Interaction between aspirin and angiotensin-converting enzyme inhibitors: should they be used together in older adults with heart failure?

PURPOSE: To determine whether the prostacyclin-inhibiting properties of aspirin counteracts the bradykinin-induced prostacyclin-stimulating effects of angiotensin-converting enzyme (ACE) inhibitors, thereby attenuating the beneficial effects of ACE inhibitors in heart failure patients.

BACKGROUND: Most heart failure patients are older adults. Heart failure is the number one hospital discharge diagnosis of older Americans. The renin-angiotensin system plays a major role in the pathophysiology of heart failure, and ACE inhibitors play a pivotal role in the management of heart failure. Large-scale double-blind randomized trials have demonstrated the survival benefits of using ACE inhibitors in patients with heart failure associated with left ventricular systolic dysfunction. In addition to inhibiting the conversion of angiotensin I to angiotensin II, ACE inhibitors also decrease the breakdown of bradykinin. Bradykinin, a potent vasodilator, acts by stimulating formation of vasodilatory prostaglandins such as prostacyclin, whereas aspirin or acetyl salicylic acid inhibits the enzyme cyclooxygenase, which in turn decreases the production of the prostaglandins. Coronary artery disease and hypertension are the two major underlying causes of heart failure. Most heart failure patients are also on aspirin. There is evidence that aspirin at a daily dose of 80 to 100 mg prevents the synthesis of thromboxane A2 by platelets while relatively sparing the synthesis of prostacyclin in the vascular endothelium. Aspirin at a daily dose of 325 mg has significant inhibitory effects on the vasodilatory prostacyclin synthesis. Studies have demonstrated that, in heart failure patients, low-dose aspirin has no adverse effect on hemodynamic, neurohumoral, or renal functions. Whether the prostacyclin-inhibiting effects of aspirin attenuate some of the beneficial effects of ACE inhibitors mediated by prostacyclin stimulation in heart failure patients is currently unknown.

METHODS: Data from large clinical trials investigating the interaction between aspirin and ACE inhibitors were analyzed to determine the effect of aspirin on the vasodilatory actions of ACE inhibitors in heart failure patients, and the results were analyzed on the basis of theoretical and laboratory findings. The studies included are the Studies of Left Ventricular Dysfunction (SOLVD) (N=6,797), the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) (N=6,090), the Captopril and Thrombolysis Study (CATS) (N=296), and another study involving 317 subjects. The data from these clinical trials investigating the interaction between aspirin and ACE inhibitors included 13,470 subjects. Most of the subjects received aspirin. In the SOLVD study, subjects received aspirin or dipyridamole. Subjects were followed up for an average of about 6 years.

RESULTS: In the SOLVD study, subjects were followed up for 41.1 months in the treatment trial and 37.4 months in the prevention trial. Patients who received aspirin or dipyridamole at baseline did not receive the survival benefits of enalapril, whereas patients who received enalapril did not receive the survival benefits of aspirin. In a rather small study of 317 subjects with left ventricular systolic dysfunction (ejection fraction <35%) who were followed up for a relatively longer period of time (5.7 years), the favorable long-term prognosis of patients receiving aspirin was independent of receipt of an ACE inhibitor. A retrospective subgroup analysis of data from the CONSENSUS II study demonstrated that the 6-month mortality rate of patients with acute myocardial infarction (MI) who received enalapril and aspirin was higher than the combined mortality rates of patients receiving enalapril or aspirin alone. This strong interaction between aspirin and the ACE inhibitor enalapril suggests that the survival benefit of enalapril was significantly lower in patients also taking aspirin than in those taking enalapril alone. This interaction was not associated with other nonfatal major events. In the CATS study, use of low-dose aspirin (80 or 100 mg) did not attenuate beneficial effects of captopril (immediate and 1-year follow up) after acute MI.

CONCLUSION: There is a theoretical possibility that the negative interaction between ACE inhibitors and aspirin may reduce the beneficial effects of ACE inhibitors in patients with heart failure, but the information obtained from the existing databases is limited by the retrospective nature of the analyses and does not establish the association definitively. Double-blind randomized controlled trials should be conducted to determine whether such a negative interaction indeed exists.