Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials.

Angiotensin-converting enzyme (ACE) inhibitor therapy has been associated with a substantial (> or = 20%) reduction in the risk of major ischemic events in two recent clinical trials with long-term follow-up: Studies of Left Ventricular Dysfunction (SOLVD) and the Survival and Ventricular Enlargement (SAVE) study. Participants in these studies included patients with a low ejection fraction (< or = 0.35 in SOLVD and < or = 0.40 in SAVE), generally without symptoms of congestive heart failure. Approximately 80% of patients enrolled in SOLVD and all participants in SAVE had histories of ischemic heart disease or acute myocardial infarction (SAVE). In both SOLVD and SAVE the risk of experiencing a major ischemic event such as myocardial infarction was reduced significantly following prolonged ACE inhibitor therapy. In the SOLVD trial, this effect was evident across a range of patient subgroups, including varying concomitant drug therapies. In both studies, several months elapsed before this benefit became apparent, suggesting an effect on underlying ischemic pathophysiology. A third trial of ACE inhibitor therapy postinfarction, the Acute Infarction Ramipril Efficacy (AIRE) Study, demonstrated a 27% reduction in all cause mortality but no effect on myocardial infarction after a 15-month mean follow-up. No effect of ACE inhibition on risk of survival or reinfarction was reported in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-II), which began the drug within 24 hours of infarction and terminated follow-up at 6 months, a time not likely to demonstrate infarction reduction benefit based on the SOLVD and SAVE observations. Neither AIRE nor CONSENSUS-II had objectively determined left ventricular dysfunction as an entry criterion, as did SOLVD and SAVE, but AIRE mandated "clinical" congestive heart failure prior to randomization. More recently, preliminary results from the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3), the Fourth International Study of Infarct Survival (ISIS-4), and the Chinese Captopril Trial suggested that angiotensin-converting enzyme (ACE) inhibitor mortality benefits post-myocardial infarction would be detected in these megatrials as early as 35 days after the event.(ABSTRACT TRUNCATED AT 400 WORDS)