Does Aspirin Attenuate the Beneficial Effects of ACE Inhibitors?

Source: Leor J, et al. J Am Coll Cardiol 1999;33:1920-1925.

For the past several years, there has been a contradiction regarding a possible adverse reaction between the use of aspirin and ACE inhibitors regarding major clinical end points. Several important clinical trials, including SOLVD, CONSENSUS II, GUSTO-I, and GISSI-3, all demonstrated in retrospective analyses a reduction of benefits when aspirin was used with ACE inhibitors. Furthermore, several hemodynamic studies in patients with congestive heart failure demonstrate attenuation of the beneficial effects of ACE inhibitors on a variety of renal and cardiac parameters; on the other hand, other small studies have not shown a negative interaction. Investigators from the Bezafibrate Infarction Prevention (BIP) study performed a retrospective analysis on a large BIP registry cohort. A total of 1196 subjects were identified who were treated with ACE inhibitors and were followed for at least five years. These patients represented 11% of the entire cohort registry. ACE inhibitors and aspirin were given to 618 subjects, whereas 579 received only an ACE inhibitor. A subgroup analysis was also done on 464 patients with clinical congestive heart failure, NYHA Class II or greater. Total and cardiovascular mortality as well as adjusted survival for age, gender, and a variety of other clinical conditions were calculated. The results indicated a substantial difference in total and cardiovascular mortality for the entire cohort, as well as for approximately 50% of individuals with heart failure. Thus, the five-year mortality for those on combination therapy was 19% vs. 27% for the patients on ACE inhibitors alone (P = 0.002). Cardiovasvcular mortality was 12% vs. 18%, respectively. These differences remained robust after adjustment for a variety of parameters. In the heart failure cohort, similar findings were noted, with 35% total mortality in the nonaspirin users compared to 24% in the combination therapy cohort. Cardiovascular mortality was 17% in aspirin users vs. 26% in nonaspirin users. Again, there was a significant risk reduction after adjustment for age, gender, diabetes, and various medications. Leor and colleagues conclude that in coronary artery disease subjects treated with both an ACE inhibitor and aspirin, survival is enhanced and the "beneficial association" is even more prominent in subjects with heart failure.

Leor et al emphasize the classic pharmacophysiologic rationale for a potential negative interaction, which is impairment of bradykinin generation due to use of aspirin (or nonsteroidals), resulting in a decrease in production of vasodilator prostaglandins and nitric oxide. Several studies from Europe have demonstrated inhibition of the hemodynamic effects of ACE inhibitors when aspirin is co-administered. Furthermore, a report suggests that enalapril may reduce the formation of thromboxane A2, resulting in an independent antithrombotic effect of ACE inhibitors that might attenuate the beneficial effects of aspirin. On the other hand, a recent study suggests that aspirin may improve endothelial function. Thus, there are a number of conflicting mechanisms that could explain both a positive and negative interaction of these two agents.

The BIP investigators recognize that major clinical trials do not support a favorable interaction or association between ACE inhibitors and aspirin. They point out the limitations of their study being a post hoc analysis, with the therapeutic designation based on a single report form. They believe that possible crossover between the groups regarding aspirin use might underestimate the benefits associated with combination therapy. They call for further research in this area and suggest that low-dose aspirin (most patients received less than 250 mg/d) are safe and can be given with an ACE inhibitor in patients with heart failure and coronary artery disease (CAD).

Comment by Jonathan Abrams, MD

This controversy is very important. Because all currently support the use of aspirin in patients with CAD, it is inappropriate to preclude this compound. It is known that the majority of patients with heart failure have CAD as the primary etiology. Thus, the potential downside of a negative interaction between two commonly used agents is of widespread interest. Adequate data are clearly not available to resolve this question. The BIP registry experience data are reassuring; however, it is unclear how and when the diagnosis of heart failure was made, how long the patients were treated with an ACE inhibitor and aspirin or ACE inhibitor alone, or why an ACE inhibitor was chosen. The indications for ACE inhibitors are increasing beyond patients with abnormal ventricular systolic function. The unreported results of the HOPE Trial indicate that an ACE inhibitor may improve survival in high-risk subjects who do not have overt CAD. Other data are concordant with a beneficial effect of ACE inhibitors in postinfarction patients regarding recurrent myocardial infarction and unstable angina.

Given the absence of prospective data, the differences in patient populations, and drug use among the various studies, it seems prudent not to withhold aspirin from patients with CAD with or without congestive heart failure who are taking an ACE inhibitor. The data from BIP do not prove that there is no negative interaction, but they are inconsistent with an adverse association. Whether individuals treated with ACE inhibitors should be given a lower dose of aspirin, as suggested by the BIP investigators, is unresolved but seems like a harmless and prudent strategy.

Dr. Abrams is Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque.