Interaction Between Enalapril and Aspirin on Mortality After Acute Myocardial Infarction: Subgroup Analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

doi:10.1016/S0002-9149(96)00696-0

The American Journal of Cardiology

Volume 79, Issue 2, 15 January 1997, Pages 115-119

https://doi.org/10.1016/S0002-9149(96)00696-0 Get rights and content

Abstract

The use of angiotensin-converting enzyme (ACE) inhibitors early after an acute myocardial infarction to reduce mortality has been studied in several trials with inconsistent results. Aspirin (ASA) has become a well-documented therapeutic adjunct in patients with coronary heart disease. Attention has recently been focused on a possible interaction between ASA and ACE inhibitors. We therefore reanalyzed data from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) to find any evidence of differential effects of the ACE inhibitor enalapril in subgroups defined by use of ASA at baseline. Logistic regression tested the multiplicative interaction. We used Rothman synergy index S, which would be equal to unity under additivity, and less than unity when suggesting antagonism, to examine the postulated interaction with departure from an additive model. Logistic regression showed that the enalapril-ASA interaction term was a significant predictor of mortality at the end of the study (p = 0.047), and was a borderline significant predictor of mortality 30 days after randomization (p = 0.085). The Rothman synergy index S 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 with departure from an additive model. Thus, we found evidence of enalapril-ASA interaction. The effect of enalapril was less favorable among patients taking ASA than among patients not taking ASA at baseline.

Section snippets

Methods

The CONSENSUS II trial included 6,090 patients with AMI, who were assigned to treatment with enalapril or placebo in a randomized, double-blind, placebo-controlled parallel-group design. The primary end point was death due to any cause that occurred within 6 months. Secondary end points included death ≤1 month, the cause of death, reinfarction, and worsening CHF as indicated by a change in treatment or hospitalization due to CHF. Details of the study design and results were previously presented.

Results

The use of ASA at baseline was equally represented in the enalapril (76.5%) and placebo (77.8%) groups. The difference between the ASA and non-ASA group is slight, but statistically significant (p <0.05), regarding several baseline characteristics (Table 1). The effect of enalapril on mortality and all major events was previously described.[2]Overall, enalapril increased relative risk of deaths by 10%, though not significantly. Fig. 1 shows the unadjusted odds ratios and their 95% confidence

Aspirin

ASA use at baseline was associated with lower mortality and rates of all nonfatal major events. The odds reduction in mortality found in this study (odds ratio 0.41) was far larger than the odds reduction of about 25% observed in previous studies.[1]The reason for this difference may be that the ASA group at baseline seemed to be slightly healthier: lower age, less frequent previous AMI, CHF, diabetes, and angina, and more frequent use of thrombolytics (Table 1). The main purpose of this study,

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Interaction Between Enalapril and Aspirin on Mortality After Acute Myocardial Infarction: Subgroup Analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

Abstract

Section snippets

Methods

Results

Aspirin

Collaborative overview of randomized trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

Br Med J

Rasmussen K, Ryden L, Wedel H. Effects of early administration of enalpril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

New Engl J Med

Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure

Lancet

GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction

Lancet

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial

New Engl J Med

The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction

New Engl J Med

ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction

Lancet