REVIEW JOHN G. PETERSON, MD MICHAEL S. LAUER, MD Staff cardiologist, Spokane Cardiology, Director of Clinical Research, Department Spokane, WA of Cardiology, Cleveland Clinic Using aspirin and ACE inhibitors in combination: Why the hullabaloo? ■ ABSTRACT HOULD WE AVOID giving aspirin and S angiotensin-converting enzyme (ACE) Observational studies indicate that aspirin may counteract inhibitors concomitantly? Both are often used the beneficial effect of angiotensin-converting enzyme in combination in patients with coronary (ACE) inhibitors, but the data are not yet sufficient for artery disease, especially if it is complicated by making firm recommendations. We review the available heart failure. Yet investigators have raised con- data and offer tentative conclusions. cerns about a possible adverse interaction between aspirin and ACE inhibitors in patients with heart failure,1,2 and perhaps even ■ KEY POINTS in patients without heart failure. Given the utility of both these drugs in Aspirin blocks production of prostaglandins, potentially treating heart disease, theories about a poten- counteracting or reducing the beneficial effects of ACE tial negative interaction have created quite a inhibitors. hullabaloo. This is especially true since some of the data pointing toward a negative interac- Evidence of an adverse interaction between aspirin and ACE tion are seemingly strong, but based on retro- inhibitors comes from retrospective analyses of studies that spective analyses of studies designed to exam- were not designed to examine this issue. ine other issues. In this review, we examine the basis for For patients with heart failure who take an ACE inhibitor this concern and discuss the implications of current data for clinical practice. and aspirin, it may be appropriate to limit the aspirin dosage in long-term therapy to less than 100 mg/day, since ■ ASPIRIN AND ACE INHIBITORS larger doses have not been proven more effective. ARE BENEFICIAL BY THEMSELVES After an acute myocardial infarction (MI), aspirin reduces short-term mortality by approximately 25%.3 Its continued use after the acute phase of an MI may reduce the inci- dence of a recurrence and of death from vascu- lar events.4 ACE inhibitors reduce the mortality rate both in the short term and in the long term after an MI in patients with clinical heart fail- ure or depressed left ventricular function.5,6 They also reduce the mortality rate by a small but statistically significant amount when they are started early after an MI and continued for several weeks in patients not selected by left CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 6 JUNE 2001 569 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. ASPIRIN AND ACE INHIBITORS PETERSON AND LAUER If aspirin counteracts ACE inhibitors, what is the mechanism? Angiotensin I Bradykinin Arachidonic acid ACE inhibitors block Theoretic negative ACE inhibitors the breakdown of effect: Aspirin seems to Aspirin blocks decrease bradykinin, so that counteract the effect of COX-1, reducing angiotensin II more bradykinin ACE inhibitors synthesis of both production is available for on bradykinin, ie, to platelet activator the synthesis of promote the synthesis thromboxane A2 vasodilatory of vasodilatory and vasodilatory prostaglandins prostaglandins prostaglandins Breakdown Cyclo-oxygenase 1 COX-1 of bradykinin (COX-1) Angiotensin II Prostaglandins E2,I2 Prostaglandins G2,H2 Vasoconstriction Increased aldosterone Vasodilation Thromboxane A2 Hypertension Reduced blood pressure Platelet activation Left ventricular hypertrophy FIGURE 1. Theoretical interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors decrease angiotensin II production and inhibit breakdown of bradykinin. Bradykinin stimulates vasodilator prostaglandins via a cyclo-oxygenase–dependent pathway. Aspirin inhibits cyclo-oxygenase-1 (COX-1), thereby reducing synthesis of vasodilatory prostaglandins. 7,8 ventricular function. A2. The vascular endothelium also produces In addition, the ACE inhibitor ramipril PGE2 and PGI2, and aspirin inhibits this pro- was recently shown to reduce death and vas- duction as well (FIGURE 1). cular events in patients who either had ACE inhibitors probably produce their known vascular disease or were at high risk favorable effects through several mecha- for vascular events.9 nisms. They reduce plasma levels of the vasoconstrictor angiotensin II by blocking ■ MECHANISMS its conversion from its precursor, angio- OF POTENTIAL INTERACTION tensin I. They also inhibit breakdown of the potent vasodilator bradykinin,11 which Aspirin is believed to reduce death and rein- stimulates prostaglandin synthesis. Re- farction in MI patients by reducing platelet search suggests that the increase in activation. Platelets produce the vasodilatory bradykinin is the predominant mechanism prostaglandins PGE2 and PGI2 and the responsible for the antihypertensive effect 12,13 platelet activator thromboxane A2, with the of ACE inhibitors. Any reduction in cyclo-oxygenase enzyme type-1 (COX-1) as a the ability to produce vasodilatory pro- common pathway.10 Aspirin irreversibly staglandins—as occurs with aspirin thera- inhibits COX-1, simultaneously decreasing py—may also reduce ACE inhibitor activi- production of PGE2, PGI2, and thromboxane ty (FIGURE 1). 570 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 6 JUNE 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Prostaglandins may be because the ACE inhibitor would already be a compensatory response to heart failure inhibiting platelet activation. Vasodilatory prostaglandins are important in heart failure.14 A landmark study15 found that ■ EVIDENCE FROM CLINICAL TRIALS patients with severe heart failure had plasma levels of the vasodilatory prostaglandins PGI2 Trials in heart failure and PGE2 that were 3 to 10 times higher than The SOLVD trial (Studies of Left in healthy subjects. These elevations were Ventricular Dysfunction)22,23 randomized thought to be a compensatory response to ele- patients with left ventricular dysfunction to vated levels of vasoconstrictors such as receive either the ACE inhibitor enalapril or angiotensin II, norepinephrine, and vaso- placebo. The results: patients who received pressin. When given indomethacin (an enalapril had significantly lower rates of inhibitor of prostaglandin synthesis), patients death, congestive heart failure, and MI. with the most severe heart failure had signifi- However, a retrospective analysis of the cant hemodynamic worsening (a lower car- SOLVD data2 showed something interesting: diac index and a higher pulmonary artery although antiplatelet agents (almost exclu- wedge pressure) as assessed by right heart sively aspirin) were independently associated catheterization. with reduced mortality, the addition of At the time of this study, none of the enalapril did not decrease the mortality rate in major trials of ACE inhibitors had been con- patients receiving antiplatelet agents, and ducted, and there were few data supporting conversely neither did the addition of aspirin the use of aspirin. However, the study obser- in patients receiving enalapril. vations gave rise to further investigation as This analysis supported the hypothesis of the neurohormonal hypothesis of heart failure a complex interaction between aspirin and was being developed. ACE inhibitors in heart failure patients, as Subsequent physiologic studies looked anticipated by the hemodynamic studies. directly at the concomitant use of aspirin and However: ACE inhibitors in patients with heart failure. The SAVE trial (Survival and Most evidence Hall et al16 observed the acute hemodynamic Ventricular Enlargement),6 in patients with so far is from effects of enalapril 10 mg in 18 patients with left ventricular dysfunction, did not reveal heart failure before and after giving them such an interaction. observational aspirin 350 mg. Enalapril without aspirin had The AIRE trial (Acute Infarction studies significant beneficial hemodynamic effects, Ramipril Efficacy)5 showed less benefit from decreasing systemic vascular resistance, left an ACE inhibitor in patients receiving aspirin ventricular filling pressure, and total pul- vs not receiving aspirin, but the trend was not monary resistance while increasing cardiac statistically significant. output. Aspirin abolished all of these changes. All in all, most of the hemodynamic However, similar studies yielded inconsistent data and some of the retrospective clinical results, perhaps because they used different data support the argument that a clinically aspirin doses or the duration of treatment with important interaction exists between aspirin ACE inhibitors was different.17–19 and ACE inhibitors in patients with heart Further complicating the issue, some stud- failure. ies suggested another mechanism of interac- tion.19,20 ACE inhibitors also inhibit platelet Studies in ischemic heart disease activation, mainly by reducing thromboxane Almost all studies of ACE inhibitors in A2. The reductions seen in ischemic events ischemic heart disease showed beneficial with the use of ACE inhibitors in multiple tri- effects. Some, however, suggested a clinically als would be consistent with this significant adverse interaction between process.6,9,21–23 If this mechanism really does aspirin and ACE inhibitors. mediate a reduction in ischemic events, then CONSENSUS II (the second one would expect