Efficacy of Zofenopril Compared With Placebo and Other Angiotensin-converting Enzyme Inhibitors in Patients With Acute Myocardial Infarction and Previous Cardiovascular Risk Factors: A Pooled Individual Data Analysis of 4 Randomized, Double-blind, Controlled, Prospective Studies

The Survival of Myocardial Infarction Long-term Evaluation (SMILE) project is a comprehensive program of 4 randomized controlled studies aimed to evaluate the efficacy and safety profile of zofenopril in post–acute myocardial infarction (AMI) patients compared with that of placebo or other angiotensin-converting enzyme (ACE) inhibitors (ramipril and lisinopril) in preventing cardiovascular (CV) events.1–4 In the SMILE-1 study, 1556 patients were enrolled within 24 hours after the onset of symptoms of AMI, and they were randomly assigned in a double-blind balanced fashion to receive either placebo or zofenopril for 6 weeks. The incidence of death or severe congestive heart failure during the study was 34% lower with zofenopril.1 The SMILE-2 study was the first direct comparative study between 2 ACE inhibitors in post-AMI.2 Overall, 1024 thrombolyzed patients with AMI were randomized to receive one or the other drug starting within 12 hours of completion of thrombolytic therapy and continuing for 6 weeks. The primary study end point was the incidence of severe hypotension, which was slightly but significantly lower with zofenopril than with lisinopril (6.7% vs. 9.8%). In this study, the 6-week mortality rate was not significantly different between the study groups. The anti-ischemic effects of zofenopril were documented in the SMILE-3 study which included 349 post-AMI patients with preserved left ventricular function.3 The risk of combined occurrence of significant ST-T abnormalities on ambulatory electrocardiography, electrocardiography abnormalities or symptoms of angina during standard exercise test, recurrence of AMI, and need for revascularization procedures for angina was 44% lower under zofenopril than under placebo. Finally, a 30% reduced risk of 1-year combined occurrence of death or hospitalization for CV causes was observed in 365 post-AMI patients with left ventricular dysfunction (LVD) treated with zofenopril versus 351 patients treated with ramipril, both combined with acetylsalicylic acid (ASA) in the SMILE-4 study.4 The results of the 4 SMILE studies were an important source of additional information regarding subpopulations of patients. For this aim, the individual data were first included in a previous pooled analysis5 where the cumulative efficacy of zofenopril on CV mortality and morbidity in post-AMI patients was evaluated by increasing the robustness of the evidence related to the prevention of major CV events. The SMILE project further encompassed in-depth analyses of patient subgroups such as patients with diabetes6,7 or hypertension.8,9 It is generally known that CV risk factors and comorbidities before AMI are strongly predictive of unfavorable prognosis after AMI.10,11 Hence, further analyses of the SMILE data were planned to investigate the efficacy of zofenopril versus placebo and other ACE inhibitors, by focusing on the subgroup of patients with at least one additional CV risk factor. The selection of these patients was based on the presence of one or more of the following factors: previous angina pectoris or congestive heart failure, arterial hypertension, diabetes mellitus, hypercholesterolemia, peripheral arterial occlusive disease, coronary artery bypass graft surgery, percutaneous coronary intervention, recent ST-elevation myocardial infarction (STEMI), or non–ST-segment elevation myocardial infarction (NSTEMI), with or without signs and symptoms of heart failure. In this article, we report the results of the pooled analysis of the 4 SMILE studies in these patients at higher risk, specifically aiming at comparing the efficacy of zofenopril versus that of placebo, lisinopril, and ramipril in terms of prevention of major CV outcomes.