Early and late angiotensin-converting enzyme inhibition after myocardial infarction: an overview of randomized clinical trials

Abstract

An association between the activation of the reninangiotensin-aldosterone system and the development of atherosclerotic disease and its complications has been demonstrated in both experimental and clinical conditions (1), thereby confirming that pharmacologic blockade favorably affects the prognosis of patients with coronary artery disease. The first demonstrations of the efficacy of angiotensin-converting enzyme (ACE) inhibitors in the setting of myocardial infarction date back more than 20 years when captopril was observed to protect infarcted myocardium in animal models (2,3). Other findings at the time suggested that the beneficial effects of ACE inhibitors in patients with coronary artery disease might be related to their ability to reduce the extent of myocardial ischemia by interfering with the mechanisms responsible for coronary blood supply and, probably, adrenergic stimulation (4). Since then, many controlled clinical trials have shown that blockade of the renin-angiotensin-aldosterone system has numerous beneficial effects in a wide range of patients with myocardial infarction (5), including high-risk patients, such as the elderly and those with diabetes or hypertension (6,7). One possible explanation for the favorable interaction between ACE inhibitors and the clinical evolution of myocardial infarction may be the capacity of ACE inhibitors to exert a “broad” protective role by affecting the various time-related determinants of poor clinical prognosis, thus reducing both in-hospital and long-term mortality (8). Furthermore, the extent of the benefit of ACE inhibition in patients with myocardial infarction could be largely influenced by the time of drug administration after myocardial infarction. In this issue of the Journal, Rodrigues et al (9) have provided an extensive and systematic overview of the effects of early and late administration of ACE inhibitors on mortality in patients with myocardial infarction. In particular, they summarize the results of more than 20 randomized, placebo-controlled trials with at least 1 month of follow-up. They confirm that ACE inhibitors, when given both early and late after myocardial infarction, are associated with a survival benefit that can be demonstrated from weeks to years after the index infarction. Even the smallest survival benefit (about a 7% reduction in mortality), which was observed after 4 weeks of early ACE inhibitor treatment, suggests that ACE inhibition can further improve survival even when most of the established, life-saving procedures have been correctly adopted. The reduction in mortality was linearly related to the length of follow-up and was larger for patients with left ventricular dysfunction or heart failure complicating myocardial infarction. This somewhat supports the hypothesis that the efficacy of ACE inhibitors in patients with myocardial infarction is influenced by concomitant factors such as the extent of their interaction with early and late determinants of survival, as well as by baseline patient characteristics. In clinical terms, this can translate into substantial differences in the number of patients needed to be treated to prevent an adverse event, which is lower for patients in whom myocardial infarction is complicated by heart failure (Acute Infarction Ramipril Efficacy [AIRE] and Trandolapril Cardiac Evaluation [TRACE] studies) or left ventricular dysfunction (Sur