Abstract
Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of therapy for congestive heart failure (CHF). Because ischemic heart disease is the most common cause of CHF, aspirin is frequently given concomitantly with ACE inhibitors in patients with CHF. Increased bradykinin levels, with the consequent enhanced synthesis of vasodilatory prostaglandins, appear to mediate a significant benefit of ACE inhibitor therapy in these patients. In contrast, aspirin inhibits cylcooxygenase, and thereby suppresses prostaglandin production. Thus, these counteracting effects on prostaglandins may result in antagonism between ACE inhibitor and aspirin therapy in heart failure patients. Several early reports questioned the safety of aspirin in CHF, and the potential antagonistic interaction between ACE inhibitors and aspirin in patients with heart failure has become the focus of both increasing research and intense debate. This article briefly highlights the theoretic considerations underlying this interaction, and reviews the available evidence for such an interaction from clinical trials.
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References and Recommended Reading
American Heart Association: 1997 Heart and Stroke Update: Statistical Update. Dallas: American Heart Association; 1996:1–29.
Kannel WB, Belanger AJ: Epidemiology of heart failure. Am Heart J 1991, 121:951–957.
Kjekshus J, Swedberg K, Snapinn S, for the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS) Trial Group: Effects of enalapril on long-term mortality in severe congestive heart failure. Am J Cardiol 1992, 69:103–107.
The Studies of Left Ventricular Dysfunction (SOLVD) Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991, 325:293–302.
The Studies of Left Ventricular Dysfunction (SOLVD) Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992, 327:685–691.
Pfeffer MA, Braunwald E, Moye LA, et al. for the Survival and Ventricular Enlargement (SAVE) Investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992, 327:669–677.
Parmley WW: Pathophysiology of congestive heart failure. Am J Cardiol 1985, 56:7A-11A.
Teerlink JR, Goldhaber SZ, Pfeffer MA: An overview of contemporary etiologies of congestive heart failure. Am Heart J 1991, 121:1852–1853.
Massie BM, Shah NB: Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. Am Heart J 1997, 133:703–712.
Baigent C, Collins R, Appleby P, et al.: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither: The ISIS-2 (Second International Study of Infarct Survival) collaborative group. BMJ 1998, 316:1337–1343.
Antiplatelet Trialists’ Collaboration: Collaborative overview of randomised trials of antiplatelet therapy-I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994, 308:81–106.
Sbarouni E, Bradshaw A, Andreotti F, et al.: Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994, 127:607–612.
Goto S, Sakai H, Ikeda Y,et al.: Arterial thrombosis in heart failure (letter). Lancet 1998, 351:1558–1559.
Pitt B: Use of converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction. J Am Coll Cardiol 1993, 22(Suppl A):158A-161A.
Cleland JGF, Bulpitt CJ, Falk RH, et al.: Is aspirin safe for patients with heart failure? Br Heart J 1995, 74:215–219.
Dzau VJ, Packer M, Lilly LS, et al.: Prostaglandins in severe congestive heart failure: relation to activation of the renninangiotensin system and hyponatremia. N Engl J Med 1984, 310:347–352.
Gainer JV, Morrow JD, Loveland A, et al.: Effect of bradykininreceptor blockade on the response to angiotensin-converting- enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998, 339:1285–1292.
Blais Jr. C, Drapeau G, Raymond P, et al.: Contribution of angiotensin-converting enzyme to the cardiac metabolism of bradykinin: an interspecies study. AM J Physiol 1997, 273:H2263-H2271.
Swartz SL, Williams GH, Hollenberg NK, et al.: Captoprilinduced changes in prostaglandin production. J Clin Invest 1980, 65:1257–1264.
Moore TJ, Crantz FR, Hollenberg NK, et al.: Contribution of prostaglandins to the antihypertensive action of capropril in essential hypertension. Hypertension 1981, 3:168–173.
Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins: kallikerins, kininogens, and kinases. Pharmacol Rev 1992, 44:1–80.
Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971, 231:232–235.
Jorde UP, Ennezat PV, Lisker J, et al.: Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000, 101:844–846.
Nishimura H, Kubo S, Ueyama M, et al.: Peripheral hemodynamic effects of captopril in patients with congestive heart failure. Am Heart J 1989, 117:100–105.
Townend JN, Doran J, Lote CJ, et al.: Peripheral hemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril. Br Heart J 1995, 73:434–441.
Hall D, Zeitler H, Rudolph W: Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. Journal of the American College of Cardiology 1992, 20:1549–1555.
Nakamura M, Funakoshi T, Arakawa N, et al.: Effect of angiotensin-converting enzyme inhibitors on endotheliumdependent peripheral vasodilation in patients with chronic heart failure. J Am Coll Cardiol 1994, 24:1321–1327.
Spaulding C, Charbonnier B, Cohen-Solal A, et al.: Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation 1998, 98:757–765. An elegant study utilizing the differing mechanisms of antiplatelet action of aspirin and ticlopidine to demonstrate antagonism between aspirin and enalapril.
Evans MA, Burnett JC, Redfield MM: Effect of low dose aspirin on cardiorenal function and acute hemodynamic response to enalaprilat in a canine model of severe heart failure. J Am Coll Cardiol 1995, 25:1445–1450.
van Wijngaarden J, Smit AJ, de Graeff PA, et al.: Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 1994, 23:240–245.
Baur LHB, Schipperheyn JJ, van der Laarse A, et al.: Combining salicylate and enalapril in patients with coronary artery disease and heart failure. Br Heart J 1995, 73:227–236.
Jeserich M, Pape L, Just H, et al.: Effect of long-term angiotensin- converting enzyme inhibition on vascular function in patients with chronic congestive heart failure. Am J Cardiol 1995, 76:1079–1082.
Clarke RJ, Mayo G, Price P, et al.: Suppression of thromboxane A2 but not systemic prostacyclin by controlled-release aspirin. N Engl J Med 1991, 325:1137–1141.
Oosterga M, Anthonio RL, de Kam P, et al.: Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction. Am J Cardiol 1998, 81:1178–1181.
Siegel JL, Miller A, Brown LK, et al.: Pulmonary diffusing capacity in left ventricular dysfunction. Chest 1990, 98:550–553.
Puri S, Baker BL, Dutka DP, et al.: Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure: its pathophysiological relevance and relationship to exercise performance. Circulation 1995, 91:2769–2774.
Guazzi M, Marenzi G, Alimento M, et al.: Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997, 95:1930–1936.
Guazzi M, Melzi G, Agostoni P: Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997, 80:1572–1576.
Guazzi M, Pontone G, Agostoni P: Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors. Am Heart J 1999, 138:254–260. This group from the Institute of Cardiology in Milan, Italy has extensively studied the effects of aspirin and ACE inhibitors on pulmonary function in patients with heart failure, demonstrating counteracting effects of aspirin on ACE inhibitor-induced improvements in pulmonary function and exercise performance.
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. Am J Cardiol 1997, 79:115–119.
Peterson JG, Topol EJ, Sapp SK, et al.: Evaluation of the effects of aspirin combined with angiotensin-converting enzyme inhibitors in patients with coronary artery disease. Am J Med 2000, 109:371–377. The most recent study suggesting negative interaction between ACE inhibitors and aspirin in ischemic heart disease.
Garg R, Yusuf S: Overview of randomized trials of angiotensin- converting enzyme inhibitors on mortality and morbidity in patients with heart failure: Collaborative Group on ACE Inhibitor Trials. JAMA 1995, 273:1450–1456.
Leor J, Reicher-Reiss H, Goldbourt U, et al.: Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease. J Am Coll Cardiol 1999, 33:1920–1925. A subgroup analysis of the BIP trial suggesting there may be synergy between ACE inhibitors and aspirin in the treatment of ischemic disease, both with and without heart failure.
Latini R, Santoro E, Masson S, et al. for the GISSI-3 Investigators: Aspirin does not interact with ACE inhibitors when both are given early after acute myocardial infarction: results of the GISSI-3 trial. Heart Disease 2000, 2:185–190.
Latini R, Tognoni G, Maggioni AP, et al. for the Angiotensinconverting Enzyme Inhibitor Myocardial Infarction Collaborative Group: Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. J Am Coll Cardiol 2000, 35:1801–1807. Very recent meta-analysis finding no significant antagonism between ACE inhibitor and aspirin therapy in the treatment of acute myocardial infarction.
Pitt B, Yusuf S, et al. for the Studies of Left Ventricular Dysfunction (SOLVD) Investigators: Studies of Left Ventricular Dysfunction (SOLVD): subgroup results. J Am Coll Cardiol 1992, 19(Suppl A):215A.
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 1998, 31:419–425. The first major post hoc analysis of a large clinical trial in heart failure patients, suggesting a negative interaction with concomitant ACE inhibitor and antiplatelet administration (> 95% on aspirin).
Flather MD, Yusuf S, Kober L, et al. for the ACE-Inhibitor Myocardial Infarction Collaborative Group: Long-term ACEinhibitor therapy in patients with heart failure or leftventricular dysfunction: a systematic overview of data from individual patients. Lancet 2000, 355:1575–1581. Large meta-analysis of heart failure patients on chronic ACE inhibitor therapy demonstrating efficacy in reducing morbidity and mortality regardless of concomitant aspirin use.
Harjai KJ, Solis S, Prasad A, et al.: The use of aspirin in conjunction with angiotensin converting enzyme inhibitors does not worsen long-term survival in heart failure. Circulation 2000, 102(Suppl II):413.
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Moskowitz, R. The angiotensin-converting enzyme inhibitor and aspirin interaction in congestive heart failure:Fear or reality?. Curr Cardiol Rep 3, 247–253 (2001). https://doi.org/10.1007/s11886-001-0030-0
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DOI: https://doi.org/10.1007/s11886-001-0030-0