Antagonism Between Enalapril and Aspirin: Subgroup Analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

Several drugs have been investigated regarding their effect on mortality when given early after an acute myocardial infarction. The use of angiotensin-converting enzyme (ACE) inhibitors has been studied in several trials with inconsistent results. Aspirin (ASA) has become well documented therapeutic adjunct in patients with coronary heart disease. Attention has recently been focused on possible interaction between aspirin and ACE inhibitors. We therefore reanalyzed dat from the CONSENSUS II to find any evidence of differential effects of the ACE inhibitor enalapril in subgroups defined by use of AS at baseline. Stepwise logistic regression tested the multiplicative interaction. The enalapril-AS interaction term was significant predictor of at the end of the study (odds ratio 1.442, P = 0.047), and was borderline-significant predictor of mortality 30 days after randomization (odds ratio 1.450, P = 0.085). We used Rothman synergy index S to examine the postulated interaction with departure from an additive model. S would be equal to unity under additivity, and less than unity when suggesting antagonism. The synergy index was 0.66 (95% confidence interval 0.46 to 0.94) for mortality at the end of the study, and 0.68 (0.44 to 1.04) for 30-day mortality, indicating antagonism between enalapril and ASA. No significant interaction was found regarding nonfatal major events. Conclusion: We found evidence of enalapril-AS interaction. Excess mortality occurred when enalapril was randomized to patients using AS at baseline.