Angiotensin-receptor blockade in acute myocardial infarction--a matter of dose.

Beta-blockers, angiotensin-converting–enzyme (ACE) inhibitors, and aldosterone antagonists have been shown to reduce the overall risk of death as well as the risk of major nonfatal cardiovascular events when they are administered to patients with acute myocardial infarction who also have left ventricular systolic dysfunction, clinical evidence of heart failure, or both. 1,2 However, there remains a sizable subgroup of patients in whom clinical heart failure worsens despite optimal medical therapy after acute myocardial infarction. Relevant to this discussion is the observation that ACE inhibitors block only 13 percent of the total production of angiotensin II in the human heart 3 because of the existence of ACE-independent pathways (e.g, chymase, cathepsin, and kallikrein) that convert angiotensin I to angiotensin II. These observations provided the impetus for the development of angiotensin-receptor antagonists that offer more complete protection against angiotensin II by directly blocking the angiotensin type I receptor. However, when this therapeutic approach was tried in the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL), in which the angiotensin-receptor antagonist losartan (at a dose of 50 mg per day) was compared with the ACE inhibitor captopril (at a dose of 150 mg per day) in high-risk patients with acute myocardial infarction, 4 there was a strong trend in favor of captopril with respect to the primary end point of death from any cause (P=0.07) and a significant difference in favor of captopril with respect to the prespecified end point of death from cardiovascular causes (P=0.03). Thus, the OPTIMAAL trial raised important questions regarding the role of selective angiotensin-receptor antagonism after acute myocardial infarction. The Valsartan in Acute Myocardial Infarction (VALIANT) trial reported by Pfeffer et al. in this issue of the Journal 5 compared the effects of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of valsartan and captopril in a population of high-risk patients with clinical or radiologic evidence of heart failure, evidence of left ventricular systolic dysfunction, or both after acute myocardial infarction. A total of 14,808 patients underwent randomization in a 1:1:1 ratio to receive valsartan (titrated to 160 mg twice daily), captopril (titrated to 50 mg three times daily), or the combination of valsartan (titrated to 80 mg twice daily) and captopril (titrated to 50 mg three times daily) beginning 12 hours to 10 days after a myocardial infarction. The primary end point of the study was death from any cause, and a prespecified analysis was designed to demonstrate the noninferiority, or equivalence, of valsartan to captopril in the event that valsartan was not clearly shown to be superior in the primary analysis. During a median follow-up of 24.7 months, mortality was 19.9 percent in the valsartan group, 19.5 percent in the captopril group, and 19.3 percent in the valsartan-and-captopril group. The hazard ratio for death in the valsartan group as compared with the captopril group was 1.00 (97.5 percent confidence interval, 0.90 to 1.11; P=0.98), and the hazard ratio for death in the valsartan-andcaptopril group as compared with the captopril group was 0.98 (97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The comparison of valsartan with captopril showed that these two agents were equivalent in terms of overall mortality and in terms of the rate of the composite end point of fatal and nonfatal cardiovascular events. Adverse events were less common with mono-