Zofenopril and ramipril plus ASA in post-myocardial infarction patients with left ventricular systolic dysfunction: a post-hoc analysis in preserved or impaired left ventricular fraction at entry

Background: Concomitant administration of an angiotensin-converting enzyme inhibitor (ACEI) and acetyl salicylic acid (ASA) is a common option in patients with both heart failure and ischemic heart disease. However, the well-known pharmacological interaction between ACEI and ASA may be responsible for a reduction of the positive effect of ACEI on cardiovascular outcomes. In the SMILE-4 Study we have shown a more favorable impact of zofenopril plus ASA than ramipril plus ASA combination on 1-year occurrence of major cardiovascular events in patients with acute myocardial infarction (AMI) complicated by left ventricular dysfunction (LVD). Objective: to compare zofenopril and ramipril efficacy in combination with ASA in a subgroup of patients of the SMILE-4 with preserved (>40%) or impaired (≤40%) left ventricular ejection fraction at the time of enrolment in the study. Methods: The SMILE-4 was a phase IIIb, randomized, double-blind, parallel-group, multicenter, European study comparing the safety and efficacy of zofenopril 60 mg/day and ramipril 10 mg/day plus ASA 100 mg/day, in patients with LVD (clinical signs of heart failure or a left ventricular ejection fraction or LVEF <45%) following AMI. The primary study end-point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Information on LVEF at baseline was available in 710 out of the 716 patients of the intention-to-treat population. Results: In the main study population the primary outcome was significantly reduced by zofenopril vs. ramipril (odds ratio, OR and 95% confidence interval, CI: 0.70, 0.51-0.96; p=0.028). Overall, 448 (63.1%) patients had preserved and 262 (36.9%) impaired LVEF at baseline. In the first group, the rate of major cardiovascular events was significantly lower under zofenopril than under ramipril (22.5% vs. 32.8%; OR: 0.60, 0.39-0.91; p=0.016). This was the case also for the group of patients with impaired LVEF, though between-group difference was not statistically significant (37.7% zofenopril vs. 44.4% ramipril; OR: 0.77, 0.47-1.26; p=0.297). The reduction in the risk of major cardiovascular events was significantly larger (p=0.019) in patients with preserved LVEF at baseline. Conclusions: This retrospective analysis of the SMILE-4 Study confirmed the superiority of zofenopril plus ASA as compared to ramipril plus ASA in the prevention of long-term cardiovascular outcomes. The benefit was particularly evident in subjects with preserved left ventricular function at study entry.