Angiotensin-converting enzyme inhibitors after myocardial infarction: Indications and timing

Abstract

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction. In contrast, the Acute Infarction Ramipril Efficacy (AIRE) study demonstrated a marked reduction in mortality rate (27% risk reduction, 95% CI 11% to 40%) when the angiotensin-converting enzyme inhibitor ramipril was given to patients manifesting some clinical evidence of heart failure, even if transient, 3 to 10 days after myocardial infarction for an average period of 15 months. Extrapolation from the findings of the AIRE study and from subgroup analyses of GISSI-3 and ISIS-4 indicate that patients manifesting clinical evidence of heart failure after myocardial infarction derive most of the benefit to be gained from the use of angiotensin-converting enzyme inhibitors. Appropriate selection of patients and careful timing of treatment after myocardial infarction to allow patients to achieve clinical stability will maximize potential benefit against potential harm from these effective agents.