NEJM 1992;327:669-77 Background After a large heart attack, cardiac hemodynamics are altered, which leads to a series of changes in the heart muscle itself. The immediate consequence of a large heart attack is decreased myocardial contractility. This leads to a reduction in stroke volume and cardiac output. Compensatory mechanisms governed by the renin-angiotensin-aldosterone system and sympathetic nervous system become activated and may lead to ventricular dilation or “remodeling”, which has negative short and long-term consequence for the heart muscle.By the mid-1980’s, angiotensin converting enzyme inhibitors (ACEi) were commonly used for patients with chronic systolic heart failure and laboratory work had shown they could improve ventricular remodeling, reduce heart failure and prolong survival in animal models of AMI. Several studies had also shown promise in humans but they were too small to test hypotheses involving hard clinical endpoints. The Survival and Ventricular Enlargement (SAVE) trial sought to test the hypothesis that administration of captopril to patients with AMI complicated by left ventricular dysfunction but who did not have overt heart failure requiring vasodilatory therapy would reduce morbidity and mortality over long-term follow-up.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Eligible patients were between 21 to 80 years of age with a definite myocardial infarction occurring 3 to 16 days prior to randomization with a left ventricular ejection fraction (EF) ≤40%, measured by radionuclide ventriculography. Patients were excluded with relative contraindications to ACEi or if an ACEi was indicated for treatment of symptomatic congestive heart failure or systemic hypertension. Other exclusion criteria included serum creatinine >2.5 mg/dl, other conditions limiting survival (unspecified) or who had an unstable course following AMI (also unspecified).Baseline characteristics The average age of patients was 59 years and 82% were men. Approximately one third of patients had a prior MI, more than 20% had diabetes, 40% had hypertension and over 50% were current smokers. The average ejection fraction was 31% and over half of patients had an anterolateral Q wave MI. The mean time to randomization was 11 days. Prior to randomization approximately a third received thrombolysis, over 50% underwent coronary angiography, and approximately 25% underwent either percutaneous coronary angioplasty or coronary artery bypass surgery. At the time of randomization, the average blood pressure was 113/70 mmHg and heart rate was 78 beats per minute. Within 24 hours of randomization approximately one third of patients received a beta blocker and a quarter received digoxin.Procedures There was a mini run-in period where all 2,250 eligible patients were given a test dose of 6.25 mg of captopril. This led to exclusion of 19 patients (3 for ischemic discomfort and 16 for symptomatic hypotension).Patients received either captopril or placebo. The initial dose of the blinded study drug was 12.5 mg but could be administered at 6.25 mg to patients who had marked, yet asymptomatic, reduction in BP with the run-in dose. The target dose was 25 mg three times a day by the end of the in-hospital phase and was gradually increased to 50 mg three times a day unless side effects occurred. There was no prespecified level of blood pressure in the titration regimen.Outpatient visits were scheduled 2 weeks following randomization and then every 3 months during year 1 and every 4 months thereafter. Compliance with the study drug was assessed by pill count.Endpoints There were no prespecified hypothesis tests used to determine sample size. Prospectively defined measures of outcomes included all cause death, cardiovascular death, incidence of clinical congestive heart failure and first hospitalization for heart failure. Once the clinical endpo