

1978. 

38. Yui Y, Aoyama T, Morishita H, et al: Serum prostacyclin 

stabilizing factor is identical to apoprotein 

A-I (apo-I): A novel function of apo A-I. J Clin Invest 

82:803, 1988. 

39. Rubin LJ, Mendoza J, Hood M, et al: Treatment of 

primary pulmonary hypertension with continuous 

intravenous prostacyclin (epoprostenol): Results of 

a randomized trial. Ann Intern Med 112:485, 1990. 

40. Barst RJ, Rubin LJ, McGoon MD, et al: Survival in 

primary pulmonary hypertension with long term 

continuous intravenous prostacyclin. Ann Intern 

Med 121:409, 1994. 

41. Barst RJ, Rubin LJ, Long WA, et al: A comparison of 

continuous epoprostenol (prostacyclin) with conventional 

therapy for primary pulmonary hypertension. 

N Engl J Med 334:296, 1996. 

42. Hinderliter AL, Park WW, Barst RJ, et al: Effects of 

long-term infusion of prostacyclin (epoprostenol) 

on echocardiographic measures of right ventricular 

structure and function in primary pulmonary 


43. McLaughlin VV, Genthner DE, Panella MM, Rich 

S: Reduction in pulmonary vascular resistance with 

long-term epoprostenol (prostacyclin) therapy in 

primary pulmonary hypertension. N Engl J Med 

338:273, 1998. 

44. Higenbottam TW, Spiegelhalter D, Scott JP, et al: 

Prostacyclin (epoprostenol) and heart-lung transplantation 

as treatments for severe pulmonary hy-

pertension. Br Heart J 70:366, 1993. 

45. Cremona A, Higenbottam T: Role of prostacyclin 

in the treatment of primary pulmonary hypertension. 

Am J Cardiol 75: 67A, 1995. 

46. Rich S, McLaughlin VV: The effects of chronic 

prostacyClin Therapy on cardiac output and symptoms 

in primary pulmonary hypertension. J Am 

Coll Cardiol 34: 1184, 1999. 

47. Marshall RJ, Helmholz HF, Shepherd JT: Effect of 

acetylcholine on pulmonary vascular resistance in 

a patient with idiopathic pulmonary hypertension. 


48. Morgan MJ, McCormack DG, Griffiths MJD, et al: 

Adenosine as a vasodilator in primary pulmonary 


49. Frostell C, Fratacci MD, Wain JC, et al: Inhaled 

nitric oxide: A selective pulmonary vasodilator reversing 

hypoxic pulmonary vasoconstriction. Circulation 

83:2038, 1991. 

50. Rozkovec A, Stradling JR, Shepherd G, et al: Prediction 

of favorable responses to long term vasodilator 

treatment of pulmonary hypertension by 

short term administration of epoprostenol (prostacyclin) 

or nifedipine. Br Heart J 59:696, 1988. 

51. Palewsky HI, Long W, Crow J, Fishman AP: Prostacyclin 

and acetylcholine as screening agents for 

acute pulmonary vasodilator responsiveness in 

primary pulmonary hypertension. Circulation 

82:2018, 1990. 

52. Scrader BJ, Inbar S, Kaufman L, et al: Comparison 

of the effects of adenosine and nifedipine in pulmonary 

hypertension. J Am Coll Cardiol 19:1060, 

1992. 

53. Inbar S, Schrader BJ, Kaufmann E, et al: Effects of 

adenosine in combination with calcium channel 

blockers in patients with primary pulmonary hypertension. 


54. Jolliet P, Bulpa P, Thorens JB, et al: Nitric oxide and 

prostacyclin as test agents of vasoreactivity in severe 

precapillary pulmonary hypertension: Predictive 

ability and consequences on haemodynamics 

and gas exchange. Thorax 52:369, 1997. 

55. Sitbon O, Brenot F, Denjean A, et al: Inhaled nitric 

oxide as a screening vasodilator agent in primary 

pulmonary hypertension: A dose-response study 

and comparison with prostacyclin. Am J Respir Crit 

Care Med 151:384, 1995. 

56. Badesch DB, Abman SH, Simonneau G, et al.: 

Medical therapy for pulmonary arterial hypertension 

updated ACCP evidence-based clinical practice 

guidelines. Chest 131;1917-1928, 2007. 

57. Shapiro SM, Oudiz RJ, Cao T, et al: Primary pulmonary 

hypertension: Improved long-term effects 

and survival with continuous intravenous epopros- 


tenol infusion. J Am Coll Cardiol 30:343, 1997. 

58. Sakamaki F, Kyotani S, Nagaya N, et al: Increased 

plasma P-selectin and decrease thrombo-modulin 

in pulmonary arterial hypertension were improved 

by continuous prostacyClin Therapy. Circulation 

102:2720, 2000. 

59. Langleben D, Barst RJ, Badesch D, et al: Continuous 

infusion of epoprostenol improves the net balance 

between pulmonary endothelin-1 clearance 

and release in primary pulmonary hypertension. 


60. Sitbon O, Humbert M, Nunes H, et al: Long-term 

intravenous epoprostenol infusion in primary pulmonary 

hypertension. J Am Coll Cardiol 40:780, 

2002. 

61. Fisher CA, Kappa JR, Sinha AK, et al: Comparison 

of equimolar concentrations of iloprost, prostacyclin, 

and prostaglandin E 1 on human platelet function. 

J Lab Clin Med 109:184, 1987. 

62. Saniabadi AR, Belch JJF, Lowe GDO, et al: Comparison 

of inhibitory actions of prostacyclin and a 

new prostacyclin analogue on the aggregations of 

human platelet in whole blood. Hemostasis 17:147, 

1987. 

63. Schror K, Darius H, Matzky R, Ohlendorf R: The 

antiplatelet and cardiovascular action of a new carbacyclin 

derivative (ZK 36 374)-equipotent to PGI 2 

in vitro. Naunyn Schmiedebergs Arch Pharmacol 

316:252, 1981. 

64. Parsons AA, Whalley ET: Effects of prostanoids on 

human and rabbit basilar arteries precontracted in 

vitro. Cephalalgia 9:165, 1989. 

65. Schroder G, Beckman R, Schillinger E: Studies on 

vasorelaxant effects and mechanisms of iloprost in 

isolated preparations. In: Gryglewski RJ, Stock G, 

eds. Prostacyclin and Its Stable Analogue Iloprost. 

Berlin: Springer Verlag, 1987:129. 

66. Belch JJ, Greer I, McLaren M, et al: The effects of 

intravenous ZK 36-374, a stable prostacyclin analogue, 

on normal volunteers. Prostaglandins 28:67, 

1984. 

67. Kaukinen S, Ylitalo P, Pessi T, Vapaatalo H: Hemodynamic 

effects of iloprost, a prostacyclin analog. 


68. Krause W, Humpel M, Hoyer GA: Biotransformation 

of the stable prostacyclin analogue, iloprost, in 

the rat. Drug Metab 12:645, 1984. 

69. Hildebrand M, Krause W, Fabian H, et al: Pharmacokinetics 

of iloprost in patients with chronic renal 

failure and maintenance hemodialysis. Int J Clin 

Pharmacol Res 10:285, 1990. 

70. Hildebrand M, Krause W, Angeli P, et al: Pharmacokinetics 

of iloprost in patients with hepatic dysfunction. 

Int J Clin Pharmacol Ther Toxicol 28:430,


1990. 

71. Scott JP, Higenbottam T, Wallwork J: The acute effect 

of the synthetic prostacyclin analogue iloprost 

in primary pulmonary hypertension. Br J Clin 

Pract 44:231, 1990. 

72. Olschewski H, Ghofrani H, Walmrath D, et al: Inhaled 

prostacyclin and iloprost in severe pulmonary 

hypertension secondary to lung fibrosis. Am 

J Respir Crit Care Med 160:600, 1999. 

73. De La Mata J, Gomez-Sanchez MA, Aranzana M, 

Gomez-Reino JJ: Long-term iloprost infusion therapy 

for severe pulmonary hypertension in patients 

with connective tissue diseases. Arthritis Rheum 

37:1528, 1994. 

74. Olschewski H, Walmrath D, Schermuly R, et al: 

Aerosolized prostacyclin and iloprost in severe 

pulmonary hypertension. Ann Intern Med 124:820, 

1996. 

75. Mikhail G, Gibbs J, Richardson M, et al: An evaluation 

of nebulized prostacyclin in patients with primary 

and secondary pulmonary hypertension. Eur 

Heart J 18:1499, 1997. 

76. Olschewski S, Simonneau G, Galié N, et al: Inhaled 

iloprost for severe pulmonary hypertension. N Engl 

J Med 347:322, 2002. 

77. Wiedemann R, Ardeschir Ghofrani H, Weissmann 

N, et al: Atrial natriuretic peptide in severe primary 

and nonprimary pulmonary hypertension: 

response to iloprost inhalation. J Am Coll Cardiol 

38:1130, 2001. 

78. Hoeper M, Schwarze M, Ehlerding S, et al: Longterm 

treatment of primary pulmonary hypertension 

with aerosolized iloprost, a prostacyclin 

analogue. N Engl J Med 342:1866, 2000. 

79. Olschewski H, Ardeschir H, Schmehl T, et al: Inhaled 

iloprost to treat severe pulmonary hypertension. 


80. Wilkens H, Guth A, König J, et al: Effect of inhaled 

iloprost plus oral sildenafil in patients with primary 

pulmonary hypertension. Circulation 104:1218, 

2001. 

81. Ghofrani HA, Wiedemann R, Rose F, et al: Combination 

therapy with oral sildenafil and inhaled 

iloprost for severe pulmonary hypertension. Ann 

Intern Med 136:515, 2002. 

82. Schenk P, Petkov V, Madl C, et al: Aerosolized iloprost 

therapy could not replace long-term intravenous 

epoprostenol (prostacyclin) administration 

in severe pulmonary hypertension. Chest 119:296, 

2000. 

83. Ewert R, Wensel R, Opitz CF: Aerosolized iloprost 

for primary pulmonary hypertension (correspondence). 

N Engl J Med 343:1421, 2000. 

84. Machherndl S, Kneussl M, Baumgartner H, et al: 

Long-term treatment of pulmonary hypertension 

with aerosolized iloprost. Eur Respir J 17:8, 2001. 

85. Skoro-Sajer N, Lang I: The role of treprostinil in 

the management of pulmonary hypertension: Am 

J Cardiovasc Drugs 8: 213, 2008. 

86. Channick RN, Olschewski H, Seeger W eta l.: 

Safety and efficacy of inhaled treprostinil as add-on 

therapy to bosentan in pulmonary arterial hypertension. 

J Am Coll Cardiol 2006:48;1433-1437. 

87. McLaughlin V, Rubin L, Benza R. TRIUMPH I: 

efficacy and safety of inhaled treprostinil sodium 

in patients with pulmonary arterial hypertension 

(PAH). Am J Respir Crit Care Med 2008; 177: 

A965. 

88. Hildebrand M, Staks T, Nieuweboer B: Pharmacokinetics 

and pharmacodynamics of cicaprost in 

healthy volunteers after oral administration of 5 to 

20 micrograms. Eur J Clin Pharmacol 39:149, 1990. 

89. Melian EB, Goa KL: Beraprost: A review of its 

pharmacology and therapeutic efficacy in the treatment 

of peripheral arterial disease and pulmonary 

arterial hypertension. Drugs 62:107, 2002. 

90. Nagaya N, Uematsu M, Okano Y, et al: Effect of 

orally active prostacyclin analogue on survival of 

outpatients with primary pulmonary hypertension. 


91. Galié N, Humbert M, Vachiéry J-L, et al: Effects of 

beraprost sodium, an oral prostacyclin analogue, 

in patients with pulmonary arterial hypertension: 

A randomized, placebo-controlled, double-blind 


92. Ichida F, Uese K, Tsubata S, et al: Additive effect 

of beraprost on pulmonary vasodilation by inhaled 

nitric oxide in children with pulmonary hypertension. 

Am J Cardiol 80:662, 1997. 

93. Okano Y, Hoshioka T, Shimouchi A, et al: Orally 

active prostacyclin analogue in primary pulmonary 

hypertension (letter). Lancet 349:1365, 1997. 

94. Hickey KA, Rubanyi GM, Paul RJ, Highsmith RF: 

Characterization of a coronary vasoconstrictor 

produced by cultured endothelial cells. Am J Physiol 

248:550, 1985. 

95. Yanagisawa M, Kurihara H, Kimura S, et al: A novel 

potent vasoconstrictor peptide produced by vascular 

endothelial cells. Nature 332:411, 1988. 

96. Kloog Y, Ambar I, Sokolovsky M, et al: Sarafotoxin, 

a novel vasoconstrictor peptide: Phosphoinositide 

hydrolysis in rat heart and brain. Science 242:268, 

1988. 

97. Kramer BK, Nishida M, Kelly RA, Smith TW: Endothelins: 

Myocardial actions of a new class of cytokines. 


98. Inoue A, Yanagisawa M, Takuwa Y, et al: The human 

preproendothelin-1 gene. J Biol Chem 264:14954,

1989. 

99. Inoue A, Yanagisawa M, Kimura S, et al: The human 

endothelin family: Three structurally and 

pharmacologically distinct isopeptides predicted 

by three separate genes. Proc Natl Acad Sci U S A 

86:2863, 1989. 

100. Arai H, Hori S, Aramori I, et al: Cloning and expression 

of a cDNA encoding an endothelial receptor. 

Nature 348:730, 1990. 

101. Lin HY, Kaji EH, Winkel GK, et al: Cloning and 

functional expression of a vascular smooth muscle 

endothelin 1 receptor. Proc Natl Acad Sci U S A 

88:3l85, 1991. 

102. Sakurai T, Yanagisawa M, Masaki T: Molecular 

characterization of the endothelin receptors. 

Trends Pharmacol Sci l3:l03, 1992. 

103. Sakamoto A, Yanagisawa M, Sakurai T, et al: Cloning 

and functional expression of human cDNA for 

the ETB endothelin receptor. Biochem Biophys Res 

Commun l78:656, 1991. 

104. Webb DJ, Strachan FE: Clinical experience with 

endothelin antagonists. Am J Hypertens 11 (4 Pt 3): 

71S, 1998. 

105. Bax WA, Saxena PR: The current endothelin receptor 

classification: Time for reconsideration? Trends 

Pharmacol Sci 15(10):379, 1994. 

106. Sakurai T, Goto K: Endothelins: Vascular actions 

and clinical implications. Drugs 46(5):795, 1993. 

107. Hosoda K, Nakao K, Hiroshi-Arai, et al: Cloning 

and expression of human endothelin-1 receptor 

cDNA. FEBS Lett 287(1–2):23, 1991. 

108. Levin ER: Mechanisms of disease: endothelin. N 

Engl J Med 333: 356, 1995. 

109. Yoshimoto S, Ishizaki Y, Sasaki T, Murota SI: Effect 

of carbon dioxide and oxygen on endothelin production 

by cultured porcine cerebral endothelial 

cells. Stroke 22:378, 1991. 

110. Nathan C, Sporn M: Cytokines in context. J Cell 

Biol 113:98l, 1991. 

111. Chan J, Greenberg DA: Endothelin and calcium 

signaling in NG l08-l5 neuroblastoma X glioma 

cells. J Pharmacol Exp Ther 258:524, 1991. 

112. Ohnishi A, Yamaguchi K, Kusuhara M, et al: Mobilization 

of intracellular calcium by endothelin 

in Swiss 3T3 cells. Biochem Biophys Res Commun 

l6l:489, 1989. 

113. Takuwa N, Takuwa Y, Yanagisawa M, et al: A novel 

vasoactive peptide stimulates mitogenesis through 

inositol lipid turnover in Swiss 3T3 fibroblasts. J 

Biol Chem 264:7856, 1989. 

114. Takuwa Y, Masaki T, Yamashita K: The effects of the 

endothelin family peptides on cultured osteoblastic 

cells from rat calvariae. Biochem Biophy Res Commun 

l70:998, 1990. 


115. Miller RC, Pelton JT, Huggins JP: Endothelins— 

from receptors to medicine. Trends Pharmacol Sci 

l4(2):54, 1993. 

116. Nakaki T, Nakayama M, Yamamoto S, Kato R: Endothelin-mediated 

stimulation of DNA synthesis 

in vascular smooth muscle cells. Biochem Biophy 

Res Commun l58:880, 1989. 

117. Nilsson J, Sjolund M, Palmberg L, et al: The calcium 

antagonist nifedipine inhibits arterial smooth 

muscle proliferation. Atherosclerosis 58:l09, 1985. 

118. Battistini B, Chailler P, D’Orleans-Juste P, et al: 

Growth regulatory properties of endothelins. Peptides 

l4:385, 1993. 

119. Brown KD, Littlewood CJ: Endothelin stimulates 

DNA synthesis in Swiss 3T3 cells, synergy with 

polypeptide growth factors. Biochem J 263:977, 

1989. 

120. Fabiato A, Fabiato F: Effects of pH on the myofilaments 

and the sarcoplasmic reticulum of skinned 

cells from cardiac and skeletal muscles. J Physiol 

276:233, 1978. 

121. Allen DG, Orchard CH: The effects of changes of 

pH on intracellular calcium transits in mammalian 

cardiac muscle. J Physiol 335:555, 1983. 

122. Komuro I, Kurihara H, Sugiyama T, et al: Endothelin 

stimulates c-fos and c-myc expression and 

proliferation of vascular smooth muscle cells. FEBS 

Lett 238:249, 1988. 

123. Simonson MS, Wann S, Mene P, et al: Endothelin 

stimulates phospholipase C, Na + /H + exchange, cfos 

expression, and mitogenesis in rat mesangial 

cells. J Clin Invest 83:708, 1989. 

124. DiNucci G, Thomas R, D’Orleans-Juse P, et al: Pressor 

effects of circulating endothelin are limited by 

its removal in the pulmonary Circulation and by 

the release of prostacyclin and endothelin-derived 

relaxing factor. Proc Natl Acad Sci USA 85: 9797, 

1988. 

125. Chakravarthy U, Archer DB: Endothelin—a new 

vasoactive ocular peptide. Br J Ophthalmol 76:l07, 

1992. 

126. Nakami A, Hirata Y, Ishikawa M, et al: ET-1 and 

ET-3 induce vasorelaxation via common generation 

of endothelium derived nitric oxide. Life Sci 

50:677, 1992. 

127. Nakamuta M, Takayanagi R, Sakai Y, et al: Cloning 

and sequence analysis of cDNA encoding human 

non-selective type of endothelin receptor. Biochem 

Biophys Res Commun l77:34, 1991. 

128. Vincent R, Hogie M, Clozel M, Thuillez C: In vivo 

evidence of an endothelin-induced vasopressor 

tone after inhibition of nitric oxide synthesis in rats 

(abstr). Circulation 90(4 Pt 2):1, 1994. 

129. Haynes WG, Waugh CJ, Dockrell MEC, et al: Mod-


ulators of calcium and potassium channels: their 

effects on endothelin-1 binding to cardiac membranes. 

J Cardiovasc Pharmacol 22(Suppl):S154, 

1993. 

130. Grover GJ, Dzwonczyk S, Parham CS, Sleph PG: 

The protective effects of cromakalim and pinacidil 

on reperfusion function and infarct size in anaesthetized 

dogs. Cardiovasc Drugs Ther 4:465, 1990. 

131. Kerr MJ, Wilson R, Shanks RG: Suppression of ventricular 

arrhythmias after coronary artery ligation 

by pinacidil, a vasodilator drug. J Cardiovasc Pharmacol 

7:875, 1985. 

132. Weber MA, Black H, Bakris G, et al: A selective 

endothelin-receptor antagonist to reduce blood 

pressure in patients with treatment-resistant hypertension: 

a randomised, double-blind, placebocontrolled 

trial. Lancet 374: 1423, 2009. 

133. Prasad VS, Palaniswamy C, Frishman WH: Endothelin 

as a clinical target in the treatment of systemic 

hypertension. Cardiol in Rev 17: 181, 2009. 

134. Benigni A, Remuzzi G: Endothelin antagonists. 

Lancet 353: 133, 1999. 

135. Stewart DJ, Levy RD, Cernacek P, Langleben D: Increased 

plasma endothelin-1 in pulmonary hypertension: 

Marker or mediator of disease? Ann Intern 

Med 114:464, 1991. 

136. Snopek G, Pogorzelska H, Rywik TM, et al: Usefulness 

of endothelin-1 concentration in capillary 

blood in patients with mitral stenosis as a predictor 

of regression of pulmonary hypertension after mitral 

valve replacement or valvuloplasty. Am J Cardiol 

90:188, 2002. 

137. Li H, Chen SJ, Chen YF, et al: Enhanced endothelin-1 

and endothelin receptor gene expression in 

chronic hypoxia. J Appl Physiol 77(3):1451, 1994. 

138. Dupuis J, Cernacek P, Tardif JC, et al: Reduced pulmonary 

clearance of endothelin-1 in pulmonary 

hypertension. Am Heart J 135(4):614, 1998. 

139. Mikhail G, Chester AH, Gibbs JS, et al: Role of 

vasoactive mediators in primary and secondary 

pulmonary hypertension. Am J Cardiol 82(2):254, 

1998. 

140. Barman SA, Isales CM: Fenfluramine potentiates 

canine pulmonary vasoreactivity to endothelin-1. 

Pulm Pharmacol Ther 11(2–3):183, 1998. 

141. Reddy VM, Hendricks-Munoz KD, Rajasinghe HA, 

et al: Post-cardiopulmonary bypass pulmonary 

hypertension in lambs with increased pulmonary 

blood flow. A role for endothelin 1. Circulation 

95(4):1054, 1997. 

142. Akazawa H, Ikeda U, Kuroda T, Shimada K: Plasma 

endothelin-1 levels in Takayasu’s arteritis. Cardiology 

87(4):303, 1996. 

143. Lutz J, Gorenflo M, Habighorst M, et al: Endo- 

thelin-1- and endothelin-receptors in lung biopsies 

of patients with pulmonary hypertension due 

to congenital heart disease. Clin Chem Lab Med 

37(4):423, 1999. 

144. Sartori C, Vollenweider L, Löffler B-M, et al: Exaggerated 

endothelin release in high-altitude pulmonary 

edema. Circulation99:2665, 1999. 

145. Chen SJ, Chen YF, Meng QC, et al: Endothelinreceptor 

antagonist bosentan prevents and reverses 

hypoxic pulmonary hypertension in rats. J Appl 

Physiol 79(6):2122, 1995. 

146. Itoh H, Yokochi A, Yamauchi-Kohno R, Maruyama 

K: Effects of the endothelin ET(A) receptor antagonist, 

TA-0201, on pulmonary arteries isolated from 

hypoxic rats. Eur J Pharmacol 376(3):233, 1999. 

147. Sheedy W, Haleen S, Morice AH: The effect of the 

ETA receptor antagonist (CI-1020) in rats with established 

hypoxic pulmonary hypertension. Pulm 

Pharmacol Ther 11(2–3):173, 1998. 

148. Ueno M, Miyauchi T, Sakai S, Goto K: The combined 

treatment of oral endothelin (ET)-A receptor 

antagonist and oral prostacyclin (PGI2) analog is 

more greatly effective in ameliorating pulmonary 

hypertension (PH) and right ventricular (RV) hypertrophy 

than each drug alone in rats (abstr). Circulation 

100 (Suppl l):I, 1999. 

149. Jasmin J-F, Lucas M, Cernacek P, Dupuis J: Effectiveness 

of a nonselective ET A/B and a selective 

ET A antagonist in rats with monocrotaline-induced 

pulmonary hypertension. Circulation 103: 314, 

2001. 

150. Apostolopoulou SC, Kyriakides Z, Webb DJ, et al: 

Endothelin A receptor antagonism improves pulmonary 

and systemic hemodynamics in patients 

with severe pulmonary hypertension (abstr). Circulation 

100(Suppl l):I, 1999. 

151. Goldberg A: Pulmonary arterial hypertension in 

connective tissue diseases. Cardiol in Rev 18: 85, 

2010. 

152. Elliott WT, Chan J: Bosentan tablets (Tracleer-Actelion). 

Intern Med Alert 4:13, 2002. 

153. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan 

therapy for pulmonary arterial hypertension. N 

Engl J Med. 346:896-903, 2002. 

154. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of 

patients with mildly symptomatic pulmonary arterial 

hypertension with bosentan (EARLY study): a 

double blind, randomized controlled trial. Lancet 

371:2093-2100, 2008. 

155. Behr J, Lyseng-Williamson KA: Ambrisentan: a 

guide to its use in pulmonary arterial hypertension. 

Drugs Ther Perspect 25: 1, 2009. 

156. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan 

for the treatment of pulmonary hypertension:

Results of the ambrisentan in pulmonary arterial 

hypertension, randomized, double-blind, placebocontrolled, 

multicenter, efficacy (ARIES) study 1 

and 2. Circ. 117:3010-3019, 2008. 

157. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan 

therapy for pulmonary arterial hypertension. Am J 

Respir Crit Care Med. 169:441-447, 2004. 

158. Barst RJ, Langleben D, Badesch D, et al. Treatment 

of pulmonary arterial hypertension with the selective 

endothelin-A receptor antagonist sitaxsentan. 

JACC. 47:2049-2056, 2006. 

159. Krum H, Viskoper RJ, Lacourciere Y, et al—Bosentan 

Hypertension Investigators: The effect of an endothelin-receptor 

antagonist, bosentan, on blood 

pressure in patients with essential hypertension. N 

Engl J Med 338(12):784, 1998. 

160. Packer M, Caspi A, Charlon V, et al: Multicenter, 

double-blind, placebo-controlled study of longterm 

endothelin blockade with bosentan in chronic 

heart failure—results of the REACH-1 trial. Circulation 

98 (Suppl S):12, 1998. 

161. Fattinger K, Funk C, Pantze M, et al: The endothelin 

export pump: A potential mechanism for hepatic 

adverse reactions. Clin Pharmacol Ther 69:223, 

2001. 

162. Stieger B, Fattinger K, Madon J, et al: Drug- and 

estrogen-induced cholestasis through inhibition of 

the hepatocellular bile salt export pump of rat liver. 

Gastroenterol 118: 422, 2000. 

163. Moore J: ENABLE 1, 2: Bosentan did not improve 

HF symptoms. Today Cardiol 5:8, 2002. 

164. Archer SL, Michelakis ED: Phosphodiesterase type 

5 inhibitors for pulmonary arterial hypertension. N 

Engl J Med 361: 1864, 2009. 

165. Rosenblum WD: Pulmonary arterial hypertension. 

Pathobiology, diagnosis, treatment and emerging 

therapies. Cardiol in Rev 18: 58, 2010. 

165a. Schwartz BG, Kloner RA: Drug interactions with 

phosphodiesterase 5 inhibitors used for the treatment 

of erectile dysfunction or pulmonary hypertension. 

Circulation 122: 88, 2010. 

166. Galie N, Ghofrani HA, Torbicki A, et al: Sildenafil 

citrate therapy for pulmonary arterial hypertension. 

N Engl J Med 353: 2148, 2005. 

167. Rubin LJ, Badesch D, Fleming T, et al: Long-term 

treatment with sildenafil citrate in pulmonary arterial 

hypertension. Chest 134: 403S, 2008. 


167a. The Idiopathic Pulmonary Fibrosis Clinical Research 

Network: A controlled trial of sildenafil in 

advanced idiopathic pulmonary fibrosis. N Engl J 

Med 363: 620, 2010. 

168. Galie N, Brudage BH, Ghofrani HA, et al: Tadalafil 

therapy for pulmonary hypertension. Circulation 

119: 2894, 2009. 

169. Akagi S, Matsubara H, Miyaji K, et al: Additional 

effects of bosentan in patients with idio-pathic pulmonary 

arterial hypertension already treated with 

high-dose epoprostenolol. Circulation J 72: 1142, 

2008. 

170. Faruqi S, Fathi H, Morice AH: Combination of 

sitaxsentan and tadalafil for idiopathic pulmonary 

arterial hypertension following relapse on 

bosentan. Intl J Cardiol 2009 epub/171. Gruenig 

E, Michelakis E, Vachiery JL, et al: Acute hemodynamic 

effects of single-dose sildenafil when 

added to established bosentan therapy in patients 

with pulmonary arterial hypertension: results of 

the COMPASS-1 study. J Clin Pharmacol 49: 1343, 

2009. 

172. Hoeper MM, Leuchte H, Halank H, et al: Combining 

inhaled iloprost with bosentan in patients with 

idiopathic pulmonary arterial hypertension. Eur 

Respir J 28: 691, 2006. 

173. Humbert M, Barst RJ, Robbins IM, et al: Combination 

of bosentan with epoprostenolol in pulmonary 

arterial hypertension. Breathe-2. Eur Respir J 24: 

353, 2004. 

174. Mathai SC, Girgis RE, Risher MR, et al: Addition of 

sildenafil to bosentan monotherapy in pulmonary 

arterial hypertension. Eur Respir J 29: 469, 2007. 

175. Murthy SN, Nossaman BD, Kadowitz PJ: New approaches 

to the treatment of pulmonary hypertension. 

From bench to bedside. Cardiol in Rev 18: 76, 

2010. 

175a. Hingorany S, Frishman WH: Soluble guanylate cyclase 

activation with cinaciquat: a new approach to 

the treatment of decompensated heart failure. Cardiol 

in Rev 19: 2011 in press. 

176. Saji T, Nakayama T, Ishikita T, Matsuura H: Current 

status and future prospect of prostacyClin Therapy 

for pulmonary hypertension – intravenous, subcutaneous, 

inhaled and oral PGI2 derivatives. Nippon 

Rinsho 59: 1132, 2001.


Selective and Nonselective 

Dopamine-Receptor Agonists 


Chandrasekar Palaniswamy, MD 

1. Goldberg LI, Volkman PH, Kohli JD: A comparison 

of the vascular dopamine receptor with other 

dopamine receptors. Annu Rev Pharmacol Toxicol 

18:57, 1978. 

2. Goldberg LI, Kohli JD: Peripheral pre- and postsynaptic 

dopamine receptors: Are they different 

from dopamine receptors in the central nervous 

system? Commun Psychopharmacol 3:447, 1979. 

3. Goldberg LI, Kohli JD: Identification and characterization 

of dopamine receptors in the cardiovascular 

system. Cardiologia 32:1603, 1987. 

4. Berecek KH, Carey RM: Adrenergic and dopaminergic 

receptors and actions. In Izzo JL Jr., Sica 

DA, Black HR: Hypertension Primer 4th ed. Texas: 

American Heart Assn 2008: 39. 

5. Hampton JR, van Veldhuisen DJ, Kleber FX, et al: 

Randomised study of effect of ibopamine on survival 

in patients with advanced severe heart failure. 

Second Prospective Randomised Study of Ibopamine 

on Mortality and Efficacy (PRIME II) Investigators. 

Lancet 349:971, 1997. 

6. Francis GS: Receptor systems involved in norepinephrine 

release in heart failure: focus on dopaminergic 

systems. Clin Cardiol 18:I13, 1995. 

7. Lee MR: Dopamine and the kidney. Clin Sci (Colch) 

62:439, 1982. 

8. Lee MR: Dopamine and the kidney: Ten years on. 

Clin Sci (Colch) 84:357, 1993. 

9. Bertorello A, Aperia A: Regulation of Na + ,K + - 

ATPase activity in kidney proximal tubules: Involvement 

of GTP binding proteins. Am J Physiol 

256:F57, 1989. 

10. Felder CC, Campbell T, Albrecht F, Jose PA: Dopamine 

inhibits Na(+)-H+ exchanger activity in renal 

BBMV by stimulation of adenylate cyclase. Am 

J Physiol 259:F297, 1990. 

11. Felder CC, Albrecht FE, Campbell T, et al: cAMPindependent, 

G protein-linked inhibition of Na+/ 

H+ exchange in renal brush border by D1 dopamine 

agonists. Am J Physiol 264:F1032, 1993. 

12. Gesek FA, Schoolwerth AC: Hormonal interactions 

with the proximal Na(+)-H+ exchanger. Am J 

Physiol 258:F514, 1990. 

13. Carey RM: Renal dopamine system. Paracrine regulator 

of sodium homeostasis and blood pressure. 


14. Jose PA, Eisner GM, Felder RA: Role of dopamine 

in the pathogenesis of hypertension. Clin Exp 

Pharmacol Physiol Suppl 26:S10, 1999. 

15. Zeng C, Felder Ra, Jose PA: A new approach for 

treatment of hypertension: modifying D1 dopamine 

receptor function. Cardiovasc Hematol Agts 

Med Chem 4: 369, 2006. 

16. Shi Y, Zalewski A, Bravette B, et al: Selective dopamine-1 

receptor agonist augments regional myocardial 

blood flow: Comparison of fenoldopam and 

dopamine. Am Heart J 124:418, 1992. 

17. Murphy MB, Vaughn CJ: Dopamine. In: Messerli 

FH (ed). Cardiovascular Drug Therapy. Philadelphia: 

WB Saunders, 1996:1162–1166. 

18. Lokhandwala MF, Barrett RJ: Cardiovascular dopamine 

receptors: Physiological, pharmacological 

and therapeutic implications. J Auton Pharmacol 

2:189, 1982. 

19. Lokhandwala MF, Hegde SS: Cardiovascular pharmacology 

of adrenergic and dopaminergic receptors: 

Therapeutic significance in congestive heart 

failure. Am J Med 90:2S, 1991. 

20. Carey RM: Dopamine, hypertension and the potential 

for agonist therapy. In: Laragh JG, Brenner 

BB, eds. Hypertension Pathophysiology, Diagnosis 

and Management, 2nd ed. New York: Raven Press, 



26-1


1995: 2937–2952. 

21. Haeusler G, Lues I, Minck KO, et al: Pharmacological 

basis for antihypertensive therapy with a novel 

dopamine agonist. Eur Heart J 13(Suppl D):129, 

1992. 

22. van Veldhuisen DJ, Girbes AR, de Graeff PA, Lie 

KI: Effects of dopaminergic agents on cardiac and 

renal function in normal man and in patients with 

congestive heart failure. Int J Cardiol 37:293, 1992. 

23. Kellum JA, Decker JM: Use of dopamine in acute 

renal failure: A meta-analysis. Crit Care Med 

29:1526, 2001. 

24. Bellomo R, Chapman M, Finfer S, et al: Low dose 

dopamine in patients with early renal dysfunction: 

A placebo-controlled randomized trial. Australian 

and New Zealand Intensive Care Society (ANZICS) 

Clinical Trials Group. Lancet 356:2139, 2000. 

25. Lassnigg A, Donner E, Grubhofer G, et al: Lack of 

renoprotective effects of dopamine and furosemide 

during cardiac surgery. J Am Soc Nephrol 11(1):97, 

2000. 

25a. Murphy MB, Murray C, Shorten GD: Fenoldopam: 

A selective peripheral dopamine receptor agonist. 

N Engl J Med 345:1548, 2001. 

26. Pilmer BL, Green JA, Panacek EA, et al: Fenoldopam 

mesylate versus sodium nitroprusside in the 

acute management of severe systemic hypertension. 


27. Blanchett DG, Green JA, Nara A, et al: The effect of 

food on pharmacokinetics and pharmacodynamics 

of fenoldopam in class III heart failure. Clin Pharmacol 

Ther 49:449, 1991. 

28. Clancy A, Locke-Haydon J, Cregeen RJ, et al: Effect 

of concomitant food intake on absorption kinetics 

of fenoldopam (SK&F 82526) in healthy volunteers. 


29. Mansoor GA, Frishman WH: Comprehensive 

management of hypertensive emergencies and urgencies. 

Heart Disease 4:358, 2002. 

29a. Phillips RA, Greenblatt J, Krakoff LR: Hypertensive 

emergencies: Diagnosis and management. Prog 


30. Abdelwahab W, Frishman W, Landau A: Management 

of hypertensive urgencies and emergencies. J 


31. Rhoney D, Peacock WF: Intravenous therapy for 

hypertensive emergencies. Part 1. Am J Health Syst 

Pharm 66: 1343, 2009. 

32. Elliott WJ: Clinical features in the management of 

selected hypertensive emergencies. Prog Cardiovasc 

Dis 48: 316, 2006. 

33. Calhoun DA: Hypertensive crisis. In Oparil S, Weber 

MA: Hypertension: a Companion to Brenner 

and Rector’s “The Kidney”. Philadelphia: Saunders 

2000: 715. 

34. Katakam R, Townsend RR: Hypertensive emergencies. 

In Antman EM: Cardiovascular Therapeutics 

3rd ed. Philadelphia: Saunders/Elsevier, 2007, 666. 

35. Oparil S, Aronson S, Deeb GM, et al: Fenoldopam: 

A new parenteral antihypertensive. Consensus 

round table on the management of perioperative 

hypertension and hypertensive crises. Am J Hypertens 

12:653, 1999. 

36. Rodriguez MA, Kumar SK, DeCaro M: Hypertensive 

crisis. Cardiol in Rev 18: 102: 2010. 

37 Munger MA, Rutherford WF, Anderson L, et al: 

Assessment of intravenous fenoldopam mesylate in 

the management of severe systemic hypertension. 

Crit Care Med 18:502, 1990. 

38. Panacek EA, Bednarczyk EM, Dunbar LM, et al: 

Randomized, prospective trial of fenoldopam vs 

sodium nitroprusside in the treatment of acute severe 

hypertension. Fenoldopam Study Group. Acad 

Emerg Med 2:959, 1995. 

39. Post JB, Frishman WH: Fenoldopam: a new dopamine 

agonist for the treatment of hypertensive 

urgencies and emergencies. J Clin Pharmacol 38:2, 

1998. 

40. Tumlin JA, Dunbar LM, Oparil S, et al: Fenoldopam, 

a dopamine agonist, for hypertensive emergency: A 

multicenter randomized trial. Fenoldopam Study 

Group. Acad Emerg Med 7:653, 2000. 

41. Murphy MB, McCoy CE, Weber RR, et al: Augmentation 

of renal blood flow and sodium excretion 

in hypertensive patients during blood pressure 

reduction by intravenous administration of the dopamine-1 

agonist fenoldopam. Circulation 76:1312, 

1987. 

42. Shusterman NH, Elliott WJ, White WB: Fenoldopam, 

but not nitroprusside, improves renal function 

in severely hypertensive patients with impaired 

renal function. Am J Med 95:161, 1993. 

43. Elliott WJ, Karnezis TA, Silverman RA, et al: Intraocular 

pressure increases with fenoldopam, but not 

nitroprusside, in hypertensive humans. Clin Pharmacol 

Ther 49:285, 1991. 

44. Everitt DE, Boike SC, Piltz-Seymour JR, et al: Effect 

of intravenous fenoldopam on intraocular pressure 

in ocular hypertension. J Clin Pharmacol 37:312, 

1997. 

45 Kini A, Mitre C, Kamran M, et al: Changing trends 

in incidence and predictors of radiographic contrast 

nephropathy after percutaneous coronary intervention 

with use of fenoldopam. Am J Cardiol 

89:999, 2002. 

46. Tumlin JA, Wang A, Murray PT, Mathur VS: 

Fenoldopam mesylate blocks reductions in renal 

plasma flow after radiocontrast dye infusion: A pi-

lot trial in the prevention of contrast nephropathy. 

Am Heart J 143:894, 2002. 

47. Teirstein PS, Price MJ, Mathur VS, et al: Differential 

effects between intravenous and targeted 

renal delivery of fenoldopam on renal function 

and blood pressure in patients undergoing cardiac 

catheterization. Am J Cardiol 97: 1076, 2006. 

48. Weisz G, Filby SJ, Cohen MG, et al: Safety and performance 

of targeted renal therapy: the Be-RITe! 

Registry. J Endovasc Ther 16:1, 2009. 

49. Gilbert TB, Hasnain JU, Flinn WR, et al: Fenoldopam 

infusion associated with preserving renal 

function after aortic cross-clamping for aneurysm 

repair. J Cardiovasc Pharmacol Ther 6:31, 2001. 

50. Barr LF, Kolodner K: N-acetylcysteine and fenoldopam 

protect the renal function of patients with 

chronic renal insufficiency undergoing cardiac surgery. 

Crit Care Med 36: 1427, 2008. 

51. Roasio A, Lobreglio R, Santin A, et al: Fenoldopam 

reduces the incidence of renal replacement therapy 

after cardiac surgery. J Cardiothorac Vasc Anesth 

22: 23, 2008. 

52. Cogliati AA, Vellutini R, Nardini A, et al: Fenoldopam 

infusion for renal protection in high-risk cardiac 

surgery patients: a randomized clinical study. J 

Cardiothorac Vasc Anesth 21: 847, 2007. 

53. Meco M, Cirri S: Effects of fenoldopam mesylate 

on central hemodynamics and renal flow in patients 

undergoing cardiac surgery: color Doppler 

echocardiographic evaluation. J Cardiothorac Vasc 

Anesth 24: 58, 2010. 

54. Bove T, Landoni G, Calabro MG, et al: Renoprotective 

action of fenoldopam in high-risk patients 

undergoing cardiac surgery: a prospective, doubleblind, 

randomized clinical trial. Circulation 111: 

3230, 2005. 


55. Shepherd AMM: Nitrates, dopamine agonists, potassium 

channel openers, and serotonic-related 

agents. In Izzo JL Jr, Sica DA, Black HR: Hypertension 

Primer 4th ed. Dallas: American Heart Assn 

2008: 472. 

56. Quinn N, Illas A, Lhermitte F, Agid Y: Bromocriptine 

in Parkinson’s disease: A study of cardiovascular 

effects. J Neurol Neurosurg Psychiatry 44:426, 

1981. 

57. Walden RJ, Hernandez J, Bhattacharjee P, et al: Bromocriptine 

in the treatment of hypertension. Eur J 


58. Lahlou S, Duarte GP, Demenge P: Central dopaminergic 

origin of bromocriptine induced tachycardia 

in normotensive rats. Cardiovasc Res 27:2022, 

1993. 

59. Eickman FM: Recurrent myocardial infarction in a 

postpartum patient receiving bromocriptine. Clin 

Cardiol 15:781, 1992. 

60. Kuznar W: Timed dopamine agonist therapy reduced 

cardiovascular events in type 2 diabetes. 

Cardiology Today September 2007: 20. 

60a. Bromocriptine (Cycloset) for type 2 diabetes. The 

Med Ltr 52: 97, 2010. 

60b. Scranton R, Cincotta A: Bromocriptine- unique 

formulation of a dopamine agonist for the treatment 

of type 2 diabetes. Expert Opin Pharmacother 

11: 269, 2010. 

60c. Gaziano JM, Cincotta AH, O’Connor CM, et al: 

Randomized clinical trial of quick-release bromocriptine 

among patients with type 2 diabetes on 

overall safety and cardiovascular outcomes. Diabetes 

Care 33: 1503, 2010. 

61. Carmoxirole. In: Messerli FH, ed. Cardiovascular 

Drug Therapy, 2nd ed. Philadelphia: Saunders, 

1996:1189.


Natriuretic Peptides 

Nesiritide 



1. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg 

H: A rapid and potent natriuretic response to intravenous 

injection of atrial myocardial extract in 

rats. Life Sci 28: 89, 1981. 

2. de Bold AJ, Raymond JJ, Bencosme SA: Atrial specific 

granules of the rat heart : light microscopic 

staining and histochemical reactions. Histochem 

Cytochem 26: 1094, 1978. 

3. Garcia R, Cantin M, Thibault G, et al: Relationship 

of specific granules to the natriuretic and diuretic 

activity of rat atria. Experientia 38: 1071, 1982. 

4. Sudoh T, Kangawa K, Minamino N, Matsuo H: A 

new natriuretic peptide in porcine brain. Nature 

332: 78, 1988. 

5. Hosoda K, Nakao K, Mukoyama M, et al: Expression 

of brain natriuretic peptide gene in human 

heart: production in the ventricle. Hypertension 17: 

1152, 1991. 

6. Sudoh I, Minamino N, Kangawa K, Matsuo H: Ctype 

natriuretic peptide (NP): a new member of natriuretic 

peptide family identified in porcine brain. 

Biochem Biophy Res Commun 168: 863, 1990. 

7. Wong SK, Garbers DL. Receptor guanylyl cyclases. 

J Clin Invest 1992;90(2):299-305. 

8. Cheng JWM: Nesiritide: a review of clinical pharmacology 

and role in heart failure management. 

Heart Dis 4: 199, 2002. 

9. Achilihu G, Frishman WH, Landau A: Neutral endopeptidase 

inhibitors and atrial natriuretic peptide. 

J Clin Pharmacol 31: 758, 1991. 

10. Tsukamoto O, Fujita M, Kato M, et al: Natriuretic 

peptides enhance the production of adiponectin 

in human adipocytes and in patients with chronic 

heart failure. J Am Coll Cardiol 53: 2070, 2009. 

11. Colucci WS, Elkayan U, Horton SP, et al. Intravenous 

nesiritide, a natriuretic peptide, in the treat- 

ment of decompensated congestive heart failure. N 

Engl J Med 343:246, 2000. 

12. Abraham WT, Cheng ML, Smoluk G for the 

VMAC Study Group: Clinical and hemodynamic 

effects of nesiritide (B-type natriuretic peptide) in 

patients with decompensated heart failure receiving 

beta blockers. Congest Heart Fail 11: 59, 2005. 

13. Frishman WH, Nawarskas J, Rajan V, Sica DA: 

Vasopeptidase inhibitors: neutral endopeptidase 

inhibitors and dual inhibitors of angiotensin converting 

enzyme and neutral endopeptidase. In 

Frishman WH, Sonnenblick EH, Sica DA (eds): 

Cardiovascular Pharmacotherapeutics 2nd ed. New 

York: McGraw Hill 2003: 813. 

14. Nawarskas J, Anderson JR: Omapatrilat: a unique 

new agent for the treatment of cardiovascular disease. 

Heart Dis 2: 266, 2000. 

15. Cowie MR, Mendez GF: BNP and congestive heart 

failure. Prog Cardiovasc Dis 44: 293, 2002. 

16. Rubattu S, Sciarretta S, Valenti V, et al: Natriuretic 

peptides: an update on bioactivity, potential therapeutic 

use, and implication in cardiovascular diseases. 

Am J Hypertens 21: 733, 2008. 

17. Burger AJ, Horton DP, Elkayam U, et al. Nesiritide 

is not associated with proarrhythmic effects of dobutamine 

in the treatment of decompensated CHF: 

The PRECEDENT study. J Card Fail 5 (suppl 1):49, 

1995. 

18. Burger AJ, Horton DP, Elkayam U, et al. Evidence 

of ventricular ectopy at baseline is not predictive 

of the proarrhythmic effects of dobutamine in the 

treatment of decompensated CHF: The PRECE- 

DENT study. J Card Fail;6 (suppl 2):46, 2000. 

19. Elkayam U, Silver MA, Burger AJ, Horton DP. The 

effect of short-term therapy with nesiritide (B-type 

natriuretic peptide) or dobutamine on long-term 



27-1


survival. J Card Fail 6 (suppl 2):45, 2000. 

19a. Abraham WT, Trupp RJ, Jarjoura D: Nesiritide in 

acute decompensated heart failure: a pooled analysis 

of randomized controlled trials. Clin Cardiol 33: 

484, 2010. 

20. Silver MA, Horton DP, Ghali JK, Elkayam U: Effect 

of nesiritide versus dobutamine on short-term 

outcomes in the treatment of patients with acute 

decompensated heart failure. J Am Coll Cardiol 39: 

798, 2002. 

21. Hernandez AF, O’Connor CM, Starling RC, et al: 

Rationale and design of the Acute Study of Clinical 

Effectiveness of Nesiritide in Decompensated 

Heart Failure trial (ASCEND-HF). Am Heart J 157: 

271, 2009. 

22. Ezekowitz JA, Hernandez AF, Starling RC, et al: 

Standardizing care for acute decompensated heart 

failure in a large megatrial: the approach for the 

Acute Studies of Clinical Effectiveness of Nesiritide 

in Subjects with Decompensated Heart Failure 

(ASCEND-HF). Am Heart J 157: 219, 2009. 

22a. AHA News Release: Large study of patients with 

severe heart failure confirms nesiritide safe, but 

shows no significant benefit on symptoms or mortality. 

American Heart Association Scientific Sessions, 

Chicago, Ill., November 14, 2010. 

22b. George I, Xydas S, Klotz S, et al: Long-term effects 

of B-type natriuretic peptide infusion after acute 

myocardial infarction in a rat model. J Cardiovasc 

Pharmacol 55: 14, 2010. 

23. Sackner-Bernstein JD, Skopicki HA, Aaronson KD: 

Risk of worsening renal function with nesiritide in 

patients with acutely decompensated heart failure. 

Circulation 111: 1487, 2005. 

24. Lewicki JA, Protter AA: Physiologic studies of the 

natriuretic peptide family. In Laragh JH, Brenner 

BM (eds): Hypertension: Pathophysiology, Diagnosis 

and Management 2nd ed. New York: Raven Press 

1995: 1029. 

25. Elkayam U, Silver MA, Burger AJ, et al. Limitations 

of commonly used titrated doses of intravenous nitroglycerin 

in patients with acute decompensated 

heart failure. J Card Fail 7:Suppl 2: 12, 2001. 

26. Givertz MM, Stevenson LW, Colucci WS: Strategies 

for management of decompensated heart failure. 

In Antman EM (ed) Cardiovascular Therapeutics. 

A Companion to Braunwald’s Heart Disease 3rd ed. 

Philadelphia: Saunders, 2007: 385. 

27. Wang DJ, Dowling TC, Meadows D, et al: Nesiritide 

does not improve renal function in patients 

with chronic heart failure and worsening serum 

creatinine. Circulation 110: 1620, 2004. 

28. Michaels AD, Chatterjee K, DeMarco T: Effects of 

intravenous nesiritide on pulmonary vascular he- 

modynamics in pulmonary hypertension. J Card 

Fail 11: 425, 2005. 

29. Leyh RG, Kofidis T, Struber M, et al: Methylene 

blue: the drug of choice for catecholamine-refractory 

vasoplegia after cardiopulmonary bypass? J 

Thorac Cardiovasc Surg 125: 1426, 2003. 

30. Yancy CW, Saltzberg MT, Berkowitz RL, et al: Safety 

and feasibility of using infusions of nesiritide for 

heart failure in an outpatient setting (from the FU- 

SION 1 Trial). Am J Cardiol 94: 595, 2004. 

31. Yancy CW, Singh A: Potential applications of outpatient 

nesiritide infusions in patients with advanced 

heart failure and concomitant renal insufficiency 

(from the Follow-Up Serial Infusions of Nesiritide 

(FUSION 1) trial. Am J Cardiol 98: 226, 2006. 

32. Yancy CW, Krum H, Massie BM, et al for the FU- 

SION II investigators: Safety and efficacy of outpatient 

nesiritide in patients with advanced heart 

failure. Results of the Second Follow Up Serial Infusions 

of Nesiritide (FUSION II) trial. Circ Heart 

Fail 1: 9, 2008. 

33. Peacock WF, Holland R, Gyarmathy R, et al: Observation 

unit treatment of heart failure with nesiritide: 

results from the Proaction Trial. J Emerg 

Med 29: 243, 2005. 

34. Kragelund C, Grønning B, Køber L, et al: N-terminal 

pro-B-type natriuretic peptide and long-term 

mortality in stable coronary heart disease. N Engl J 

Med 352: 666, 2005. 

35. de Lemos JA, McGuire DK, Drazner MH: B-type 

natriuretic peptide in cardiovascular disease. Lancet 

362: 316, 2003. 

36. Wang TJ, Larson MG, Levy D, et al: Plasma natriuretic 

peptide levels and the risk of cardiovascular 

events and death. N Engl J Med 350: 655, 2004. 

37. Mueller C, Scholer A, Laule-Kilian K, et al: Use of 

B-type natriuretic peptide in the evaluation and 

management of acute dyspnea. N Engl J Med 350: 

647, 2004. 

38. Shadman R, Allison MA, Criqui MH: Glomerular 

filtration rate and N-terminal pro-brain natriuretic 

peptide as predictors of cardiovascular mortality in 

vascular patients. J Am Coll Cardiol 49: 2172, 2007. 

39. Bergler-Klein J, Mundigler G, Pibarot P, et al: Btype 

natriuretic peptide in low-flow, low-gradient 

aortic stenosis. Relationship to hemodynamics 

and clinical outcome: results from the Multicenter 

Truly or Pseudo-Severe Aortic Stenosis (TOPAS) 


40. Bibbins-Domingo K, Gupta R, Na B, et al: Nterminal 

fragment of the prohormone brain-type 

natriuretic peptide (NT-ProBNP), cardiovascular 

events, and mortality in patients with stable coronary 

heart disease. JAMA 297: 169, 2007.

41. Mutlu B, Bayrak F, Kahveci G, et al: Usefulness of 

N-terminal pro-B-type natriuretic peptide to predict 

clinical course in patients with hypertrophic 

cardiomyopathy. Am J Cardiol 98: 1504, 2006. 

42. Bernus A, Wagner BD, Accurso F, et al: Brain natriuretic 

peptide levels in managing pediatric patients 

with pulmonary arterial hypertension. Chest 135: 

745, 2009. 

43. Jarai R, Fellner B, Haoula D, et al: Early assessment 

of outcome in cardiogenic shock: relevance of plasma 

N-terminal pro-B-type natriuretic peptide and 

interleukin-6 levels. Crit Care Med 37: 1837, 2009. 

44. Sodeck G, Domanovits H, Schillinger M, et al: Preoperative 

N-terminal pro-brain natriuretic peptide 

predicts outcome in type A aortic dissection. J Am 

Coll Cardiol 51: 1092, 2008. 

45. Battaglia M, Pewsner D, Jüni P, et al: Accuracy of Btype 

natriuretic peptide tests to exclude congestive 

heart failure. Arch Intern Med 166: 1073, 2006. 

46. Shapiro BP, Chen HH, Burnett JC Jr., Redfield MM: 

Use of plasma brain natriuretic peptide concentration 

to aid in the diagnosis of heart failure. Mayo 

Clin Proc 78: 481, 2003. 

47. Januzzi JL Jr., Camargo CA, Anwaruddin S, et al: 

The N-terminal pro-BNP Investigation of Dyspnea 

in the Emergency Department (PRIDE) study. Am 

J Cardiol 95: 948, 2005. 

48. Maisel AS, McCord J, Nowak RM, et al for the 

Breathing Not Properly Multinational Study Investigators: 

Bedside B-type natriuretic peptide in the 

emergency diagnosis of heart failure with reduced 

or preserved ejection fraction. J Am Coll Cardiol 

41: 2010, 2003. 


49. Nicholls MG, Obineche EN, Frampton CM, Richards 

AM: Plasma cardiac natriuretic peptide levels 

in screening for cardiac disease. Am J Med 116: 561, 

2004. 

50. Wazni OM, Martin DO, Marrouche NF, et al: Plasma 

B-type natriuretic peptide levels predict postoperative 

atrial fibrillation in patients undergoing 

cardiac surgery. Circulation 110: 124, 2004. 

51. Krüger S, Graf J, Merx MW, et al: Brain natriuretic 

peptide predicts right heart failure in patients with 

acute pulmonary embolism. Am Heart J 147: 60, 

2004. 

52. Bhalla MA, Chiang A, Epshteyn VA, et al: Prognostic 

role of B-type natriuretic peptide levels in 

patients with type 2 diabetes mellitus. J Am Coll 

Cardiol 44: 1047, 2004. 

53. Siriwardena M, Kleffmann T, Ruygrok P, et al: Btype 

natriuretic peptide signal peptide circulates in 

human blood. Evaluation as a potential biomarker 

of cardiac ischemia. Circulation 122: 255, 2010. 

53a. Lam LL, Camerson PA, Schneider HG: Meta analysis: 

effect of B-type natriuretic peptide testing on 

clinical outcomes in patients with acute dyspnea in 

the emergency setting. Ann Intern Med 153: 728, 

2010. 

54. Pfisterer M, Buser P, Rickli H, et al for the TIME- 

CHF Investigators: BNP-guided vs symptom-guided 

heart failure therapy. The Trial of Intensified vs 

Standard Medical Therapy in Elderly Patients with 

Congestive Heart Failure (TIME-CHF) randomized 

trial. JAMA 301: 383, 2009.


Vasopressin and Vasopressin Receptor Antagonists 


Marc Klapholz, MD 

Gerard Oghlakian, MD 

Jacqueline M. Cook, MD 

1. Sachs H: Biosynthesis and release of vasopressin. 

Am J Med 1967; 42: 687-700. 

2. Cowley JF, Ausello DA: Vasopressin Cellular and 

Integrative Functions. Raven Press, New York: 

1988. 

3. Schrier RW: Vasopressin. Raven Press, New York: 

1985. 

4. Schrier RW, Cadnapaphornchai MA, Umenishi F: 

Water-losing and water-retaining states: role of water 

channels and vasopressin receptor antagonists. 

Heart Disease 3: 210, 2001. 

5. Manning M, Sawyer W: Discovery, development, 

and some uses of vasopressin and oxytocin antagonists. 

J Lab Clin Med 1989; 114: 617-32. 

6. Robertson GL, Harris A: Clinical use of vasopressin 

analogues. Hosp Prac 1989; 24: 114-133. 

7. Maggi M, Fantoni G, Peri A, et al: Steroid modulation 

of oxytocin/vasopressin receptors in the uterus. 

J Steroid Biochem Molec Biol 1991; 40: 481-91. 

8. deKeyzer Y, Auzan C, Lenne F, et al: Cloning and 

characterization of the human V3 pituitary vasopressin 

receptors. FEBS Lett 1994; 345: 215-20. 

9. Fahrenholz F, Jurzak M, Gerstberger R, Haase W: 

Renal and central vasopressin receptors: immunocytochemical 

localization. Ann NY Acad Sci 1993; 

689: 194-206. 

10. Phillips M: Functions of angiotensin in the central 

nervous system. Ann Rev Physiol 1987; 549: 

413-35. 

11. McKinley MJ, Congiu M, Denton DA, et al: The 

anterior wall of the third cerebral ventricle and homeostatic 

responses to dehydration. J Physiol-Paris 

1984; 79: 421-27. 

12. Zeisberger E: The role of septal peptides in thermoregulation 

and fever. In Bligh J, Voigt K (eds): 

Thermoreception and Temperature Regulation. 

Springer Verlag, Berlin: 1990; 273. 

13. Stehle J, Reuss S, Riemann R, et al: The role of arginine 

vasopressin for pineal melatonin synthesis in 

the rat: involvement of vasopressinergic receptors. 

Neurosci Ltrs 1991; 123: 131-34. 

14. Kasting NW: Criteria for establishment of a physiological 

role for brain peptides. A case in point: the 

role of vasopressin in thermoregulation during fever 

and antipyresis. Brain Res Rev 1989; 14: 143-53. 

15. Meisenberg G, Simmons WH: Hypothermia induced 

by centrally administered vasopressin in 

rats. A structure-activity study. Neuropharmacol 

1984; 23: 1195-1200. 

16. Whitnall MH: Stress selectively activates the vasopressin-containing 

subset of corticotropin-releasing 

hormone neurons. Neuroendocrin 1989; 50: 

702-07. 

17. Gibbs DM: Vasopressin and oxytocin: hypothalamic 

modulators of the stress response. A review. 

Psychoneuroendocrin 1986; 11: 131-39. 

18. Diamant M, DeWied D: Differential effects of centrally 

injected AVP on heart rate, core temperature 

and behavior in rats. Am J Physiol 1993; 264: 

R51-61. 

19. Cowley AW, Cushman WC, Quillen EW, et al: Vasopressin 

elevation in essential hypertension and 

increased responsiveness to sodium intake. Hypertension 

1981; 3 (3 Pt 2): I93-100. 

20. Mohring J, Glanzer K, Maciel JA Jr., et al: Greatly 

enhanced pressor response to antidiuretic hormone 

in patients with impaired cardiovascular reflexes 

due to idiopathic orthostatic hypotension. J 

Cardiovasc Pharmacol 1980; 2: 367-76. 

21. Andrews CE, Brenner BM: Relative contributions 

of arginine vasopressin and angiotensin II to maintenance 

of systemic arterial pressure in the an- 



28-1


aesthetized water deprived rat. Circ Res 1981; 48: 

254-58. 

22. Woods RL, Johnston CI: Contribution of vasopressin 

to the maintenance of blood pressure during 

dehydration. Am J Physiol 1983; 245 (5 Pt. 1): 

F615-21. 

23. McNeill JR, Stark RD, Greenway CV: Intestinal 

vasoconstriction after hemorrhage: roles of vasopressin 

and angiotensin. Am J Physiol 1970; 219: 

1342-47. 

24. Laszlo FA, Laszlo F Jr., deWied D: Pharmacology 

and clinical perspectives of vasopressin antagonists. 

Pharmacol Rev 1991; 43: 73-108. 

25. Bichet D, Szatalowicz V, Chaimovitz C, Schrier 

RW: Role of vasopressin in abnormal water excretion 

in cirrhotic patients. Ann Intern Med 1982; 96: 

413-17. 

26. Tsuboi Y, Ishikawa S, Fujisawa G, et al: Therapeutic 

efficacy of the non-peptide AVP antagonist 

OPC 31260 in cirrhotic rats. Kidney Intl 1994; 46: 

237-44. 

27. Gueugniaud P-Y, David J-S, Chanzy E, et al: Vasopressin 

and epinephrine vs epinephrine alone in 

cardiopulmonary resuscitation. N Engl J Med 359: 

21, 2008. 

28. Barrett LK, Singer M, Clapp LH: Vasopressin: 

mechanisms of action on the vasculature in health 

and in septic shock. Crit Care Med 35: 33, 2007. 

29. Annane D: Vasopressin plus corticosteroids: the 

shock duo!. Crit Care Med 37: 1126, 2009. 

30. Oghlakian G, Klapholz M: Vasopressin and vasopressin 

receptor antagonists in heart failure. Cardiol 

in Rev 17: 10, 2009. 

31. Freeman JG, Cobden I, Lishman AH, Record CO: 

Controlled trial of terlipressin (glypressin) versus 

vasopressin in the early treatment of oesophageal 

varices. Lancet 1982; 2: 66-68. 

32. Kelsch T, Kikuchi K, Vahdat S, Frishman WH: 

Innovative pharmacologic approaches to cardiopulmonary 

resuscitation. Heart Disease 3: 46-54, 

2001. 

33. Wenzel V, Lindner KH, Krismer AC, et al: Repeated 

administration of vasopressin but not epinephrine 

maintains coronary perfusion pressure after 

early and later administration during prolonged 

cardiopulmonary resuscitation in pigs. Circulation 

99: 1379, 1999. 

34. Scharte M, Meyere J, Vanakin H, et al: Hemodynamic 

effects of terlipressin (a synthetic analog of 

vasopressin) in healthy and endotoxemic sheep. 

Crit Care Med 29: 1756, 2001. 

35. Ryckwaert F, Virsolvy A, Fort A, et al: Terlipressin, a 

provasopressin drug exhibits direct vaso-constrictor 

properties: consequences on heart perfusion 

and performance. Crit Care Med 37: 876, 2009. 

36. Chase LR, Aurbach GD: Renal adenyl cyclase: anatomically 

separate sites for parathyroid hormone 

and vasopressin. Science 1968; 159: 545-47. 

37. Butlen D, Guillon G, Rajerison RM, et al: Structural 

requirements for activation of vasopressinsensitive 

adenylate cyclase, hormone binding, and 

anti-diuretic actions: effects of highly potent analogues 

and competitive inhibitors. Molec Pharmacol 

1978; 14: 1006-17. 

38. Aiyar N, Nambi P, Stassen FL, Crooke ST: Vascular 

vasopressin receptors mediate phosphatidylinositol 

turnover and calcium efflux in an established 

smooth muscle cell line. Life Sci1986; 39: 37-45. 

39. Kelly JM, Abrahams JM, Phillips PA, et al: [ 125 I]- 

[d(CH 2 ) 3 , Sar 7 ] AVP: Selective radioligand for V1 

vasopressin receptors. J Recep Res 1989; 9: 27-41. 

40. Marchingo AJ, Abrahams JM, Woodcock EA, et al: 

Properties of [ 3 H] 1-desamino-8-D-arginine vasopressin 

as a radioligand for vasopressin V2 receptors 

in rat kidney. Endocrinol 1988; 122: 1328. 

41. Antoni FA: Receptors mediating the CRH effects of 

vasopressin and oxytocin. Ann NY Acad Sci 1987; 

512: 195-204. 

42. Baertschi AJ, Friedli M: A novel type of vasopressin 

receptor on anterior pituitary corticotrophs. Endocrinol 

1985; 116: 499-502. 

43. Nambi P, Whitman M, Gessner G, et al: Vasopressin-mediated 

inhibition of atrial natriuretic factorstimulated 

cGMP accumulation in an established 

smooth muscle cell line. Proc Natl Acad Sci USA 

1986; 83: 8492-95. 

44. Jard S, Lombard C, Marie J, Devilliers G: Vasopressin 

receptors from cultured mesangial cells resemble 

V1a type. Am J Physiol 1987; 253: F41-49. 

45. Morel A, O’Carroll AM, Brownstein MJ, Lolait 

SJ: Molecular cloning and expression of a rat V1a 

arginine vasopressin receptor. Nature 1992; 356: 

523-26. 

46. Thibonnier M: Signal transduction of V1-vascular 

vasopressin receptors. Reg Peptides 1992; 38: 1-11. 

47. Nabika T, Velletri PA, Lovenberg W, Beaven MA: 

Increase in cytosolic calcium and phosphoinositide 

metabolism induced by angiotensin II and [arg] 

vasopressin in vascular smooth muscle cell. J Biol 

Chem 1985; 260: 4661-70. 

48. Tahara A, Tomura Y, Wada K, et al: Effect of YM087, 

a potent nonpeptide vasopressin antagonist, on 

vasopressin-induced hyperplasia and hypertrophy 

of cultured vascular smooth-muscle cells. J Cardiovasc 

Pharmacol 1997; 30(6):759-66. 

49. Tahara A, Saito M, Tsukada J, et al: Vasopressin 

increases vascular endothelial growth factor secretion 

from human vascular smooth muscle cells.

Eur J Pharmacol 1999; 26: 89-94. 

50. Tahara A, Tomura Y, Wada K, et al: Effect of 

YM087, a potent nonpeptide vasopressin antagonist, 

on vasopressin-induced protein synthesis in 

neonatal rat cardiomyocyte. Cardiovase Res 1998; 

38(1): 198-205. 

51. Maggi M, Baldi E, Genazzani AD, et al: Vasopressin 

receptors in human seminal vesicles: identification, 

pharmacologic characterization, and comparison 

with the vasopressin receptors present in the human 

kidney. J Androl 1989; 10: 393-400. 

52. Liard JF: Peripheral vasodilatation induced by a 

vasopressin analogue with selective V2-agonism in 

dogs. Am J Physiol 1989; 256: H1621-26. 

53. Lolait SJ, O’Carroll AM, McBride OW, et al: Cloning 

and characterization of a vasopressin V2 receptor 

and possible link to nephrogenic diabetes 

insipidus. Nature 1992; 357: 336-39. 

54. Lolait SJ, O’Carroll AM, Mahan LC, et al: Extrapituitary 

expression of the rat V1b vasopressin receptor 

gene. Proc Natl Acad Sci USA 1995; 92: 6783-87. 

55. Chang WY, Wo NC, Stoev S, et al: Discovery of 

novel selective hypotensive vasopressin peptides. 

A new vasodilating vasopressin receptor? Adv Exp 

Med Biol 1998; 449: 451-53. 

56. Kumar R: Endocytosis of the vasopressin receptor. 

Seminars Nephrol 1994; 14: 357-67. 

57. Cowley AW, Liard JF: Cardiovascular actions of vasopressin. 

In, Gash DM, Boer GJ (eds): Vasopressin: 

Principles and Properties. Plenum: New York, 

1987: 389. 

58. Imaizumi T, Thames MD: Influence of intravenous 

and intracerebroventricular vasopressin on baroreflex 

control of renal nerve traffic. Circ Res 1986; 58: 

17-25. 

59. Masaki H, Imaizumi T, Harada S, et al: Effects of a 

novel orally effective V1-receptor antagonist OPC 

21268, on AVP-induced sympathoinhibition. Am J 

Physiol 1993; 264: R1089-94. 

60. Abboud FM, Aylward PE, Floras JS, Gupta BN: 

Sensitization of aortic and cardiac baroreceptors by 

arginine vasopressin in mammals. J Physiol 1986; 

377: 251-65. 

61. Undesser KP, Hasser EM, Haywood JR, et al: Interactions 

of vasopressin with the area postrema 

in arterial baroreflex function in conscious rabbits. 

Circ Res 1985; 56: 410-17. 

62. Hasser EM, Bishop VS: Reflex effect of vasopressin 

after blockade of V1 receptors in the area postrema. 

Circ Res 1990; 67: 265-71, 1990. 

63. Suzuki S, Takeshita A, Imaizumi T, et al : Central 

nervous system mechanisms involved in inhibition 

of renal sympathetic nerve activity induced by arginine 

vasopressin. Circ Res 1989; 65: 1390-99. 


64. Malpas SC, Coote JH: Role of vasopressin in sympathetic 

response to paraventricular nucleus stimulation 

in anesthetized rats. Am J Physiol 1994; 266: 

R228-36. 

65. Brooks VL, Osborn JW: Hormonal-sympathetic 

interactions in long-term regulation of arterial 

pressure: a hypothesis. Am J Physiol 1995; 268: 

R1343-58. 

66. Luk A, Ajaelo I, Wong V, et al: Role of V1 receptors 

in the action of vasopressin in the baroreflex control 

of heart rate. Am J Physiol 1993; 265: R524-29. 

67. Ebert TJ, Cowley AW, Skelton M: Vasopressin reduces 

cardiac function and augments cardiopulmonary 

baroreflex resistance increases in man. J 

Clin Invest 1986; 77: 1136. 

68. Unger T, Rohmeiss P, Demmert G, et al: Differential 

modulation of the baroreceptor reflex by brain 

and plasma vasopressin. Hypertension 1986; 8 

(Suppl II): II-157-62. 

69. Sampey DB, Burrell LM, Widdop RE: Vasopressin 

V2 receptor enhances gain of baroreflex in 

conscious spontaneously hypertensive rats. Am J 

Physiol 1999; 276 (3 Pt 2): R872-79. 

70. Hegarty AA, Felder RB: Antagonism of vasopressin 

V1 receptors in NTS attenuates baroreflex control 

of renal nerve activity. Am J Physiol 1995; 269: 

H1080-86. 

71. Sved AF, Imaizumi T, Talman WT, Reis DJ: Vasopressin 

contributes to hypertension caused by nucleus 

tractus solitarius lesions. Hypertension 1985; 

7: 262-67. 

72. Lowes VL, McLean LE, Kasting NW, Ferguson AV: 

Cardiovascular consequences of microinjection of 

vasopressin and angiotensin II in the area postrema. 

Am J Physiol 1993; 265: R615. 

73. Zhang X, Abdel-Rahman AR, Wooles WR: Vasopressin 

receptors in the area postrema differentially 

modulate baroreceptor responses in rats. Eur J 

Pharmacol 1992; 222: 81-91. 

74. Qu L, Hay M, Bishop VS: Administration of AVP to 

the area postrema alters response of NTS neurons 

to afferent inputs. Am J Physiol 1997; 272 (2 Pt 2): 

R519-25. 

75. Stebbins CL, Bonigut S, Liviakis LR, Munch PA: 

Vasopressin acts in the area postrema to attenuate 

the exercise pressor reflex in anesthetized cats. Am 

J Physiol 274: H2116, 1998. 

76. Goldsmith SR: Arginine vasopressin and baroreflex 

function after converting enzyme inhibition in 

normal humans. Am J Physiol 1997; 272 (3 Pt 1): 

E429-36. 

77. Cowley AW Jr., Michalkiewicz M: Vasopressin and 

neuropeptide Y. In Izzo JL Jr., Sica DA, Black HR 

(eds): Hypertension Primer 4th ed. Dallas: Ameri-


can Heart Assn, 2008: 70. 

78. Tsuneyoshi I, Yamada H, Kakihana Y, et al: Hemodynamic 

and metabolic effects of low-dose vasopressin 

infusions in vasodilatory septic shock. Crit 

Care Med 29: 487, 2001. 

79. Gazmuri RJ, Shakeri SA: Low-dose vasopressin for 

reversing vasodilation during septic shock. Crit 

Care Med 29: 673, 2001. 

80. Argenziano M, Chen JM, Choudhri AF, et al: Management 

of vasodilatory shock after cardiac surgery: 

identification of predisposing factors and use 

of a novel pressor agent. J Thorac Cardiovasc Surg 

116: 973, 1998. 

81. 2005 International Consensus on Cardiopulmonary 

Resuscitation (CPR) and Emergency Cardiovascular 

Care ECC Science with Treatment 

Recommendation. Part 2: Adult basic life support. 

Circulation 112 (Suppl): III-5, 2005. 

82. Wenzel V, Lindner KH, Prengel AW, et al: Vasopressin 

improves vital organ blood flow after 

prolonged cardiac arrest with postcountershock 

pulseless electrical activity in pigs. Crit Care Med 

27: 486, 1999. 

83. Kornberger E, Prengel AW, Krismer A, et al: Vasopressin-mediated 

adrenocorticotropin release 

increases plasma cortisol concentrations during 

cardiopulmonary resuscitation. Crit Care Med 28: 

3517, 2000. 

84. Lindner KH, Dirks B, Strohmenger H-U, et al: 

Randomised comparison of epinephrine and vasopressin 

in patients with out-of-hospital ventricular 

fibrillation. Lancet 349: 535, 1997. 

85. Callaway CW, Hostler D, Doshi AA, et al: Usefulness 

of vasopressin administered with epinephrine 

during out-of-hospital cardiac arrest. Am J Cardiol 

98: 1316, 2006. 

86. Rosenzweig EB, Starc TJ, Chen JM, et al: Intravenous 

arginine-vasopressin in children with vasodilatory 

shock after cardiac surgery. Circulation 100 

(Suppl II): II-182, 1999. 

87. Luckner G, Mayr VD, Jochberger S, et al: Comparison 

of two dose regimens of arginine vasopressin 

in advanced vasodilatory shock. Crit Care Med 35: 

2280, 2007. 

88. Landry DW, Levin HR, Gallant EM, et al: Vasopressin 

deficiency contributes to the vasodilatation 

of septic shock. Circulation 95: 1122, 1997. 

89. Sharshar T, Carlier R, Blanchard A, et al: Depletion 

of neurohypophyseal content of vasopressin septic 

shock. Crit Care med 30: 497, 2002. 

90. Hollenberg SM, Tangora JJ, Piotrowski MJ, et al: 

Impaired microvascular vasoconstrictive responses 

to vasopressin in septic rats. Cric Care Med 25: 869, 

1997. 

91. Argenziano M, Chen M, Choudhri AF, et al: A 

prospective randomized trial of arginine vasopressin 

in the treatment of vasodilatory shock after left 

ventricular assist device placement. Circulation 96 

(Suppl II): II-286, 1997. 

92. Russell JA, Walley KR, Single J, et al: Vasopressin 

versus norepinephrine infusion in patients with 

septic shock. N Engl J Med 358: 877, 2008. 

93. Lankhuizen IM, van Veghel R, Saxena PR, Schoemaker 

RG: [Arg 8 ]-vasopressin-induced responses 

on coronary and mesenteric arteries of rats with 

myocardial infarction: the effects of V 1a and V 2 receptor 

antagonists. J Cardiovasc Pharmacol 36: 38, 

2000. 

94. Kraft W, Greenberg HE, Waldman SA: Paradoxical 

hypotension and bradycardia after intravenous arginine 

vasopressin. J Clin Pharmacol 38: 283, 1998. 

95. Decaux G, Soupart A, Vassart G: Non-peptide arginine-vasopressin 

antagonists: the vaptans. Lancet 

371: 1624, 2008. 

96. Wang YX, Crofton JT, Share L: Sex differences in 

the cardiovascular and renal actions of vasopressin 

in conscious rats. Am J Physiol 272: R370, 1997. 

97. Eatman D, Stallone JN, Rutecki GW, et al: Sex differences 

in extracellular and intracellular calciummediated 

vascular reactivity to vasopressin in rat 

aorta. Eur J Pharmacol 20: 207, 1998. 

98. Liard JF: L-NAME antagonizes vasopressin V2-induced 

vasodilation in dogs. Am J Physiol 26: H99, 

1994. 

99. Leier CV, Dei Cas L, Metra M: Clinical relevance 

and management of the major electrolyte abnormalities 

in congestive heart failure: hyponatremia, 

hypokalemia and hypomagnesemia. Am Heart J 

128: 254, 1994. 

100. Francis GS, Benedict C, Johnstone DE, et al: Comparison 

of neuroendocrine activation in patients 

with left ventricular dysfunction with and without 

congestive heart failure: a substudy of the Studies 

of Left Ventricular Dysfunction (SOLVD). Circulation 

81: 1724, 1990. 

101. Bakris G, Bursztyn M, Gavras I, et al: Role of vasopressin 

in essential hypertension: racial differences. 

J Hyperten 15: 545, 1997. 

102. Gavras H: Role of vasopressin in clinical hypertension 

and congestive cardiac failure: interaction 

with the sympathetic nervous system. Clin Chem 

37 (10 Pt 2): 1828, 1991. 

103. Rouleau JL, Packer M, Moye L, et al: Prognostic 

value of neurohormonal activation in patients with 

an acute myocardial infarction: effect of captopril. J 


104. Schrier RW: Water and sodium retention in edematous 

disorders: role of vasopressin and aldosterone.

Am J Med 119 Suppl 1: S47, 2006. 

105. Ribeiro A, Mulinari R, Gavras I, et al: Sequential 

elimination of pressor mechanisms in severe hypertension 

in humans. Hypertension 8 Suppl I: 

I-169, 1986. 

106. Houck PC, Fiksen-Olsen MJ, Briton SL, Romero 

JC: Role of angiotensin and vasopressin on blood 

pressure of ganglionic blocked dogs. Am J Physiol 

244: H115, 1983. 

107. Yatsu T, Tomura Y, Tahara A, et al: Cardiovascular 

and renal effects of conivaptan hydrochloride 

(YM087), a vasopressin V1a and V2 receptor antagonist, 

in dogs with pacing induced congestive 

heart failure. Eur J Pharmacol 376: 239, 1999. 

108. Walker BR, Childs ME, Adams EM: Direct cardiac 

effects of vasopressin: role of V1 and V2 vasopressinergic 

receptors. Am J Physiol Heart Circ Physiol 

255: H261, 1988. 

109. Gavras I, Hatinoglou S, Gavras H: The adrenergic 

system and the release and pressor action of vasopressin. 

Hypertension 8 (Suppl II): 163, 1986. 

110. Nishida N, Ogura Y, Yamauchi T, Hosoya M, Ota Z: 

Treatment with cilazapril, angiotensin converting 

enzyme inhibitor, changes the affinity of arginine 

vasopressin receptor in the kidney of the spontaneously 

hypertensive rat. Res Commun Chem Pathol 

& Pharm 84: 143, 1994. 

111. Khokhar AM, Slater JDH, Ma J, Ramage CM: The 

cardiovascular effect of vasopressin in relation to 

its plasma concentration in man and its relevance 

to high blood pressure. Clin Endocrin 13: 259, 

1980. 

112. Gavras H, Hatzinikolaou P, North WG, et al: Interaction 

of the sympathetic nervous system with 

vasopressin and renin in the maintenance of blood 

pressure. Hypertension 4: 400, 1982. 

113. Domanski M, Norman J, Pitt B, et al: Diuretic use, 

progressive heart failure and death in patients in the 

Studies of Left Ventricular Dysfunction (SOLVD). J 


114. Lee DS, Austin PC, Rouleau JL, et al: Predicting 

mortality among patients hospitalized for heart 

failure: derivation and validation of a clinical model. 

JAMA 290: 2581, 2003. 

115. De Luca L, Klein L, Udelson JE, etal: Hyponatremia 

in patients with heart failure. Am J Cardiol 96: 19L, 

2005. 

116. Klein L, O’Connor CM, Leimberger JD, et al: 

Lower serum sodium is associated with increased 

short-term mortality in hospitalized patients with 

worsening heart failure: results from the Outcomes 

of a Prospective Trial of Intravenous Milrinone for 

Exacerbations of Chronic Heart Failure (OPTIME- 

CHF) study. Circulation 111: 2454, 2005. 


117. Goldsmith SR, Gheorghiade M: Vasopressin antagonism 

in heart failure. J Am Coll Cardiol 46: 1785, 

2005. 

118. Finley JJ IV, Konstam MA, Udelson JE: Arginine 

vasopressin antagonists for the treatment of heart 

failure and hyponatremia. Circulation 118: 410, 

2008. 

119. Shoaf SE, Wang Z, Bricmont P, Mallikaarjun S: 

Pharmacokinetics, pharmacodynamics, and safety 

of tolvaptan, a nonpeptide AVP antagonist, during 

ascending single-dose studies in healthy subjects. J 

Clin Pharmacol 47: 1498, 2007. 

120. Yamamura Y, Nakamura S, Itoh S, et al: OPC-41061 

a highly potent human vasopressin V2 receptor antagonist: 

pharmacologic profile and aquaretic effect 

by single and multiple oral dosing in rats. J Pharmacol 

Exp Ther 287: 860, 1998. 

121. Veeraveedu PT, Watanabe K, Ma M, et al: Effects 

of V2 receptor antagonist tolvaptan and the loop 

diuretic furosemide in rats with heart failure. Biochem 

Pharmacol 75: 1322, 2008. 

122. Hirano T, Yoshitaka Y, Nakamura S, et al: Effects 

of the V2 receptor antagonist OPC 41061 and the 

loop diuretic furosemide alone and in combination 

in rats. J Pharmacol Exp Ther 292: 288, 2000. 

123. Gheorghiade M, Gottlieb SS, Udelson JE, et al for 

the Tolvaptan investigators: Vasopressin V2 receptor 

blockade with tolvaptan versus fluid restriction 

in the treatment of hyponatremia. Am J Cardiol 97: 

1064, 2006. 

124. Gheorghiade M, Niazi I, Ouyang J, et al Vasopressin 

V2 receptor blockade with tolvaptan in patients 

with chronic heart failure: results from a doubleblind 

randomized trial. Circulation 107: 2690, 

2003. 

125. Gheorghiade M, Gattis WA, O’Connor CM, et al: 

Effects of tolvaptan, a vasopressin antagonist, in 

patients hospitalized with worsening heart failure: 

a randomized controlled trial. JAMA 291: 1963, 

2004. 

126. Gheorghiade M, Konstam MA, Burnett JC Jr., et 

al: Short-term clinical effects of tolvaptan, an oral 

vasopressin antagonist, in patients hospitalized for 

heart failure: EVEREST clinical status trial. JAMA 

297: 1332, 2007. 

127. Konstam MA, Gheorghiade M, Burnett JC Jr., et al: 

Efficacy of vasopressin antagonist in heart failure 

outcome study with tolvaptan (EVEREST) investigators: 

effects of oral tolvaptan in patients hospitalized 

for worsening heart failure. The EVEREST 

Outcomes Trial. JAMA 297: 1319, 2007. 

128. Udelson JE, McGrew FA, Flores E, et al: Multicenter, 

randomized, double-blind, placebocontrolled 

study on the effect of tolvaptan on left


ventricular dilation and function in patients with 

heart failure and systolic dysfunction. J Am Coll 

Cardiol 49: 2151, 2007. 

129. Schrier RW, Gross P, Gheorghiade M, et al for the 

SALT investigators: Tolvaptan, a selective oral vasopressin 

V2-receptor antagonist for hyponatremia. 

N Engl J Med 355: 2099, 2006. 

130. Tolvaptan (Samsca) for hyponatremia. The Medical 

Letter 51: 95, 2009. 

130a. Plosker GL: Tolvaptan. Drugs 70: 443, 2010. 

130b. Ferguson-Myrthil N: Novel agents for the treatment 

of hyponatremia. A review of conivaptan and 

tolvaptan. Cardiol in Rev 18: 313, 2010. 

131. Kruszynski M, Lammeck B, Manning M, et al: [1(bmercapto-b-cyclopentamethyl-eneproprionic 

acid)2-(O-methyl)tyrosine] argin vasopressin and 

[1-(b-mercapto-b, b-cyclopenta-methyleneproprionic 

acid)] argin vasopressin, two highly potent 

antagonists of the vasopressor response to arginine-vasopressin. 

J Med Chem 23: 364, 1980. 

132. Lee CR, Watkins M, Patterson JH, et al: Vasopressin: 

a new target for the treatment of heart failure. 

Am Heart J 146: 9, 2003. 

133. Laszlo FA, Csati S, Balaspiri L: Effect of the vasopressin 

antagonist d/CH2/5Tyr/Et/VAVP on the 

antidiuretic action of exogenous and endogenous 

vasopressin. Acta Endocrinol 106: 52, 1984. 

134. Yatsu T, Tomura Y, Tahara A, et al: Pharmacological 

profile of YM087, a novel nonpeptide dual vasopressin 

V1a and V2 receptor antagonist in dogs. 

Eur J Pharmacol 321: 225, 1997. 

135. Yamamura Y, Ogawa H, Chihara T, et al: OPC 

21268, an orally effective, nonpeptide vasopressin 

V1 receptor antagonist. Science 252: 572, 1991. 

136. Burrell LM, Phillips PA, Stephenson J, et al: Effects 

of an orally active vasopressin V1 antagonist. Clin 

Exp Pharmacol Physiol 20: 388, 1993. 

137. Burnier M, Fricker AF, Hayoz D, et al: Pharmacokinetic 

and pharmacodynamic effects of YM087, a 

combined V1/V2 vasopressin receptor antagonist 

in normal subjects. Eur J Clin Pharmacol 55: 633, 

1999. 

138. Udelson JE, Smith WB, Hendrix GH, et al: Acute 

hemodynamic effects of conivaptan, a dual V1A/ 

V2 vasopressin receptor antagonist in patients with 

advanced heart failure. Circulation 104: 2417, 2001. 

139. Abraham WT, Shamshirsaz AA, McFann K, et al: 

Aquaretic effect of lixivaptan, an oral, nonpeptide, 

selective V2 receptor vasopressin antagonist 

in NYHA functional class II and III chronic heart 

failure. J Am Coll Cardiol 47: 1615, 2006.


Drug-Eluting Stents 


Mark J. Ricciardi, MD 

1. Hoff HE, Geddes LA, McCrady JD. The contributions 

of the horse to knowledge of the heart and 

Circulation. 1. Stephen Hales and the measurement 

of blood pressure. Conn Med 29:795, 1965. 

2. Grüntzig AR. Transluminal dilation of coronaryartery 

stenosis [letter]. Lancet 311:263, 1978. 

3. Hurst JW. The first coronary angioplasty as described 

by Andreas Gruentzig. Am J Cardiol 

57:185, 1986. 

4. Serruys PW, Kutryk MJ, Ong AT. Coronary-artery 


5. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular 

stents to prevent occlusion and restenosis after 

transluminal angioplasty. N Engl J Med 316:701, 

1987. 

6. Fischman DL, Leon MB, Baim DS, et al. A randomized 

comparison of coronary-stent placement and 

balloon angioplasty in the treatment of coronary 

artery disease. N Engl J Med 331:496, 1994. 

6a. Frishman WH, Landzberg BR, Weiss M: Pharmacologic 

therapies for the prevention of restenosis 

following percutaneous coronary artery interventions. 

In Frishman WH, Sonnenblick EH, Sica DA 

(eds): Cardiovascular Pharmacotherapeutics 2nd 

ed. New York: McGraw Hill 2003: 741. 

7. Palmaz JC, Sibbitt RR, Reuter S, et al. Expandable 

intraluminal graft: a preliminary study. Work in 

progress. Radiology 156:73, 1985. 

8. Schatz RA, Palmaz JC, Tio FO, et al. Balloon-expandable 

intracoronary stents in the adult dog. Circulation 

76:450, 1987. 

9. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison 

of balloon-expandable-stent implantation 

with balloon angioplasty in patients with coronary 

artery disease. N Engl J Med 331:489, 1994. 

10. Bertrand ME, Rupprecht HJ, Urban P, et al. Dou- 

ble-blind study of the safety of clopidogrel with 

and without a loading dose in combination with 

aspirin compared with ticlopidine in combination 

with aspirin after coronary stenting: the Clopidogrel 

Aspirin Stent International Cooperative Study 

(CLASSICS). Circulation 102;624, 2000. 

11. Leon MB, Baim DS, Popma JJ, et al. A clinical 

trial comparing three antithrombotic-drug regimens 

after coronary-artery stenting. N Engl J Med 

339;1665, 1998. 

12. Steinhubl SR, Berger PB, Mann III JT, et al. Early 

and sustained dual oral antiplatelet therapy following 

percutaneous coronary intervention. A randomized 


13. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused 

updates: ACC/AHA guidelines for the management 

of patients with ST-elevation myocardial 

infarction (updating the 2004 guideline and 2007 

focused update) and ACC/AHA/SCAI guidelines 

on percutaneous coronary intervention (updating 

the 2005 guideline and 2007 focused update): a report 

of the American College of Cardiology Foundation/American 

Heart Association Task Force on 

Practice Guidelines. Circulation. 120:2271, 2009. 

14. Byrne RA, Sarafoff N, Kastrati A, et al. Drug-eluting 

stents in percutaneous coronary intervention. 

A benefit-risk assessment. Drug Safety 32:749, 

2009. 

15. Bennett MR. In-stent restenosis: pathology and 

implications for the development of drug-eluting 

stents. Heart 2003;89:218-24. 

16. Moses JW, Leon MG, Popma JJ, et al. Sirolimuseluting 

stents versus standard stents in patients 

with stenosis in a native coronary artery. N Engl J 

Med 349:1315, 2003. 

17. Maluenda G, Lemesle G, Waksman R. A critical 



29-1


appraisal of the safety and efficacy of drug-eluting 

stents. Clin Pharm Ther 85:474, 2009. 

18. Chatterjee S, Pandey A. Drug-eluting stents: friend 

or foe? A review of cellular mechanisms behind the 

effects of paclitaxel and sirolimus eluting stents. 

Curr Drug Metab 9:554, 2008. 

19. Sehgal SN. Sirolimus: its discovery, biological 

properties, and mechanism of action. Transplant 

Proc 35(suppl. 3):7S, 2003. 

20. Gregory CR, Huie P, Billingham ME, et al. Rapamycin 

inhibits arterial intimal thickening caused 

by both alloimmune and mechanical injury. Its 

effect on cellular, growth factor, and cytokine response 

in injured vessels. Transplantation 55:1409, 

1993. 

21. Marx SO, Jayaraman T, Go LO, et al. Rapamycin- 

FKBP inhibits cell cycle regulators of proliferation 

in vascular smooth muscle cells. Circ Res 76:412, 

1995. 

22. Poon M, Marx SO, Gallo R, et al. Rapamycin inhibits 

vascular smooth muscle cell migration. J Clin 

Invest 98:2277, 1996. 

23. Chen J, Fang Y. A novel pathway regulating the 

mammalian target of rapamycin (mTOR) signaling. 

Biochem Pharmacol 64:1071, 2002. 

24. Imanishi T, Kobayashi K, Kuki S, et al. Sirolimus 

accelerates senescence of endothlial progenitor 

cells through telomerase inactivation. Atherosclerosis 

189:288, 2006. 

25. Deconinck E, Sohier J, De Scheerder I, et al. Pharmaceutical 

aspects of drug eluting stents. J Pharm 

Sci 97:5047, 2008. 

26. Nakazawa G, Finn AV, Kolodgie FD, et al. A review 

of current devices and a look at new technology: 

drug-eluting stents. Expert Rev Med Devices 6:33, 

2009. 

27. Grube E, Buellesfeld L. Everolimus for stent-based 

intracoronary applications. Rev Cardiovasc Med 

5(Suppl. 2):S3, 2004. 

28. Wani MC, Taylor HL, Wall ME, et al. Plant antitumor 

agents. VI. The isolation and structure of taxol, 

a novel antileukemic and antitumor agent from 

Taxus brevifolia. J Am Chem Soc 93:2325, 1971. 

29. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule 

assembly in vitro by taxol. Nature 277:665, 

1979. 

30. Rowsinky EK, Cazenave LA, Donehower RC. Taxol: 

a novel investigational antimicrotubule agent. J 

Natl Cancer Inst 82:1247, 1990. 

31. Dustin P. Microtubules. Sci Am 243:66, 1980. 

32. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N 

Engl J Med 332:1004, 1995. 

33. Schiff PB, Horwitz SB. Taxol stabilizes microtubules 

in mouse fibroblast cells. Proc Natl Acad Sci 

USA 77:1561, 1980. 

34. Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel 

inhibits arterial smooth muscle cell proliferation 

and migration in vitro and in vivo using local drug 

delivery. Circulation 96:636, 1997. 

35. Wiskirchen J, Schober W, Schart N, et al. The effects 

of paclitaxel on the three phases of restenosis: 

smooth muscle cell proliferation, migration, and 

matrix formation: an in vitro study. Invest Radiol 

39:565, 2004. 

36. Farb A, Heller PF, Shroff S, et al. Pathological analysis 

of local delivery of paclitaxel via a polymercoated 

stent. Circulation 104:479, 2001. 

37. Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits 

neointimal smooth muscle cell accumulation after 

angioplasty in the rat. J Clin Invest 95:1869, 1995. 

38. Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel 

stent coating inhibits neointimal hyperplasia at 4 

weeks in a porcine model of coronary restenosis. 

Circulation 103:2289, 2001. 

39. Parry TJ, Brosius R, Thyagarajan R, et al. Drugeluting 

stents: sirolimus and paclitaxel differentially 

affect cultured cells and injured arteries. Eur J 

Pharmacol 524:19, 2005. 

40. Kastrati A, Mehilli J, Dirschniger J, et al. Restenosis 

after coronary placements of various stent types. 

Am J Cardiol 87:34, 2001. 

41. Shedden L, Oldroyd K, Connolly P. Current issues 

in coronary stent technology. Proc Inst Mech Eng H. 

223:515, 2009. 

42. Escaned J, Goicolea J, Alfonso F, et al. Propensity 

and mechanisms of restenosis in different coronary 

stent designs. Complementary value of the analysis 

of the luminal gain-loss relationship. J Am Coll 

Cardiol 34:1490, 1999. 

43. Palmaz JC, Bailey S, Marton D, et al. Influence of 

stent design and material composition on procedure 

outcome. J Vascular Surg 36:1031, 2002. 

44. Lau K-W, Mak K-H, Hung J-S, et al. Clinical impact 

of stent construction and design in percutaneous 

coronary intervention. Am Heart J 147:764, 

2004. 

45. Hara H, Nakamura M, Palmaz JC, et al. Role of 

stent design and coatings on restenosis and thrombosis. 

Advd Drug Delivery Rev 58:377, 2006. 

46. Kastrati A, Mehilli J, Dirschinger J, et al. Intracoronary 

stenting and angiographic results: Strut thickness 

effect on restenosis outcome. (ISAR-STEREO) 


47. Pendyala L, Jabara R, Robinson K, et al. Passive and 

active polymer coatings for intracoronary stents. J 

Interven Cardiol 22:37, 2009. 

48. Wykrzykowska JJ, Onuma Y, Serruys P. Advances 

in stent drug delivery: the future is in bioabsorb-

able stents. Expert Opin Drug Deliv 6:113, 2009. 

49. Kamath KR, Barry JJ. Miller KM. The Taxus drugeluting 

stent: a new paradigm in controlled drug 

delivery. Adv Drug Deliv Rev 58:412, 2006. 

50. Joner M. Finn AV, Farb A, et al. Pathology of drugeluting 

stents in humans: Delayed healing and late 

thrombotic risk. J Am Coll Cardiol 48:193, 2006. 

51. Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity 

cases associated with drug-eluting 

coronary stents: A review of available cases from 

the research on adverse drug events and reports 

(RADAR) project. J Am Coll Cardiol 47:175, 2006. 

52. Guagliumi G, Farb A, Musumeci G, et al. Images 

in cardiovascular medicine. Sirolimus-eluting stent 

implanted in human coronary artery for 16 months: 

Pathological findings. Circulation 107:1340, 2003. 

53. Newsome LT, Kutcher MA, Royster RL. Coronary 

artery stents: Part I. Evolution of percutaneous 

coronary intervention. Anesth Analg 107:552, 2008. 

54. Carter AJ, Brodeur A, Collingwood R, et al. Tal efficacy 

of an everolimus eluting cobalt chromium 

stent. Catheter Cardiovasc Interv 68:97, 2006. 

55. Serruys P, Ong A, Pick JJ, et al. A randomized comparison 

of a durable polymer everolimus-eluting 

stent with a bare metal coronary stent. The SPIRIT 

first trial. Eurointervention 1:58, 2005. 

56. Sheiban I, Villata G, Bollati M, et al. Next-generation 

drug-eluting stents in coronary artery disease: 

focus on everolimus-eluting stent (Xience V ® ). Vasc 

Health Risk Management 4:31, 2008. 

56a. Kaiser C, Galatius S, Erne P, et al: Drug-eluting versus 

bare-metal stents in large coronary arteries. N 

Engl J Med November 16, 2010 (epub). 

57. Butt M, Connolly D, Lip GYH. Drug-eluting stents: 

a comprehensive appraisal. Future Cardiol 5:141, 

2009. 

57a. Garg S, Serruys PW: Coronary stents. Current status. 

J Am Coll Cardiol 56 (Suppl S): S1, 2010. 

58. Indolfi C, Pavia M, Angelillo IF.Drug-eluting stents 

versus bare metal stents in percutaneous coronary 

interventions (a meta-analysis). Am J Cardiol 

95:1146, 2005. 

59. Roiron C, Sanchez P, Bouzamondo A, et al. Drug 

eluting stents: an updated meta-analysis of randomised 

controlled trials. Heart 92: 641, 2006. 

60. Schampaert E, Moses JW, Schofer J, et al. Sirolimus 

eluting stents at two years: a pooled analysis of SIR- 

IUS, E-SIRIUS, and C-SIRIUS with emphasis on 

late revascularizations and stent thromboses. Am J 

Cardiol 98:36, 2006. 

61. Nordmann AJ, Briel M, Bucher HC. Mortality in 

randomized controlled trials comparing drug-eluting 

vs bare metal stents in coronary artery disease: 

a meta-analysis. Eur Heart J 27:2784, 2006. 


62. Stettler C, Wandel S, Allemann S, et al. Outcomes 

associated with drug-eluting and bare-metal stents: 

a collaborative network meta-analysis. Lancet 

370:937, 2007. 

63. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 

trials comparing sirolimus-eluting stents with 

bare-metal stents. N Engl J Med 356:1030, 2007. 

64. Spaulding C, Daemen J, Boersma E, et al. A pooled 

analysis of data comparing sirolimus-eluting stents 

with baremetal stents. N Engl J Med 356:989, 2007. 

65. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy 

of sirolimus- and paclitaxel-eluting coronary 


66. Pasceri V, Patti G, Speciale G, et al. Meta-analysis of 

clinical trials on use of drug-eluting stents for treatment 

of acute myocardial infarction. Am Heart J 

153:749, 2007. 

67. Boyden TF, Nallamothu BK, Moscucci M, et al. 

Metaanalysis of randomized trials of drug-eluting 

stents versus bare metal stents in patients with diabetes 

mellitus. Am J Cardiol 99:1399, 2007. 

68. Kastrati A, Dibra A, Spaulding C, et al. Meta-analysis 

of randomized trials on drug-eluting stents vs 

bare-metal stents in patients with acute myocardial 

infarction. Eur Heart J 28:2706, 2007. 

69. Kumbhani DJ, Bavry AA, Kamdar AR, et al. The 

effect of drug-eluting stents on intermediate angiographic 

and clinical outcomes in diabetic patients: 

insights from randomized clinical trials. Am Heart 

J 155:640, 2008. 

70. Stettler C, Allemann S, Wandel S, et al. Drug eluting 

and bare metal stents in people with and without 

diabetes: collaborative network meta-analysis. 

BMJ 337:a1331, 2008. 

71. Brar SS, Leon MB, Stone GW, et al. Use of drugeluting 

stents in acute myocardial infarction: a 

systematic review and meta-analysis. J Am Coll 

Cardiol 53:1677, 2009. 

72. Kirtane AJ, Gupta A, Iyengar S, et al. Safety and efficacy 

of drug-eluting and bare metal stents: comprehensive 

meta-analysis of randomized trials and 

observational studies. Circulation 119:3198, 2009. 

73. Fajadet J, Wijns W, Laarman GJ, et al. for the 

ENDEAVOR II Investigators. Randomized, double-blind, 

multicenter study of the Endeavor zotarolimus-eluting 

phosphorylcholine-encapsulated 

stent for treatment of native coronary artery lesions: 

clinical and angiographic results of the EN- 

DEAVOR II trial. Circulation 114:798, 2006. 

74. Grube E, Sonoda S, Ikeno F, et al. Six- and twelvemonth 

results from first human experience using 

everolimus-eluting stents with bioabsorbable polymer. 

Circulation 109:2168, 2004. 

75. Kastrati A, Dibra A, Eberle S, et al. Sirolimus-elut-


ing stents vs paclitaxel-eluting stents in patients 

with coronary artery disease: meta-analysis of randomized 

trials. JAMA 294:819, 2005. 

76. Stettler C, Allemann S, Egger M, et al. Efficacy of 

drug eluting stents in patients with and without diabetes 

mellitus: indirect comparison of controlled 

trials. Heart 92:650, 2006. 

77. Schömig A, Dibra A, Windecker S, et al. A metaanalysis 

of 16 randomized trials of sirolimuseluting 

stents versus paclitaxel-eluting stents in 

patients with coronary artery disease. J Am Coll 

Cardiol 50:1373, 2007. 

78. Gurm HS, Boyden T, Welch KB. Comparative 

safety and efficacy of a sirolimus-eluting versus 

paclitaxel-eluting stent: a meta-analysis. Am Heart 

J 155:630, 2008. 

79. Kandzari DE, Leon MB, Popma JJ, et al. for the 

ENDEAVOR III Investigators. Comparison of 

zotarolimus-eluting and sirolimus-eluting stents 

in patients with native coronary artery disease: a 

randomized controlled trial. J Am Coll Cardiol 

48:2440, 2006. 

80. Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting 

and paclitaxel-eluting stents for coronary 

revascularization. N Engl J Med 353:653, 2005. 

81. Galløe AM, Thuesen L, Kelback H, et al. Comparison 

of paclitaxel- and sirolimus-eluting stents in 

everyday clinical practice: the SORT OUT II randomized 

trial. JAMA 299:409, 2008. 

82. Morice MC, Colombo A, Meier B, et al. Sirolimus- 

vs paclitaxel-eluting stents in de novo coronary 

artery lesions. The REALITY trial: a randomized 


83. Dibra A, Kastrati A, Mehilli J, et al. Paclitaxel-eluting 

or sirolimus-eluting stents to prevent restenosis 

in diabetic patients. N Engl J Med 353:663, 2005. 

84. Leon MB, Mauri L, Popma JJ, et al. for the EN- 

DEAVOR IV Investigators. A randomized comparison 

of the Endeavor zotarolimus-eluting stent 

versus the TAXUS paclitaxel-eluting stent in de 

novo native coronary lesions. 12-month outcomes 

from the ENDEAVOR IV trial. J Am Coll Cardiol 

55:543, 2010. 

85. Stone GW, Midei M, Newman W, et al. for the 

SPIRIT III Investigators. Randomized comparison 

of everolimus-eluting and paclitaxel-eluting stents: 

two-year clinical follow-up from the Clinical Evaluation 

of the Xience V Everolimus Eluting Coronary 

Stent System in the Treatment of Patients with 

de novo Native Coronary Artery Lesions (SPIRIT) 

III trial. Circulation 119:680, 2009. 

85a. Stone GW, Rizvi A, Newman W, et al for the SPIR- 

IT IV Investigators: Everolimus-eluting versus paclitaxel-eluting 

stents in coronary artery disease. N 

Engl J Med 362: 1663, 2010. 

85b. Holmes DR, Kereiakes DJ, Garg S, et al: Stent 

thrombosis. J Am Coll Cardiol 56: 1357, 2010. 

86. Urao N, Okigaki M, Yamada H, et al. Erythropoietin-mobilized 

endothelial progenitors enhance reendothelialization 

via Akt-endothelial nitric oxide 

synthase activation and prevent neointimal hyperplasia. 

Circ Res 98:1405, 2006. 

87. Butzal M, Loges S, Schweizer M, et al. Rapamycin 

inhibits proliferation and differentiation of human 

endothelial progenitor cells in vitro. Exp Cell Res 

300:65, 2004. 

88. McFadden EP, Stabile E, Regar E, et al. Late thrombosis 

in drug-eluting coronary stents after discontinuation 

of antiplatelet therapy. Lancet 364:1519, 

2004. 

89. Joner M, Finn AV, Frab A, et al. Pathology of drugeluting 

stents in humans: delayed healing and late 

thrombotic risk. J Am Coll Cardiol 48:193, 2006. 

90. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting 

stent and coronary thrombosis: biological 

mechanisms and clinical implications. Circulation 

115:1051, 2007. 

91. Kastrati A. Drug for a while, polymer for life: is it 

a good solution? Catheter Cardiovasc Interv 71:340, 

2008. 

92. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, 

predictors, and outcome of thrombosis after successful 

implantation of drug-eluting stents. JAMA 

293:2126, 2005. 

93. Eisenstein EL, Anstrom KJ, Fong DF, et al. Clopidogrel 

use and long-term clinical outcomes after 

drug-eluting stent implantation. JAMA 297:159, 

2007. 

94. Lagerqvist B, James SK, Stenestrand U, et al. 

Long-term outcomes with drug-eluting stents 

versus bare-metal stents in Sweden. N Engl J Med 

356:1009, 2007. 

95. Steg PG, Fox KA, Eagle KA, et al. Mortality following 

placement of drug-eluting and bare-metal 

stents for ST-segment elevation acute myocardial 

infarction in the Global Registry of Acute Coronary 

Events. Eur Heart J 30:321, 2009. 

96. Buch AN, Javaid A, Steinberg DH, et al. Outcomes 

after sirolimus- and paclitaxel-eluting stent implantation 

in patients with insulin-treated diabetes 

mellitus. Am J Cardiol 101:1253, 2008. 

97. Stankovic G, Cosgrave J, Chieffo A, et al. Impact 

of sirolimus-eluting and paclitaxel-eluting stents 

on outcome in patients with diabetes mellitus and 

stenting in more than one coronary artery. Am J 

Cardiol 98:326, 2006. 

98. Daemen J, Garcia-Garcia HM, Kukreja N, et al. The 

long-term value of sirolimus- and paclitaxel-elut-

ing stents over bare metal stents in patients with 

diabetes mellitus. Eur Heart J 28:26, 2007. 

99. Mauri L, Silbaugh TS, Garg O, et al. Drug-eluting 

or bare-metal stents for acute myocardial infarction. 

N Engl J Med 359:1330, 2008. 

100. Garg P, Normand SL, Silbaugh TS, et al. Drugeluting 

or bare-metal stenting in patients with diabetes 

mellitus: results from the Massachusetts Data 

Analysis Center Registry. Circulation 118:2277, 

2008. 

100a. Garg S, Serruys PW: Coronary stents. Looking forward. 

J Am Coll Cardiol 56 Suppl S: S43, 2010. 

100b. Serruys PW, Onuma Y, Ormiston JA, et al: Evaluation 

of the second generation of a bioresorbable 

everolimus drug-eluting vascular scaffold for treatment 

of de novo coronary artery stenosis. Sixmonth 

clinical and imaging outcomes. Circulation 

122: 2301, 2010. 

100c. Bittl JA: Bioresorbable stents. The next revolution. 

Circulation 122: 2236, 2010. 

101. Joyal D, Filion KB, Eisenberg MJ: Effectiveness and 

safety of drug-eluting stnets in vein grafts: a metaanalysis. 

Am Heart J 159: 159, 2010. 

102. Abualsaud AO, Eisenberg MJ: Perioperative management 

of patients with drug-eluting stents. J Am 

Coll Cardiol: Cardiovasc Intervent 3: 131, 2010. 

103. El-Menyar AA, Suwaidi JA, Holmes DR Jr.: Use of 

drug-eluting stents in patients with coronary artery 

disease and renal insufficiency. Mayo Clin Proc 85: 

165, 2010. 

104. Jabara R, Chronos N, Conway D, et al. Evaluation 

of a novel slow-release paclitaxel-eluting stent with 

a bioabsorbable polymeric surface coating. J Am 

Coll Cardiol Intv 1:81, 2008. 


105. Hamilos MI, Ostojic M, Beleslin B, et al. Differential 

effects of drug-eluting stents on local endothelium-dependent 

coronary vasomotion. J Am Coll 

Cardiol 51:2123, 2008. 

106. Inoue T, Sata M, Hikichi Y, et al. Mobilization of 

CD34-positive bone marrow-derived cells after 

coronary stent implantation : Impact on restenosis. 


107. Aoki J, Serruys PW, van Beusekom H, et al. Endothelial 

progenitor cell capture by stents coated 

with antibody against CD34. The HEALING-FIM 

(healthy endothelial accelerated lining inhibits 

neointimal growth – first in man) registry. J Am 

Coll Cardiol 45:1574, 2005. 

108. van der Giessen WJ, Lincoff AM, Schwartz RS, et 

al. Marked inflammatory sequelae to implantation 

of biodegradable and nonbiodegradable polymers 

in porcine coronary arteries. Circulation 94:1690, 

1996. 

109. Jabara R, Chronos N, Tondato F, et al. Toxic vessel 

reaction to an absorbable polymer-based paclitaxel-eluting 

stent in pig coronary arteries. J Invasive 

Cardiol 18:383, 2006. 

110. Kedhi E, Joesoef KS, McFadden E, et al: Second 

generation everolimus-eluting and paclitaxel-eluting 

stents in real-life practice (COMPARE): a randomised 

trial. Lancet 375: 201, 2010.


Alternative and Complementary 

Medicine for Preventing and Treating 

Cardiovascular Disease 


1. Eisenberg DM, Kessler RC, Foster C, et al: Unconventional 

medicine in the United States. N Engl J 

Med 328: 246, 1993. 

2. Pearson NI, Chesney MA: The CAM education 

program of the National Center for Complementary 

and Alternative Medicine: an overview. Acad 

Med 82: 921, 2007. 

3. Krucoff MW, Liebowitz R, Vogel JHK, Mark D: 

Complementary and alternative medicine therapy 

in cardiovascular care. In Fuster V, Alexander RW, 

O’Rourke RA, Roberts R, King SB, Prystowsky E, 

Nash IS: Hurst’s The Heart 11th ed. New York: Mc- 

Graw Hill 2004; 2463. 

4. Frishman WH, Lee W-N, Glasser SP, et al: The placebo 

effect in cardiovascular disease. In Frishman 

WH, Sonnenblick EH, Sica DA (eds): Cardiovascular 

Pharmacotherapeutics 2nd ed. New York: Mc- 

Graw Hill 2003: 15. 

5. Matter-Walstra K, Schoeni-Affolter F, Widmer M, 

et al: Patient-based evaluations of primary care 

for cardiovascular diseases: a comparison between 

conventional and complementary medicine. J Eval 

Clin Pract 14:75, 2008. 

6. Miller KL. Liebowitz RS. Newby LK. Complementary 

and alternative medicine in cardiovascular 

disease: a review of biologically based approaches. 

Am Heart J 147:401, 2004. 

7. Morris CD, Carson S: Routine vitamin supplementation 

to prevent cardiovascular disease: a summary 

of the evidence for the U.S. Preventive Services 

Task Force. Ann Intern Med 139: 56, 2003. 

8. Frishman WH, Sinatra ST, Kruger N: Nutraceuticals 

and cardiovascular illness. In Frishman WH, 

Weintraub MI, Micozzi M: Complementary & Integrative 

Therapies for Cardiovascular Disease. St. 

Louis: Elsevier 2005: 58. 

9. Ridinger MHT: Nutraceuticals: miracle or meme? 

Nature 82: 352-56, 2007. 

9a. Haller CA: Nutraceuticals: has there been any 

progress? Clin Pharmacol Therap 87: 137, 2010. 

10. Riccioni G, Mancini B, Di Ilio E, et al: Protective effect 

of lycopene in cardiovascular disease. Eur Rev 

Med Pharmacol Sci 12:183, 2008. 

11. Frishman WH, Kruger NA, Nayak DU, Vakili BA: 

Antioxidant vitamins and enzymatic and synthetic 

oxygen-derived free-radical scavengers in the prevention 

and treatment of cardiovascular disease. 

In Frishman WH, Sonnenblick EH, Sica DA (eds): 

Cardiovascular Pharmacotherapeutics 2nd ed. New 

York: McGraw-Hill 2003: 407. 

12. Saremi A, Arora R: Vitamin E and cardiovascular 

disease. Am J Therap 17: e56, 2010. 

13. Rapola JM, Virtamo J, Ripatti S, et al: Randomized 

trial of alpha-tocopherol and beta carotene supplements 

on incidence of major coronary events in 

men with previous myocardial infarction. Lancet 

349:1715, 1997. 

14. Stephens NG, Parsons A, Schofield PM, et al: Randomized 

controlled trial of vitamin E in patients 

with coronary disease: Cambridge Heart Antioxidant 

Study. Lancet 347:781, 1996. 

15. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-converting-enzyme 

inhibitor, ramipril, on 

cardiovascular events in high-risk patients. N Engl J 

Med 342:145, 2000. 

16. Gruppo Italiano per lo Studio della Sopravvivenza 

nell’Infarto miocardico. Dietary supplementation 

with n-3 polyunsaturated fatty acids and vitamin 

E after myocardial infarction: Results of the GISSI 

Prevenzione trial. Lancet 354:447, 1999. 

17. Jialal I, Traber M, Deveraj S: Is there a vitamin E 

paradox? Curr Opin Lipidol 12:49, 2001. 



30-1


18. Vivekananthan DP, Penn MS, Sapp SK, et al: Use 

of antioxidant vitamins for the prevention of cardiovascular 

disease: meta-analysis of randomized 

trials. Lancet 361: 2017, 2003. 

19. Heart Protection Study Collaborative Group: 

MRC/BHF Heart Protection Study of antioxidant 

vitamin supplement in 20,536 high-risk individuals: 

a randomized placebo-controlled trial. Lancet 

360: 23, 2002 

20. Rasool AH, Rahman AR, Yuen KH, et al: Arterial 

compliance and vitamin E blood levels with a self 

emulsifying preparation of tocotrienol rich vitamin 

E. Arch Pharm Res 31: 1212 2008. 

21. Glynn RJ, Ridker PM, Goldhaber SZ, Zee RYL, 

Buring JE: Effects of random allocation of vitamin 

E supplementation on the occurrence of venous 

thromboembolism. Report from the Women’s 

Health Study. Circulation 116: 1497, 2007. 

22. Cook NR, Albert CM, Gaziano JM, et al: A randomized 

factorial trial of vitamins C and E and 

beta carotene in the secondary prevention of cardiovascular 

events in women: results from the 

Women’s Antioxidant Cardiovascular Study. Arch 

Intern Med 168:773, 2008. 

22a. Roberts JM, Myatt L, Spong CY, et al: Vitamins C 

and E to prevent complications of pregnancy-associated 

hypertension. N Engl J Med 362: 1282, 2010. 

23. Sesso HD, Buring JE, Christen WG, et al: Vitamins 

E and C in the prevention of cardiovascular disease 

in men. The Physicians’ Health Study II randomized 

controlled trial. JAMA 300: 2123, 2008. 

24. Hatzigeorgiou C, Taylor AJ, Feuerstein IM, Bautista 

L, O’Malley PG: Antioxidant vitamin intake 

and subclinical coronary atherosclerosis. Prevent 

Cardiol 9: 75, 2006. 

25. Kritchevsky SB, Shimakawa T, Tell GS, et al: Dietary 

antioxidants and carotid artery wall thickness: 

The ARIC Study. Circulation 92:2142, 1995. 

26. Osganian SK, Stampfer MJ, Rimm E, et al: Vitamin 

C and risk of coronary heart disease in women. J 


27. Kaw KT, Bingham S, Welch A, et al: Relation between 

plasma ascorbic acid and mortality in men 

and women in EPIC-Norfolk Prospective Study: 

A prospective population study. Lancet 357:657, 

2001. 

28. Mikirova NA, Thomas IE, Riordan NH: Antiangiogenic 

effect of high doses of ascorbic acid. J 

Transl Med 6:50, 2008. 

29. Kruger NA, Frishman WH, Hussain J: Fish oils, the 

B vitamins and folic acid as cardiovascular protective 

agents. In Frishman WH, Sonnenblick EH, 

Sica DA (eds): Cardiovascular Pharmacotherapeutics 


30. Chan P, Huang TY, Chen YJ, et al: Randomized, 

double-blind, placebo-controlled study of the safety 

and efficacy of vitamin B complex in the treatment 

of nocturnal leg cramps in elderly patients 

with hypertension. J Clin Pharmacol 38:1151, 1998. 

31. McCully KS: Vascular pathology of homocysteinemia: 

Implications for the pathogenesis of arteriosclerosis. 

Am J Pathol 56: 111, 1969. 

32. Selhub J, Jacques PF, Bostom AG, et al: Association 

between plasma homocysteine concentrations and 

extracranial carotid artery disease. N Engl J Med 

332:286, 1995. 

33. Ridker PM, Manson JE, Buring JE, et al: Homocysteine 

and risk of cardiovascular disease among 

post-menopausal women. JAMA 281:1817, 1999. 

34. Hankey GJ, Eikeboom JW: Homocysteine and vascular 

disease. Lancet 354:407, 1999. 

35. Lonn E: Homocysteine-lowering B vitamin therapy 

in cardiovascular prevention. Wrong Again? JAMA 

299:2086, 2008. 

36. Toole JF, Malinow MR, Chambless LE, et al: Lowering 

homocysteine in patients with ischemic stroke 

to prevent recurrent stroke, myocardial infarction, 

and death: the Vitamin Intervention for Stroke Prevention 

(VISP) randomized controlled trial. JAMA 

291: 565, 2004. 

37. Spence JD, Bang H, Chambless LE, Stampfer MJ: 

Vitamin Intervention for Stroke Prevention trial: 

an efficacy analysis. Stroke 36: 2404, 2005. 

38. Ray JG, Kearon C, Yi Q, et al: Homocysteine-lowering 

therapy and risk for venous thromboembolism: 

a randomized trial. Ann Intern Med 146: 761, 

2007. 

39. Bønaa KH, Njølstad I, Ueland PM, et al: Homocysteine 

lowering and cardiovascular events after 

acute myocardial infarction. N Engl J Med 354: 

1578, 2006. 

40. Bleie O, Semb AG, Grundt H, et al: Homocysteinelowering 

therapy does not affect inflammatory 

markers of atherosclerosis in patients with stable 

coronary artery disease. J Intern Med 262: 244, 

2007. 

40a. Miller ER III, Juraschek S, Pastor-Barriuso R, et al: 

Meta-analysis of folic acid supplementation trials 

on risk of cardiovascular disease and risk interaction 

with baseline homocysteine levels. Am J Cardiol 

106: 517, 2010. 

40b. Ebbing M, Bønna KH, Nygård O, et al: Cancer incidence 

and mortality after treatment with folic acid 

and vitamin B 12 . JAMA 302: 2119, 2009. 

41. Albert CM, Cook NR, Gaziano JM, et al: Effect of 

folic acid and B vitamins on risk of cardiovascular 

events and total mortality among women at high 

risk for cardiovascular disease: a randomized trial.

JAMA 299:2027, 2008. 

42. Jamison RL, Hartigan P, Kaulman JS, Goldfarb DS, 

Warren SR, Guarino PD, Gaziano JM for the Veterans 

Affairs Site Investigators: Effect of homocysteine 

lowering on mortality and vascular disease 

in advanced chronic kidney disease and end-stage 

renal disease. A randomized controlled trial. JAMA 

298: 1163, 2007. 

43. Kamanna VS, Kashyap ML: Mechanism of action 

of niacin. Am J Cardiol 101(8A): 20B, 2008. 

44. Meyers CD, Carr MC, Park S, Brunzell JD: Varying 

cost and free nicotinic acid content in over-thecounter 

niacin preparations for dyslipidemia. Ann 

Intern Med 139: 996, 2003. 

45. Morgan JM, Capuzzi DM, Guyton JR: A new 

extended-release niacin (Niaspan):Efficacy, tolerability, 

and safety in hypercholesterolemic patients. 

Am J Cardiol 82:29U, 1998. 

46. Goldberg A, Alagona P Jr, Capuzzi DM, et al: 

Multiple-dose efficacy and safety of an extendedrelease 

form of niacin in the management of hyperlipidemia. 

Am J Cardiol 85: 1100, 2000. 

47. Cefali EA, Simmons PD, Stanek EJ, Shamp TR: Improved 

control of niacin-induced flushing using an 

optimized once-daily, extended-release niacin formulation. 

Int J Clin Pharmacol Ther 44:633, 2006. 

48. Paolini JF, Mitchel YB, Reyes R, Kheru U, Lai E, 

Watson DJ, et al: Effects of laropiprant on nicotinic 

acid-induced flushing in patients with dyslipidemia. 

Am J Cardiol 101:625, 2008. 

49. Lai E, Lepeleire I, Crumley TM, Liu F, Wenning 

LA, Michiels N, et al: Suppression of niacin-induced 

vasodilation with an antagonist to prostaglandin 

D2 receptor subtype 1. Clin Pharmacol 

Therap 81:849, 2007. 

50. Somjen D, Weisman Y, Kohen F, Gayer B, Limor 

R, Sharon O, et al: 25-Hydroxyvitamin D3-1a-hydroxylase 

is expressed in human vascular smooth 

muscle cells and is upregulated by parathyroid hormone 

and estrogenic compounds. Circulation 111: 

1666, 2005. 

51. Merke J, Milde P, Lewicka S, Hugel U, Klaus G, 

Mangelsdorf DJ, et al: Identification and regulation 

of 1,25-hydroxyvitamin D3 receptor activity and 

biosynthesis of 1,25-dihydroxyvitamin D3: studies 

in cultured bovine aortic endothelial cells and human 

dermal capillaries. J Clin Invest 83: 1903, 1989. 

52. Holick MF: High prevalence of vitamin D inadequacy 

and implications for health. Mayo Clin Proc 

81: 353, 2006. 

53. Wallis DE, Penckofer S, Sizemore GW: The “Sunshine 

Deficit” and cardiovascular disease. Circulation 

118: 1476, 2008. 

54. Zitterman A, Schleithoff SS, Koerfer R: Putting car- 


diovascular disease and vitamin D deficiency into 

perspective. Br J Nutri 94: 483, 2005. 

55. Giovannucci E, Liu Y, Hollis W, et al: 25-hydroxyvitamin 

D and risk of myocardial infarction in men: 

a prospective study. Arch Intern Med 168: 1174, 

2008. 

56. Resnick LM, Muller FB, Laragh JH: Calcium-regulating 

hormones in essential hypertension: relation 

to plasma renin activity and sodium metabolism. 

Ann Intern Med 105: 649, 1986. 

57. Zittermann A, Schleithoff SS, Koerfer R: Vitamin D 

and vascular calcification. Curr Opin Lipidol 18: 41, 

2007. 

58. Wang TJ, Pencina MJ, Booth SL, et al: Vitamin D 

deficiency and risk of cardiovascular disease. Circulation 

117: 503, 2008. 

59. Pilz S, Dobnig H, Fischer JE, et al: Low vitamin D 

levels predict stroke in patients referred to coronary 

angiography.Stroke 39: 2611, 2008 

60. Pilz S, Marz W, Wellnitz B, , et al: Association of 

vitamin D deficiency with heart failure and sudden 

cardiac death in a large cross-sectional study of 

patients referred for coronary angiography. J Clin 

Endocrinol Metab 93: 3927,2008. 

61. Fleck A: Latitude and ischaemic heart disease. Lancet 

1: 613, 1989. 

62. Zittermann A, Koerfer R: Vitamin D in the prevention 

and treatment of coronary heart disease. Curr 

Opin Clin Nutri Metab Care 11: 752, 2008. 

62a. Pittas AG, Chung M, Trikalinos T, et al: Systematic 

review: vitamin D and cardiometabolic outcomes. 

Ann Intern Med 152: 307, 2010. 

62b. Wang L, Manson JE, Song Y, Sesso HD: Systematic 

review: vitamin D and calcium supplementation 

in prevention of cardiovascular events. Ann Intern 

Med 152: 315, 2010. 

63. Erkkila AT, Booth SL: Vitamin K intake and atherosclerosis. 


64. Greenberg ER, Baron JA, Karagas MR, et al: Mortality 

associated with low plasma concentration of 

beta carotene and the effect of oral supplementation. 

JAMA 275:699, 1996. 

65. Gey FK, Puska P: Plasma vitamin E and A inversely 

correlated to mortality from ischemic heart disease 

in cross-cultural epidemiology. Ann NY Acad Sci 

570:268, 1989. 

66. Kardinaal AF, Kok FJ, Ringstad J, et al: Antioxidants 

in adipose tissue and risk of myocardial infarction: 

The EURAMIC Study. Lancet 342:1379, 1993. 

67. Gitenay D, Lyan B, Rambeau M, et al: Comparison 

of lycopene and tomato effects on biomarkers of 

oxidative stress in vitamin E deficient rats. Eur J 

Nat 46:468, 2008. 

68. Ullah MF, Khan MW: Food as medicine: potential


therapeutic tendencies of plant derived polyphenolic 

compounds. Asian Pac J Cancer Prev 9:187, 

2008. 

69. Maxwell S, Cruickshank A, Thorpe D: Red wind 

and antioxidant activity in serum. Lancet 344:193, 

1994. 

70. Hertog MC, Feskens EJ, Hollman PC, et al: Dietary 

antioxidant flavonoids and risk of coronary 

heart disease: The Zutphen Elderly Study. Lancet 

342:1007, 1993. 

71. Duffy SJ, Keaney JF, Holbrook M, et al: Short- and 

long-term black tea consumption reverses endothelial 

dysfunction in patients with coronary artery 

disease. Circulation 104:151, 2001. 

72. Gresele P, Pignatelli P, Guglielmini G, et al: Resveratrol, 

at concentrations attainable with moderate 

wine consumption, stimulates human platelet nitric 

oxide production. J Nutr 138:1602, 2008. 

73. Clinical Trial: Trial to assess bioavailability of flavonoids 

and phenolic acids. www.clinicaltrials.gov/ct. 

74. Rimm EB, Katan MB, Ascherio A, et al: Relation 

between intake of flavonoids and risk for coronary 

heart disease in male health professionals. Ann Intern 

Med 125:384, 1996. 

75. Clinical Trial: Trial to assess Concord Grape Juice. 

www.clinicaltrials.gov/ct. 

76. Frishman WH, DelVecchio A, Sanal S, Ismail A: 

Cardiovascular manifestations of substance abuse. 

Part 2: Alcohol, amphetamines, heroin, cannabis, 

caffeine. Heart Dis 5: 253, 2003. 

77. Mehrinfar R, Frishman WH: Flavonol-rich cocoa. 

A cardioprotective nutraceutical. Cardiol in Rev 16: 

109, 2008. 

78. Hollenberg NK, Fisher NDL: Is it the dark in dark 

chocolate? Circulation 116: 2360, 2007. 

79. Houston MC, Harper KJ: Potassium, magnesium, 

and calcium: their role in both the cause and treatment 

of hypertension. J Clin Hypertens (Greenwich) 

10(7 Suppl 2):3, 2008. 

80. Cojocaru IM, Cojocaru M, Burcin C, et al: Serum 

magnesium in patients with acute ischemic stroke. 

Rom J Intern Med 45:269, 2008. 

81. McLean RM: Magnesium and its therapeutic uses: 

A review. Am J Med 96:63, 1994. 

82. Shechter M: Oral magnesium in coronary artery 

disease: Fresh insight on thrombus inhibition. 

Magn Rep 1-4, 1999. 

83. Ho KM: Intravenous magnesium for cardiac arrhythmias: 

jack of all trades. Magnes Res 21:65, 

2008. 

84. Lichodziejewska B, Klos J, Rezler J, et al: Clinical 

symptoms of mitral valve prolapse are related to 

hypomagnesemia and attenuated by magnesium 

supplementation. Am J Cardiol 79:768, 1997. 

85. Preuss HG, Wallerstedr’ D, Talpur N, et al: Effects 

of niacin-bound chromium and grape seed proanthocyanidins 

extract on the lipid profile of hypercholesterolemic 

subjects: A pilot study. J Med 

31:227, 2000. 

86. Grundy SM: Cholesterol management in the era of 

managed care. Am J Cardiol 85:3A, 2000. 

87. McLaren DS: Vitamin deficiency, toxicity and dependency. 

In Berkow R, Fletcher AJ, Bondy PK, et 

al (eds): The Merck Manual 16th ed. Rahway NJ: 

Merck Research Labs., 1992. 

88. Salvini S, Hennekens CH, Morris JS, et al: Plasma 

levels of the antioxidant selenium and risk of myocardial 

infarction among US physicians. Am J Cardiol 

76:1218, 1995. 

89. Kok FJ, Hofman A, Witteman JCM, et al: Decreased 

selenium levels in acute myocardial infarction. 

JAMA 261:1161, 1989. 

90. Hercberg S, Galan P, Preziosi P, et al: The SU.VI. 

MAX Study: a randomized, placebo-controlled trial 

of the health effects of antioxidant vitamins and 

minerals. Arch Intern Med 164:2335, 2004. 

91. Salonen JT, Salonen R, Seppanen K, et al: Interactions 

of serum copper, selenium, and low density 

lipoprotein cholesterol in atherogenesis. BMJ 

302:756, 1991. 

92. Kuklinski B, Weissenbacher E, Fahnrich A, et al: 

Coenzyme Q10 and antioxidants in acute myocardial 

infarction. Mol Aspects Med 15: S143, 1994. 

93. Molyneux SL, Young JM, Florkowski CM, et al: Coenzyme 

q10: is there a clinical role and a case for 

measurement? Clin Biochem Rev 29:71, 2008. 

94. Langsjoen PH, Langsjoen AM: Overview of the use 

of CoQ10 in cardiovascular disease. Biofactors 9: 

273, 1999. 

95. Miguel-Carrasco JL, Mate A, Monserrat MT, et al: 

The role of inflammatory markers in the cardioprotective 

effect of L-carnitine in L-NAME-induced 

hypertension. Am J Hypertens 21: 1231,2008. 

96. Wierzbicki AS: A fishy business: omega-3 fatty 

acids and cardiovascular disease. Int J Clin Pract 

62:1142, 2008. 

96a. Weitz D, Weintraub H, Fisher E, Schwartzbard AZ: 

Fish oil for the treatment of cardiovascular disease. 


97. Brouwer IA, Zock PL, Camm AJ, et al: Effect of 

fish oil on ventricular tachyarrhythmia and death 

in patients with implantable cardioverter defibrillators: 

the Study on Omega-3 Fatty Acids and 

Ventricular Arrhythmia (SOFA) randomized trial. 

JAMA 295:2613, 2006. 

97a. deLeiris J, deLorgeril M, Boucher F: Fish oil and 

heart health. J Cardiovasc Pharmacol 54: 378, 2009. 

98. O’Keefe J, Harris W: Omega-3 fatty acids: Time

for clinical implementation? Am J Cardiol 85:1239, 

2000. 

99. GISSI-HF Investigators: Effect of n-3 polyunsaturated 

fatty acids in patients with chronic heart failure 

(GISSI-HF trial): a randomised, double-blind, 

placebo-controlled trial. Lancet 372: 1223, 2008. 

100. Fonarow GC: Statins and n-3 fatty acid supplementation 

in heart failure. Lancet 372: 1195, 2008. 

101. Albert CM, Hennekens CH, O’Donnell CJ, et 

al: Fish consumption and risk of sudden cardiac 

death. JAMA 279: 23, 1998. 

102. Yokoyama M, Origasa H, Matsuzaki M, et al: Effects 

of eicosapentaenoic acid on major coronary 

events in hypercholesterolaemic patients (JELIS): a 

randomised open-label, blinded endpoint analysi. 

Lancet 369: 1090, 2007. 

103. Kromhout D, Giltay EJ, Geleijnse JM for the Alpha 

Omega Trial Group: n-3 fatty acids and cardiovascular 

events after myocardial infarction. N Engl J 

Med 363: 2015, 2010. 

103a. Saravanan P, Davidson NC, Schmidt EB, Calder 

PC: Cardiovascular effects of marine omega-3 fatty 

acids. Lancet 375: 540, 2010. 

104. Siani A, Pagano E, Iacone R, et al: Blood pressure 

and metabolic changes during dietary L-arginine 

supplementation in humans. Am J Hypertens 

13:547, 2000. 

105. Candipan RC, Wang B, Buitrago R, et al: Regression 

or progression. Dependency on vascular nitric 

oxide. Arteriothromb Vasc Biol 16:44, 1996. 

106. Drexler H, Zeiher AM, Meinzer K, Just H: Correction 

of endothelial dysfunction in coronary microCirculation 

of hypercholesterolemic patients by 

L-arginine. Lancet 338:1546, 1991. 

107. Egashira K, Hirooka Y, Kuga T, et al: Effects of Larginine 

supplementation on endothelium-dependent 

coronary vasodilation in patients with angina 

pectoris and normal coronary angiograms. Circulation 

94:130, 1996. 

108. Quyyumi A, Dakak N, Diodati J, et al: Effect of 

L-arginine on human coronary endothelium-dependent 

and physiologic vasodilation. J Am Coll 

Cardiol 30:1220, 1997. 

109. Lerman A, Burnett JC Jr, Higano ST, et al: Longterm 

L-arginine supplementation improves smallvessel 

coronary endothelial function in humans. 


110. Blum A, Hathaway L, Mincemoyer R, et al: Oral 

L-arginine in patients with coronary artery disease 

on medical management. Circulation 101:2160, 

2000. 

111. Loscalzo J, Welch G: Nitric oxide and its role in the 

cardiovascular system. Prog Cardiovasc Dis 38:87, 

1995. 


112. Quyyumi A: Does acute improvement of endothelial 

dysfunction in coronary artery disease improve 

myocardial ischemia? A double-blind comparison 

of parenteral D- and L-arginine. J Am Coll Cardiol 

32:904, 1998. 

113. Ito T, Kimura Y, Uozumi Y, et al: Taurine depletion 

caused by knocking out the taurine transporter 

gene leads to cardiomyopathy with cardiac atrophy. 

J Mol Cell Cardiol 44:927, 2008. 

114. Oudit GY, Trivieri MG, Khaper N, et al: Taurine 

supplementation reduces oxidative stress and improves 

cardiovascular function in an iron-overload 

marine model. Circulation 109: 1877, 2004. 

114a. Stamler J, Brown IJ, Daviglus ML, et al for the 

INTERMAP Research Group: Glutamic acid, the 

main dietary amino acid, and blood pressure. 

The INTERMAP study (International Collaborative 

Study of Macronutrients, Micronutrients and 

Blood Pressure). Circulation 120: 221, 2009. 

115. Solerte SB, Fioravanti M, Locatelli E, et al: Improvement 

of blood glucose control and insulin 

sensitivity during a long-term (60 weeks) randomized 

study with amino acid dietary supplements in 

elderly subjects with type 2 diabetes mellitus. Am J 

Cardiol 101 Suppl 11A: 82EE, 2008. 

116. Kalantar-Zadeh K, Anker SD, Horwich TB, Fonarow 

GC: Nutritional and anti-inflammatory interventions 

in chronic heart failure. Am J Cardiol 101 

Suppl 11A: 89E, 2008. 

117. Aquilani R, Viglio S, Iadarola P, et al: Oral amino 

acid supplements improve exercise capacities in elderly 

patients with chronic heart failure. Am J Cardiol 

101 Suppl 11A:104E, 2008. 

118. Corsetti G, Pasini E, D’Antona G, et al: Morphometric 

changes induced by amino acid supplementation 

in skeletal and cardiac muscles of old mice. 

Am J Cardiol 101 Suppl 11A:26E, 2008. 

119. Scarabelli TM, Pasini E, Stephanou A, et al: Nutritional 

supplementation with mixed essential amino 

acids enhances myocycte survival, preserving mitochondrial 

functional capacity during ischemiareperfusion 

injury. Am J Cardiol 93 (8A): 35A, 

2004. 

120. Frishman WH, Sinatra ST, Moizuddin M: Herbal 

approach to cardiac disease. In Frishman WH, 

Weintraub MI, Micozzi M: Complementary & Integrative 

Therapies for Cardiovascular Disease. St. 

Louis: Elsevier, 2005: 86. 

121. Goldman P: Herbal medicines today and the roots 

of modern pharmacology. Ann Intern Med 135:594, 

2001. 

122. Sinatra ST, Frishman WH, Peterson SJ, Lin G: Use 

of alternative/complementary medicine in treating 

cardiovascular disease. In Frishman WH, Sonnen-


blick EH, Sica DA (eds): Cardiovascular Pharmacotherapeutics 

2nd ed. New York: McGraw Hill 

2003:857. 

123. Marcus DM, Grollman AP: Botanical medicine– 

the need for new regulations (sounding board). N 

Engl J Med 347: 2073, 2002. 

124. Slifman NR, Obermeyer WR, Musser SM, et al: 

Contamination of botanical dietary supplements 

by Digitalis lanata. N Engl J Med 339: 806, 1998. 

125. Radford DJ, Gillies AD, Hinds JA, et al: Naturally 

occurring cardiac glycosides. Med J Aust 144: 540, 

1986. 

126. Dasgupta A, Tso G, Wells A: Effect of Asian ginseng, 

Siberian ginseng, and Indian ayurvedic medicine 

Ashwagandha on serum digoxin measurement 

by Digoxin III, a new digoxin immunoassay. J Clin 

Lab Anal 22: 295, 2008. 

127. Aaronson K: HERB CHF (Hawthorn Extract Randomized 

Blinded Chronic HF Study) presented 

at the 8th Annual Scientific Meeting of the Heart 

Failure Society of America. September 12-15, 2004, 

Toronto, Canada. 

128. Zick SM, Gillespie B, Aaronson KD: The effect of 

Crataegus oxycantha Special Extract WS 1442 on 

clinical progression in patients with mild to moderate 

symptoms of heart failure. Eur J Heart Fail 10: 

587, 2008. 

129. Sutter MC, Wang YX: Recent cardiovascular drugs 

from Chinese medicinal plants. Cardiovasc Res 27: 

1891, 1993. 

130. Kawashima K, Hayakawa T, Miwa Y, et al: Structure 

and hypotensive activity relationships of tetrandrine 

derivatives in stroke-prone spontaneously 

hypertensive rats. Gen Pharmacol 21:343, 1990. 

131. Ody P: The Complete Medicinal Herbal. New York: 

Dorling Kindersley, 1993. 

132. Ma G, Ding S, Feng Y, et al: Tetramethylpyrazineeluting 

stents prevented in-stent restenosis in a 

porcine model. J Cardiovasc Pharmacol 50:201, 

2007. 

133. Kuramochi T, Chu J, Suga T: Gou-teng (from Uncaria 

rhynchophylla Miquel) induced endotheliumdependent 

and independent relaxations in the 

isolated rat aorta. Life Sci 54:2061, 1994. 

134. Wang L, Li W, Liu Y: Hypotensive effect and toxicology 

of total alkaloids and veratramine from roots 

and rhizomes of Veratrum nigrum L. in spontaneously 

hypertensive rats. Pharmazie 63: 606, 2008. 

135. Chang Q, Zuo Z, Harrison F, Chow MSS: Hawthorn. 

J Clin Pharmacol 42: 605-12, 2002. 

136. Vibes J, Lasserre B, Gleye J, et al: Inhibition of 

thromboxane A2 biosynthesis in vitro by the main 

components of Crataegus oxyacantha (hawthorn) 

flower heads. Prostaglandins Leukot Essent Fatty 

Acids 50:173, 1994. 

137. Shanthi S, Parasakthy K, Deepalakshmi PD, et al: 

Hypolipidemic activity of tincture of Crataegus in 

rats. Indian J Biochem Biophys 31:143, 1994. 

138. Nasa Y, Hashizume H, Hoque AN, et al: Protective 

effect of Crataegus extract on the cardiac mechanical 

dysfunction in isolated perfused working rat 

heart. Arzneimittelforschung 43:945, 1993. 

139. Roddewig C, Hensel H: Reaction of local myocardial 

blood flow in non-anesthetized dogs and 

anesthetized cats to the oral and parenteral administration 

of a Crataegus fraction (oligomere procyanidines) 

[German] Arzneimittelforschung 27:1407, 

1977. 

140. Baughman KL, Bradley DJ: Hawthorn extract: is it 

time to turn over a new leaf? Am J Med 114: 700, 

2003. 

141. Pittler MH, Schmidt K, Ernst E: Hawthorn extract 

for treating chronic heart failure: meta-analysis of 

randomized trials. Am J Med 114: 665, 2003. 

142. Schussler M, Holzl J, Fricke U: Myocardial effects 

of flavonoids from Crataegus species. Arzneim 

Forsch 45:842, 1995. 

143. Zhang W, Wojta J, Binder BR: Effect of notoginsenoside 

R1 on the synthesis of tissue-type plasminogen 

activator and plasminogen activator inhibitor-1 

in cultured human umbilical vein endothelial cells. 

Arterioscler Thromb 14:1040, 1994. 

144. Lin SG, Zheng XL, Chen QY, et al: Effect of Panax 

notoginseng saponins on increased proliferation of 

cultured aortic smooth muscle cells stimulated by 

hypercholesterolemic serum. Chung Kuo Yao Li 

Hsueh Pao 14:314, 1993. 

145. Zhang YG, Zhang HG, Zhang GY, et al: Panax Notoginseng 

saponins attenuate atherosclerosis in rats 

by regulating the blood lipid profile and an antiinflammatory 

action. Clin Exp Pharmacol Physiol 

35: 1238, 2008. 

146. Lam FF, Yeung JH, Chan KM, et al: Dihydrotanshinone, 

a lipophilic component of Salvia Miltiorrhiza 

(danshen), relaxes rat coronary artery by inhibition 

of calcium channels. J Ethnopharmacol 119: 318, 

2008. 

147. Ried K, Frank OR, Stocks NP, el al: Effect of garlic 

on blood pressure: A systematic review and metaanalysis. 

BMC Cardiovascular Disord 8:13, 2008. 

148. Lau BH: Suppression of LDL oxidation by garlic 

compounds is a possible mechanism of cardiovascular 

health benefit. J Nutr 136: 765S, 2006. 

149. Gardner CD, Lawson LD, Block E, et al: Effect of 

raw garlic vs commercial garlic supplements on 

plasma lipid concentrations in adults with moderate 

hypercholesterolemia: a randomized clinical 

trial. Arch Intern Med 167:325, 2007.

150. Ackermann RT, Mulrow CD, Ramirez G, et al: Garlic 

shows promise for improving some cardiovascular 

risk factors. Arch Intern Med 161: 813, 2001. 

151. Silagy CA, Neil HA: A meta-analysis of the effect of 

garlic on blood pressure. J Hypertens 12:463, 1994. 

152. Silagy C, Neil A: Garlic as a lipid lowering agent—a 

meta-analysis. J R Coll Physicians Lond 28:39, 1994. 

153. Clinical Trial: Trial to identify the anti-blood-clotting 

compounds in garlic. www.clinicaltrials.gov/ 

ct. 

154. Kong WJ, Wei J, Zuo ZY, et al: Combination of simvastatin 

with berberine improves the lipid-lowering 

efficacy. Metabolism 57: 1029, 2008. 

155. Low Dog T: Herbs in cardiovascular diseases. Botanical 

Medicine in Modern Clinical Practice 8th 

Annual Course. Columbia University, New York, 

June 9-13, 2003. 

156. Saper RB, Phillips RS, Sehgal A, et al: Lead, mercury 

and arsenic in US- and Indian-manufactured 

ayurvedic medicines sold via the internet. JAMA 

300: 915, 2008. 

157. Clinical Trials: Safety of an herbal treatment for 

high cholesterol in individuals with statin intolerance. 

www.clinicaltrials.gov/ct. 

158. Clinical Trials: Statin therapy vs. therapeutic lifestyle 

changes and supplements. www.clinicaltrials. 

gov/ct. 

158a. Becker DJ, Gordon RY, Halbert SC, et al: Red yeast 

rice for dyslipidemia in statin-intolerant patients. 

Ann Intern Med 150: 830, 2009. 

159. Gardner CD, Taylor-Piliae RE, Kiazand A, et al: 

Effect of Ginkgo biloba (EGb 761) on treadmill 

walking time among adults with peripheral artery 

disease: a randomized clinical trial. J Cardiopulm 

Rehabil Prev 28: 258, 2008. 

160. Stevermer JJ, Lindbloom EJ: Ginkgo biloba for dementia. 

J Fam Pract 46:20, 1998. 

161. Solomon PR, Adams F, Silver A, et al: Ginkgo for 

memory enhancement. A randomized controlled 

trial. JAMA 288:835, 2002. 

162. Matthews MK: Association of Ginkgo biloba with 

intracerebral hemorrhage. Neurology 50:1933, 

1998. 

163. Gianni L, Dreitlein WB: Some popular OTC herbals 

can interact with anticoagulant therapy. US 

Pharm 23: 80, 1998. 

164. Haraguchi H, Saito T, Okamura N, et al: Inhibition 

of lipid peroxidation and superoxide generation by 

diterpenoids from Rosmarinus officinalis. Planta 

Med 61:333, 1995. 

165. al-Hader AA, Hasan ZA, Aqel MB: Hyperglycemic 

and insulin release inhibiting effects of Rosmarinus 

officinalis. J Ethnopharmacol 43:217, 1994. 

166. Tyler VE: The Honest Herbal: A Sensible Guide to 


the Use of Herbs and Related Remedies 3rd ed. New 

York: Pharmaceutical Product Press, 1993. 

167. Diehm C, Vollbrecht D, Amendt K, et al: Medical 

edema protection—clinical benefit in patients with 

chronic deep vein incompetence: Aplacebo controlled 

double blind study. Vasa 21:188, 1992. 

168. Lang W: Studies on the percutaneous absorption of 

3H-aescin in pigs. Res Exp Med 169:175, 1977. 

169. Berg D: Venous constriction by local administration 

of ruscus extract (German). Fortschr Med 

108:473, 1990. 

170. Berg D: Venous tonicity in pregnancy varicose 

veins (German). Fortschr Med 110:67 , 1992. 

171. Li YP, Wang YM: Evaluation of tussilagone: A cardiovascular 

respiratory stimulant isolated from 

Chinese herbal medicine. Gen Pharmacol 19: 261, 

1988. 

172. Flanagan CM, Kaesberg JL, Mitchell ES, et al: Coronary 

artery aneurysm and thrombosis following 

chronic ephedra use. Int J Cardiol 139: e11, 2010. 

173. Chan TYK, Chan JCN, Tomlinson B, et al: Chinese 

herbal medicines revisited: the Hong Kong perspective. 

Lancet 342: 1532, 1993. 

174. Horowitz RS, Feldhaus K, Dart RC, et al: The clinical 

spectrum of Jin Bu Huan toxicity. Arch Intern 

Med 156: 899, 1996. 

175. Frishman WH, Opie LH, Sica DA: Adverse cardiovascular 

drug interactions and complications. In 

Fuster V, Alexander RW, O’Rourke RA, Roberts R, 

King SB, Prystowsky E, Nash IS: Hurst’s The Heart 

11th ed. New York: McGraw Hill 2004; 2169. 

176. Wang Z, Gorski C, Hamman MA, et al: The effects 

of St. John’s Wort (Hypericum perforatum) on human 

cytochrome P450 activity. Clin Pharmacol 

Ther 70: 317, 2001. 

177. Mueller SC, Uehleke B, Woehling H, et al: Effect of 

St. John’s wort dose and preparations on the pharmacokinetics 

of digoxin. Clin Pharmacol Ther 75: 

546, 2004. 

178. Ernst E: The risk-benefit profile of commonly used 

herbal therapies: ginkgo, St. John’s wort, ginseng, 

Echinacea, saw palmetto and kava. Ann Intern Med 

136: 42, 2002. 

179. Yuan C-S, Wei G, Dey L, et al: Brief communications: 

American ginseng reduces warfarin’s effect in 

healthy patients. Ann Intern Med 141: 23, 2004. 

180. Clauson KA, Santamarina ML, Rutledge JC: Clinically 

relevant safety issues associated with St. John’s 

wort product labels. BMC Complement Altern Med 

8:42, 2008. 

180a. Cohen PA: American roulette – contaminated dietary 

supplements. N Engl J Med 361: 1523, 2009. 

181. Whitmont RD, Mamtani R: Homeopathy with a 

special focus on treatment of cardiovascular dis-


ease. In Frishman WH, Weintraub MI, Micozzi M: 

Complementary & Integrative Therapies in Cardiovascular 

Disease. St. Louis: Elsevier 2005: 232. 

182. Shang A, Huwiler-Muntener K, Nartey L, et al: Are 

the clinical effects of homoeopathy placebo effects? 

Comparative study of placebo-controlled trials of 

homoeopathy and allopathy. Lancet 366: 726, 2005. 

183. Goldacre B: Benefits and risks of homeopathy. Lancet 

370(9600): 1672, 2007. 

184. Prasad R: Homeopathy booming in india. Lancet 

370(9600): 1679, 2007. 

185. Diagnostic and therapeutic technology assessment: 

chelation therapy. JAMA 250: 672, 1983. 

186. Clarke NE. Clarke CN, Mosher RF: The “in vivo” 

dissolution of metastatic calcium: an approach to 

atherosclerosis. Am J Med Sci 229: 142, 1955. 

187. Eisenberg DM, Davis RB, Ettner SL, et al: Trends in 

alternative medicine use in the United States, 1990- 

1997; results of a follow-up national survey. JAMA 

280: 1569, 1998. 

188. Chappell LT, Stahl JP: The correlation between 

EDTA chelation therapy and improvement in cardiovascular 

function: a meta-analysis. J Adv Med 6: 

139, 1993. 

189. Gibbons RJ, Abrams J, Chatterjee K, et al: ACC/ 


with chronic stable angina. A report of the 

American College of Cardiology/ American Heart 

Association Task Force on Practice Guidelines. J 


190 Cranton EM: Laguna Hills: American College of 

Advancement in Medicine, 1989. 

191. Frishman WH, Wolff AI: Chelation therapy. In Frishman 

WH, Weintraub MI, Micozzi M: Complementary 

& Integrative Therapies in Cardiovascular 

Disease. St. Louis: Elsevier 2005: 288. 

192. Mitka M: Chelation therapy trials halted (medical 

news and perspectives). JAMA 300; 2236, 2008.


Cardiovascular Drug–Drug Interactions 

Angela Cheng-Lai, PharmD 



1. In sour economy, some scale back on medications. 

New York Times article dated October 21, 2008. 

Available at http://www.nytimes.com/2008/10/22/ 

business/22drug.html. Accessed January 31, 2010. 

2. IMS Health press release dated March 12, 2008. 

Available at: http://www.imshealth.com/portal/ 

site/imshealth/menuitem.a46c6d4df3db4b3d88f61 

1019418c22a/?vgnextoid=280c1d3be7a29110Vgn 

VCM10000071812ca2RCRD&vgnextfmt=default. 

Accessed January 31, 2010. 

3. Lipitor prescribing information. Pfizer Ireland 

Pharmaceuticals. Dublin, Ireland. June 2009. 

4. Hansten P, Horn J. Drug-drug interaction mechanisms. 

Available at: http://hanstenandhorn.com/ 

article-d-i.html. Accessed January 31, 2010. 

5. Chang GW, Kam PC. The physiological and pharmacological 

roles of cytochrome P450 isoenzymes. 

Anaesthesia 54:42, 1999. 

6. Michalets EL. Update: Clinically significant cytochrome 

P-450 drug interactions. Pharmacotherapy 

18:84, 1998. 

7. Horn JR, Hansten PD. Get to know an enzyme: 

CYP3A4. Pharmacy Times 2008;9:40. Available at: 

http://www.pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687. 

Accessed January 

31, 2010. 


CYP1A2. Pharmacy Times 2007;11:76. Available 

at: http://www.pharmacytimes.com/issue/pharmacy/2007/2007-11/2007-11-8279. 


31, 2010. 


CYP2C19. Pharmacy Times 2008;5:32. Available 

at: http://www.pharmacytimes.com/issue/pharmacy/2008/2008-05/2008-05-8538. 


31, 2010. 


CYP2C9. Pharmacy Times 2008;3:37. Available at: 



31, 2010. 


CYP2D6. Pharmacy Times 2008;7:32. Available at: 



31, 2010. 

12. Anderson JR, Nawarskas JJ. Cardiovascular drugdrug 

interactions. Cardiology Clinics 19:215, 2001. 

13. Hansten PD, Horn JR, eds. Hansten and Horn’s 

Drug Interactions Analysis and Management. St. 

Louis, MO, Facts & Comparisons, 2009. 

14. Bigger JT Jr. Leahey EB Jr. Quinidine and digoxin: 

an important interaction. Drugs 24:229, 1982. 

15. Schenck-Gustafsson K, Juhlin-Dannfelt A, 

Dahlqvist R. Renal function and digoxin clearance 

during quinidine therapy. Clinical Physiology 2:401, 

1982. 

16. Horn JR, Hansten PD. Drug transporters: the final 

frontier for drug interactions. Pharmacy Times 

12:28, 2008. 

17. Horn JR, Hansten PD. Drug transporters: the final 

frontier for drug interactions – part 2. Pharmacy 

Times 2:33, 2009. 

18. Eberl S, Renner B, Neubert A, et al. Role of P-glycoprotein 

inhibition for drug interactions. Clin Pharmacokinet. 

46:1039, 2007. 

19. Rengelshausen J, Goggelmann C, Burhenne J, et al. 

Contribution of increased oral bioavailability and 

reduced nonglomerular renal clearance of digoxin 

to the digoxin-clarithromycin interaction. Br J Clin 

Pharmacol. 56:32, 2003. 

20. Gurley BJ, Swain A, Williams DK, et al. Gauging 



31-1


the clinical significance of P-glycoprotein-mediated 

herb-drug interactions: comparative effects 

of St. John’s wort, Echinacea, clarithromycin, and 

rifampin on digoxin pharmacokinetics. Mol Nutr 

Food Res. 52:772, 2008. 

21. Regazzi MB, Iacona I, Campana C, et al. Altered 

disposition of pravastatin following concomitant 

drug therapy with cyclosporin A in transplant recipients. 

Transplant Proc. 25:2732, 1993. 

22. Somogyi A, McLean A, Heinzow B. Cimetidineprocainamide 

pharmacokinetic interaction in 

man: evidence of competition for tubular secretion 

of basic drugs. Eur J Clin Pharmacol. 25:339, 1983. 

23. Micromedex Healthcare series, (electronic version). 

Thomson Micromedex, Greenwood Village, 

Colorado, USA. Available at: http://www.thomsonhc.com. 

Assessed: 1/30/2010. 

24. Quinn DI, Day RO. Drug interactions of clinical 

importance. An updated guide. Drug Safety 12: 

393, 1995. 

25. Mignat C, Unger T. ACE inhibitors. Drug interactions 

of clinical significance. Drug Safety 12: 334, 

1995. 

26. Salvetti A, Abdel-Haq B, Magagna A, et al. Indomethacin 

reduces the antihypertensive action of 

enalapril. Clin Exp Hypertens A. 9:559, 1987. 

27. Abdel-Haq B, Magagna A, Favilla S, et al. Hemodynamic 

and humoral interactions between perindopril 

and indomethacin in essential hypertensive 

subjects. J Cardiovasc Pharmacol. 18 (Suppl 7):S33, 

1991. 

28. Seelig CB, Maloley PA, Campbell JR, et al. Nephrotoxicity 

associated with concomitant ACE inhibitor 

and NSAID therapy. South Med J. 83:1144, 1990. 

29. Stys T, Lawson WE, Smaldone GC, et al. Does aspirin 

attenuate the beneficial effects of angiotensinconverting 

enzyme inhibition in heart failure? Arch 

Intern Med. 160:1409, 2000. 

30. Nguyen KN, Aursnes I, Kjekshus J. Interaction between 

enalapril and aspirin on mortality after acute 

myocardial infarction: subgroup analysis of the 

Cooperative New Scandinavian Enalapril Survival 

Study II (CONSENSUS II). Am J Cardiol. 79:115, 

1997. 

31. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet 

agents and survival: a cohort analysis from 

the studies of left ventricular dysfunction (SOLVD) 

trial. J Am Coll Cardiol. 31:419, 1998. 

32. Oosterga M, Anthonio RL, de Kam PJ, et al. Effects 

of aspirin on angiotensin-converting enzyme inhibition 

and left ventricular dilation one year after 

acute myocardial infarction. Am J Cardiol. 81:1178, 

1998. 

33. Weksler BB, Pett SB, Alonso D, et al. Differential 

inhibition by aspirin of vascular and platelet prostaglandin 

synthesis in atherosclerotic patients. N 

Engl J Med. 308:800, 1983. 

34. Arauz-Pacheco C, Ramirez LC, Rios JM, et al. Hypoglycemia 

induced by angiotensin-converting 

enzyme inhibitors in patients with non-insulindependent 

diabetes receiving sulfonylurea therapy. 

The American Journal of Medicine. 89:811, 1990. 

35. Ahmad S. Drug interaction induces hypoglycemia. 

J Fam Pract. 40:540, 1995. 

36. Page RL II, Miller GG, Lindenfeld J. Drug therapy 

in the heart transplant recipient. Part IV: Drug- 

Drug interactions. Circlation. 111:230, 2005. 

37. Gossmann J, Thürmann P, Bachmann T, et al. 

Mechanism of angiotensin converting enzyme 

inhibitor-related anemia in renal transplant recipients. 

Kidney Int. 50:973, 1996. 

38. Gossmann J, Kachel HG, Schoeppe W, et al. 

Anemia in renal transplant recipients caused by 

concomitant therapy with azathioprine and angiotensin-converting 

enzyme inhibitors. Transplantation. 

56:585, 1993. 

39. Ahmad S. Allopurinol and enalapril. Drug induced 

anaphylactic coronary spasm and acute myocardial 

infarction. Chest. 108:586, 1995. 

40. Pennell DJ, Nunan TO, O’Doherty MJ, et al. Fatal 

Stevens-Johnson syndrome in a patient on captopril 

and allopurinol. Lancet. 1:463, 1984. 

41. Samanta A, Burden AC. Fever, myalgia, and arthralgia 

in a patient on captopril and allopurinol. 

Lancet. 1:679, 1984. 

42. Murray BM, Venuto RC, Kohli R, et al. Enalaprilassociated 

acute renal failure in renal transplants: 

possible role of cyclosporine. Am J Kidney Dis. 

16:66, 1990. 

43. Douste-Blazy P, Rostin M, Livarek B, et al. Angiotensin 

converting enzyme inhibitors and lithium 

treatment. Lancet. 1:1448, 1986. 

44. Correa FJ, Eiser AR. Angiotensin-converting enzyme 

inhibitors and lithium toxicity. Am J Med. 

93:108, 1992. 

45. Baldwin CM, Safferman AZ. A case of lisinoprilinduced 

lithium toxicity. DICP. 24:946, 1990. 

46. Unger T, Kaschina E. Drug interactions with angiotensin 

receptor blockers: A comparison with other 

antihypertensives. Drug Safety 26:707, 2003. 

47. Böhler S, Pittrow D, Bramlage P, et al. Drug interactions 

with angiotensin receptor blockers. Expert 

Opin. Drug Saf. 4:7, 2005. 

48. Kazierad DJ, Martin DE, Blum RA, et al. Effect of 

fluconazole on the pharmacokinetics of eprosartan 

and losartan in healthy male volunteers. Clin Pharmacol 

Ther. 62:417, 1997. 

49. Williamson KM, Patterson JH, McQueen RH, et

al. Effects of erythromycin or rifampin on losartan 

pharmacokinetics in healthy volunteers. Clin Pharmacol 

Ther. 63:316, 1998. 

50. Marino MR, Vachharajani NN. Drug interactions 

with irbesartan. Clin Pharmacokinet. 40:605, 2001. 

51. Mangold B, Gielsdorf W, Marino MR. Irbesartan 

does not affect the steady-state pharmacodynamics 

and pharmacokinetics of warfarin. Eur J Clin Pharmacol. 

55:593, 1999. 

52. Trujillo TC, Nolan PE. Antiarrhythmic agents. 

Drug interactions of clinical significance. Drug 

Safety 23:509, 2000. 

53. Spinler SA, Cheng JW, Kindwall KE, et al. Possible 

inhibition of hepatic metabolism of quinidine by 

erythromycin. Clin Pharmacol Ther. 57:89, 1995. 

54. Yamreudeewong W, DeBisschop M, Martin LG, et 

al. Potentially significant drug interactions of class 

III antiarrhythmic drugs. Drug Safety 26:421, 2003. 

55. Bailey DG, Dresser GK. Interactions between 

grapefruit juice and cardiovascular drugs. Am J 

Cardiovasc Drugs 4:281, 2004. 

56. Kappenberger TR, Steinbrunn W, Meyer UA. Dangerous 

interactions between amiodarone and quinidine. 

Lancet. 1:1327, 1982. 

57. Baker BJ, Gammill J, Massengill J, et al. Concurrent 

use of quinidine and disopyramide: evaluation of 

serum concentrations and electrocardiographic effects. 

Am Heart J. 105:12, 1983. 

58. Hughes B, Dyer JE, Schwartz AB. Increased procainamide 

plasma concentrations caused by quinidine: 

a new drug interaction. Am Heart J. 114(4 Pt 

1):908, 1987. 

59. Saal AK, Werner JA, Greene HL, et al. Effect of 

amiodarone on serum quinidine and procainamide 

levels. Am J Cardiol. 53:1264, 1984. 

60. Mörike KE, Roden DM. Quinidine-enhanced beta-blockade 

during treatment with propafenone in 

extensive metabolizer human subjects. Clin Pharmacol 

Ther. 55:28, 1994. 

61. Cooke CE, Sklar GE, Nappi JM. Possible pharmacokinetic 

interaction with quinidine: ciprofloxacin 

or metronidazole? Ann Pharmacother. 30:364, 

1996. 

62. Lin JC, Quasny HA. QT prolongation and development 

of torsades de pointes with the concomitant 

administration of oral erythromycin base and 

quinidine. Pharmacotherapy. 17:626, 1997. 

63. Kaukonen KM, Olkkola KT, Neuvonen PJ. Itraconazole 

increases plasma concentrations of quinidine. 

Clin Pharmacol Ther. 62:510, 1997. 

64. Farringer JA, Green JA, O’Rourke RA, et al. Nifedipine-induced 

alterations in serum quinidine 

concentrations. Am Heart J. 108:1570, 1984. 

65. Data JL, Wilkinson GR, Nies AS. Interaction of 


quinidine with anticonvulsant drugs. N Engl J Med. 

294:699, 1976. 

66. Koch-Weser J. Quinidine-induced hypoprothrombinemic 

hemorrhage in patients on chronic warfarin 

therapy. Ann Intern Med. 68:511, 1968. 

67. Vlasses PH, Kosoglou T, Chase SL, et al. Trimethoprim 

inhibition of the renal clearance of procainamide 

and N-acetylprocainamide. Arch Intern 

Med. 149:1350, 1989. 

68. Rocci ML Jr, Kosoglou T, Ferguson RK, et al. Ranitidine-induced 

changes in the renal and hepatic 

clearances of procainamide are correlated. J Pharmacol 

Exp Ther. 248;923, 1989. 

69. Martin DE, Shen J, Griener J. Effects of ofloxacin 

on the pharmacokinetics and pharmacodynamics 

of procainamide. J Clin Pharmacol. 36:85, 1996. 

70. Bonde J, Bødtker S, Angelo HR, et al. Atenolol inhibits 

the elimination of disopyramide. Eur J Clin 

Pharmacol. 28:41, 1985. 

71. Kapil RP, Axelson JE, Mansfield IL, et al. Disopyramide 

pharmacokinetics and metabolism: effect of 

inducers. Br J Clin Pharmacol. 24:781, 1987. 

72. Ragosta M, Weihl AC, Rosenfeld LE. Potentially 

fatal interaction between erythromycin and disopyramide. 

Am J Med. 86:465, 1989. 

73. Siegmund JB, Wilson JH, Imhoff TE. Amiodarone 

interaction with lidocaine. J Cardiovasc Pharmacol. 

21:513, 1993. 

74. Conrad KA, Byers JM 3rd, Finley PR, et al. Lidocaine 

elimination: effects of metoprolol and of propranolol. 


75. Feely J, Wilkinson GR, McAllister CB, et al. Increased 

toxicity and reduced clearance of lidocaine 

by cimetidine. Ann Intern Med. 96:592, 1982. 

76. Katz A, Buskila D, Sukenik S. Oral mexiletine-theophylline 

interaction. Int J Cardiol. 17:227, 1987. 

77. Tjandra-Maga TB, Van Hecken A, Van Melle P, et 

al. Altered pharmacokinetics of oral flecainide by 

cimetidine. Br. J. Clin. Pharmac. 22:108, 1986. 

78. Spinler SA, Gammaitoni A, Charland SL. Propafenone-theophylline 

interaction. Pharmacotherapy. 

13:68, 1993. 

79. Kates RE, Yee YG, Kirsten EB. Interaction between 

warfarin and propafenone in healthy volunteer 

subjects. Clin Pharmacol Ther. 42:305, 1987. 

80. Rees A, Dalal JJ, Reid PG, et al. Dangers of amiodarone 

and anticoagulant treatment. Br Med J(Clin 

Res Ed). 282:1756, 1981. 

81. Hamer A, Peter T, Mandel WJ, et al. The potentiation 

of warfarin anticoagulation by amiodarone. 

Circulation. 65:1025, 1982. 

82. Leor J, Levartowsky D, Sharon C, et al. Amiodarone 

and beta-adrenergic blockers: an interaction 

with metoprolol but not with atenolol. Am Heart J.


116(1 Pt 1):206, 1988. 

83. Nicolau DP, Uber WE, Crumbley AJ 3rd, et al. 

Amiodarone-cyclosporine interaction in a heart 

transplant patient. J Heart Lung Transplant. 11(3 Pt 

1):564, 1992. 

84. Nademanee K, Kannan R, Hendrickson J, et al. 

Amiodarone-digoxin interaction: clinical significance, 

time course of development, potential 

pharmacokinetic mechanisms and therapeutic implications. 

J Am Coll Cardiol. 4:111, 1984. 

85. Nolan PE Jr, Marcus FI, Karol MD, et al. Effect of 

phenytoin on the clinical pharmacokinetics of amiodarone. 

J Clin Pharmacol. 30:1112, 1990. 

86. Windle J, Prystowsky EN, Miles WM, et al. Pharmacokinetic 

and electrophysiologic interactions 

of amiodarone and procainamide. Clin Pharmacol 

Ther. 41:603, 1987. 

87. Lohman JJ, Reichert LJ, Degen LP. Antiretroviral 

therapy increases serum concentrations of amiodarone. 

Ann Pharmacother 33:645, 1999. 

88. Kerin NZ, Blevins RD, Goldman L, et al. The incidence, 

magnitude, and time course of the amiodarone-warfarin 

interaction. Arch Intern Med. 

148:1779, 1988. 

89. Abel S, Nichols DJ, Brearley CJ, et al. Effect of cimetidine 

and ranitidine on pharmacokinetics and 

pharmacodynamics of a single dose of dofetilide. 

Br J Clin Pharmacol. 49:64, 2000. 

90. Garcia D, Cheng-Lai A. Dronedarone. A new antiarrhythmic 

agent for the treatment of atrial fibrillation. 

Cardiology in Review 17:230, 2009. 

91. Elliott HL, McLean K, Summer DJ, et al. Immediate 

cardiovascular responses to oral prazosin-effects 

of concurrent beta-blockers. Clin Pharmacol 

Ther. 29:303, 1981. 

92. Singh S, Saini RK, DiMarco J, et al. Efficacy and 

safety of sotalol in digitalized patients with chronic 

atrial fibrillation. The sotalol study group. Am J 

Cardiol. 68:1227, 1991. 

93. Frishman WH, Cheng-Lai A, Nawarska J (eds): 

Current Cardiovascular Drugs, 4th ed. Philadelphia: 

Current Medicine, 2005. 

94. Harder S, Thürmann P. Clinically important drug 

interactions with anticoagulants. An update. Clin. 

Pharmacokinet. 30:416, 1996. 

95. Chesebro JH, Fuster V, Elveback LR, et al. Trial of 

combined warfarin plus dipyridamole or aspirin 

therapy in prosthetic heart valve replacement: danger 

of aspirin compared with dipyridamole. Am J 

Cardiol. 51:1537, 1983. 

96. Jähnchen E, Meinertz T, Gilfrich HJ, et al. Enhanced 

elimination of warfarin during treatment 

with cholestyramine. Br J Clin Pharmacol. 5:437, 

1978. 

97. Rindone JP, Keng HC. Gemfibrozil-warfarin drug 

interaction resulting in profound hypoprothrombinemia. 

Chest. 114:641, 1998. 

98. O’Reilly RA. Interaction of chronic daily warfarin 

therapy and rifampin. Ann Intern Med. 83:506, 

1975. 

99. Bachmann K, Schwartz JI, Forney R Jr, et al. The effect 

of erythromycin on the disposition kinetics of 

warfarin. Pharmacology. 28:171-6, 1984. 

100. Kazmier FJ. A significant interaction between metronidazole 

and warfarin. Mayo Clin Proc. 51:782, 

1976. 

101. O’Reilly RA. The steroselective interaction of warfarin 

and metronidazole in man. N Engl J Med. 

295:354, 1976. 

102. Gericke KR. Possible interaction between warfarin 

and fluconazole. Pharmacotherapy. 13:508, 1993. 

103. Smith AG. Potentiation of oral anticoagulants by 

ketoconazole. Br Med J (Clin Res Ed). 288:188, 

1984. 

104. Hassall C, Feetam CL, Leach RH, et al. Letter: Potentiation 

of warfarin by co-trimoxazole. Lancet. 

2:1155, 1975. 

105. Singleton JD, Conyers L. Warfarin and azathioprine: 

an important drug interactions. Am J Med. 

92:217, 1992. 

106. Levine M, Sheppard I. Biphasic interaction of phenytoin 

with warfarin. Clin Pharm. 3:200, 1984. 

107. Khalique SC, Cheng-Lai A. Drug interaction between 

clopidogrel and proton pump inhibitors. 

Cardiology in Review 17:198, 2009. 

108. Ho PM, Maddox TM, Wang L, et al. Risk of adverse 

outcomes associated with concomitant use of 

clopidogrel and proton pump inhibitors following 

acute coronary syndrome. JAMA 301:937, 2009. 

109. Juurlink DN, Gomes T, Ko DT, et al. A populationbased 

study of the drug interaction between proton 

pump inhibitors and clopidogrel. CMAJ 180:713, 

2009. 

110. Stanek EJ, Aubert RE, Flockhart DA, et al. A national 

study of the effect of individual proton pump 

inhibitors on cardiovascular outcomes in patients 

treated with clopidogrel following coronary stenting: 

The Clopidogrel Medco Outcomes Study. 

http://www.scai.org/pdf/20090506Medcoabstract. 

pdf (Abstract). 

111. O’Donoghue ML, Braunwald E, Antman EM, et 

al. Pharmacodynamic effect and clinical efficacy 

of clopidogrel and prasugrel with or without a proton-pump 

inhibitor: an analysis of two randomized 

trials. Lancet. 374:989, 2009. 

112. Rassen JA, Choudhry NK, Avorn J, et al. Cardiovascular 

outcomes and mortality in patients using 

clopidogrel with proton pump inhibitors after per-

cutaneous coronary intervention or acute coronary 

syndrome. Circulation. 120:2322, 2009. 

113. Information for Healthcare Professionals: Update 

to the labeling of clopidogrel bisulfate (marketed 

as Plavix) to alert healthcare professionals about 

a drug interaction with omeprazole (marketed as 

Prilosec and Prilosec OTC). http://www.fda. 

gov/Drugs/DrugSafety/PostmarketDrugSafety- 

InformationforPatientsandPrescribers Assessed: 

1/18/2010. 

114. Juurlink DN. Proton pump inhibitors and clopidogrel. 

Putting the interaction in perspective. Circulation. 

120:2310, 2009. 

115. Laine L, Hennekens C. Proton pump inhibitor and 

clopidogrel interaction: fact or fiction? Am J Gastroenterol 

105:34, 2010. 

116. Blaufarb I, Pfeifer TM, Frishman WH. b-Blockers. 

Drug interactions of clinical significance. Drug 

Safety 13:359, 1995. 

117. Findlay IN, McInnes GT, Dargie HJ. Beta blockers 

and verapamil: a cautionary tale. Br Med J (Clin Res 

Ed). 289:1074, 1984. 

118. Benaim ME. Asystole after verapamil. Br Med J. 

2:169, 1972. 

119. Hunt BA, Bottorff MB, Herring VL, et al. Effects of 

calcium channel blockers on the pharmacokinetics 

of propranolol stereoisomers. Clin Pharmacol Ther. 

47(5):584, 1990. 

120. Bailey RR, Neale TJ. Rapid clonidine withdrawal 

with blood pressure overshoot exaggerated by beta-blockade. 

Br Med J. 1:942, 1976. 

121. Deacon CS, Bax LNDS, Woods HF, et al. Inhibition 

of oxidative drug metabolism by b-adrenoceptor 

antagonists is related to their lipid solubility. Br J 

Clin Pharmac 12:429, 1981. 

122. Silver JM, Yudofsky SC, Kogan M, et al. Elevation 

of thioridazine plasma levels by propranolol. Am J 

Psychiatry. 143;1290, 1986. 

123. Wagner F, Kalusche D, Trenk D, et al, Drug interaction 

between propafenone and metoprolol. Br J 

Clin Pharmacol. 24:213, 1987. 

124. Kowey PR, Kirsten EB, Fu CH, et al. Interaction 

between propranolol and propafenone in healthy 

volunteers. J Clin Pharmacol. 29:512, 1989. 

125. Schneck DW, Luderer JR, Davis D, et al. Effects of 

nadolol and propranolol on plasma lidocaine clearance. 


126. Walley T, Pirmohamed M, Proudlove C, et al. Interaction 

of metoprolol and fluoxetine. Lancet. 

341:967, 1993. 

127. Miners JO, Wing LM, Lillywhite KJ, et al. Selectivity 

and dose-dependency of the inhibitory effect of 

propranolol on theophylline metabolism in man. 

Br J Clin Pharmacol. 20:219, 1985. 


128. Rosenthal T, Ezra D. Calcium antagonists. Drug 

interactions of clinical significance. Drug Safety 

13:157, 1995. 

129. Ahmad S. Nifedipine-phenytoin interaction. J Am 

Coll Cardiol. 3:1582, 1984. 

130. Bahls FH, Ozuna J, Ritchie DE. Interactions between 

calcium channel blockers and the anticonvulsants 

carbamazepine and phenytoin. Neurology. 

41:740, 1991. 

131. Sica DA. Interaction of grapefruit juice and calcium 

channel blockers. Am J Hypertens 19:768, 2006. 

132. Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole 

greatly increases plasma concentrations and effects 

of felodipine. Clin Pharmacol Ther. 61:410, 1997. 

133. Azie NE, Brater DC, Becker PA, et al. The interaction 

of diltiazem with lovastatin and pravastatin. 


134. Kantola T, Kivistö KT, Neuvonen PJ. Erythromycin 

and verapamil considerably increase serum simvastatin 

and simvastatin acid concentrations. Clin 

Pharmacol Ther. 64:177, 1998. 

135. Kohlhaw K, Wonigeit K, Frei U, et al. Effect of the 

calcium channel blocker diltiazem on cyclosporine 

A blood levels and dose requirements. Transplant 

Proc. 20(2 Suppl 2):572, 1988. 

136. Lindholm A, Henricsson S. Verapamil inhibits cyclosporine 

metabolism. Lancet 1:1262, 1987. 

137. Pesavento TE, Jones PA, Julian BA, et al. Amlodipine 

increases cyclosporine levels in hypertensive 

renal transplant patients: results of a prospective 

study. J Am Soc Nephrol. 7:831, 1996. 

138. Madsen JK, Jensen JD, Jensen LW, et al. Pharmacokinetic 

interaction between cyclosporine and the 

dihydropyridine calcium antagonist felodipine. Eur 

J Clin Pharmacol. 50:203, 1996. 

139. Bourbigot B, Guiserix J, Airiau J, et al. Nicardipine 

increases cyclosporine blood levels. Lancet. 1:1447, 

1986. 

140. Verschraagen M, Koks CHW, Schellens JHM, et 

al. P-glycoprotein system as a determinant of drug 

interactions: The case of digoxin-verapamil. PharmacoRes 

40:301, 1999. 

141. Rameis H, Magometschnigg D, Ganzinger U, et al. 

The diltiazem-digoxin interaction. Clin Pharmacol 

Ther. 36:183, 1984. 

142. Winship LC, McKenney JM, Wright JT Jr, et al. The 

effect of ranitidine and cimetidine on single-dose 

diltiazem pharmacokinetics. Pharmacotherapy. 

5:16, 1985. 

143. Smith SR, Kendall MJ, Lobo J, et al. Ranitidine and 

cimetidine; drug interactions with single dose and 

steady-state nifedipine administration. Br J Clin 

Pharmacol. 23:311, 1987. 

144. Smith MS, Benyunes MC, Bjornsson TD, et al. In-


fluence of cimetidine on verapamil kinetics and dynamics. 


145. Laganière S, Davies RF, Carignan G, et al. Pharmacokinetic 

and pharmacodynamic interactions 

between diltiazem and quinidine. Clin Pharmacol 

Ther. 60:255, 1996. 

146. Van Lith RM, Appleby DH. Quinidine-nifedipine 

interaction. Drug Intell Clin Pharm. 19:829, 1985. 

147. Trohman RG, Estes DM, Castellanos A, et al. Increased 

quinidine plasma concentrations during 

administration of verapamil: a new quinidineverapamil 

interaction. Am J Cardiol. 57:706, 1986. 

148. Klein HO, Beker B, DiSegni E, et al. Asystole produced 

by the combination of amiodarone and digoxin. 

Am Heart J. 113:399, 1987. 

149. Kounis NG. Asystole after verapamil and digoxin. 

Br J Clin Pract. 34:57, 1980. 

150. Steiness E, Olesen KH. Cardiac arrhythmias induced 

by hypokalaemia and potassium loss during 

maintenance digoxin therapy. Br Heart J. 38:167, 

1976. 

151. Seller RH, Cangiano J, Kim KE, et al. Digitalis 

toxicity and hypomagnesemia. Am Heart J. 79:57, 

1970. 

152. Lindenbaum J, Rund DG, Butler VP Jr, et al. Inactivation 

of digoxin by the gut flora: reversal by 

antibiotic therapy. N Engl J Med. 305:789, 1981. 

153. Magnani B, Malini PL. Cardiac Glycosides. Drug 

interactions of clinical significance. Drug Safety 

12:97, 1995. 

154. Robinson K, Johnston A, Walker S, et al. The digoxin-amiodarone 

interaction. Cardiovasc Drugs Ther. 

3:25, 1989. 

155. Calvo MV, Martin-Suarez A, Martin Luengo C, et 

al. Interaction between digoxin and propafenone. 

Ther Drug Monit. 11:10, 1989. 

156. Guven H, Tuncok Y, Guneri S, et al. Age-related 

digoxin-alprazolam interaction. Clin Pharmacol 

Ther. 54:42, 1993. 

157. Nola GT, Pope S, Harrison DC. Assessment of the 

synergistic relationship between serum calcium 

and digitalis. Am Heart J. 79:499, 1970. 

158. Weeks CE, Conard GJ, Kvam DC, et al. The effect of 

flecainide acetate, a new antiarrhythmic, on plasma 

digoxin levels. J Clin Pharmacol. 26:27, 1986. 

159. Sachs MK, Blanchard LM, Green PJ. Interaction of 

itraconazole and digoxin. Clin Infect Dis. 16:400, 

1993. 

160. Waldorff S, Andersen JD, Heebøll-Nielsen N, et al. 

Spironolactone-induced changes in digoxin kinetics. 


161. Davis A, Day RO, Begg EJ. Interactions between 

non-steroidal anti-inflammatory drugs and antihypertensives 

and diuretics. Aust N Z J Med. 16:537, 

1986. 

162. Finley PR, Warner MD, Peabody CA. Clinical relevance 

of drug interactions with lithium. Clin Pharmacokinet. 

29:172, 1995. 

163. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. The 

ACC/AHA expert consensus document: Use of 

sildenafil (Viagra) in patients with cardiovascular 

disease. J Am Coll Cardiol 33:273, 1999. 

164. Cialis (tadalafil) Tablet [prescribing information]. 

Indianapolis, Indiana: Eli Lilly and Company; 

2010. 

165. Levitra (vardenafil) Tablet [prescribing information]. 

Wayne, NJ: Bayer Health Care Pharmaceuticals 

Inc; 2008. 

166. Brown DD, Juhl RP, Warner SL. Decreased bioavailability 

of digoxin due to hypocholesterolemic 

interventions. Circulation. 58:164, 1978. 

167. Pierce LR, Wysowski DK, Gross TP. Myopathy and 

rhabdomyolysis associated with lovastatin-gemfibrozil 

combination therapy. JAMA. 264:71, 1990. 

168. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis 

associated with simvastatin-gemfibrozil therapy. 

South Med J. 90:546, 1997. 

169. Jacobson TA. Myopathy with statin-fibrate combination 

therapy: clinical considerations. Nat Rev 

Endocrinol. 5:507, 2009. 

170. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis 

with fenofibrate + statin versus gemfibrozil 

+ any statin. Am J Cardiol. 95:120, 2005. 

171. Drug interactions with simvastatin. The Medical 

Letter 50:83, 2008. 

172. Jacobson TA. Comparative pharmacokinetic interaction 

profiles of pravastatin, simvastatin, and atorvastatin 

when coadministered with cytochrome 

P450 inhibitors. Am J Cardiol. 94:1140, 2004. 

173. Frishman WH, Horn J: Statin drug interactions: 

not a class effect. Cardiol in Rev 16: 205, 2008.

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