Val-HeFT and angiotensin-receptor blockers in perspective: A tale of the blind man and the elephant

Abstract

EDITOR SUMMARY Background: The role of angiotensin-receptor blockers (ARBs) in the therapy of chronic heart failure (CHF) has not been clarified. There are no large placebo-controlled trials with these agents. The second Evaluation of Losartan in the Elderly trial (ELITE-II) compared the ARB losartan with captopril in 3,152 patients ≥60 years old with New York Heart Association (NYHA) class II-IV and left ventricular ejection fraction ≤40% and did not establish the efficacy of the ARB or its equivalent to angiotensin-converting enzyme inhibitor. The Valsartan Heart Failure Trial was designed to determine whether addition of valsartan improved the outcomes of patients receiving standard therapy for heart failure, which in most cases included an ACE inhibitor. Methods and Results: A total of 5,010 patients with NYHA class II-IV CHF and ejection fraction <40% were assigned to receive 160 mg valsartan or placebo twice daily. The 2 coprimary end points were all-cause mortality and the composite of mortality and morbidity, defined as the incidence of hospitalization for heart failure, resuscitated sudden death, or receipt of intravenous inotropic or vasodilator therapy for at least 4 hours (with hospitalizations accounting for 94% of the nonfatal end points). Mortality was similar in the 2 groups, but the combined mortality and morbidity end point was 13.2% lower with valsartan (relative risk, 0.87; 95% confidence interval, 0.77-0.97; P.009), primarily because of a reduction in the number of patients hospitalized for CHF (13.8% v 18.2%). There were improvements in several secondary end points, including ejection fraction, signs and symptoms of CHF, and quality of life with valsartan. Of note is that analyses of subgroups defined according to background therapy at baseline showed highly significant interactions. For instance, the small subgroup of 366 patients (7%) who were not receiving ACE inhibitors had a 33% reduction in mortality and a 44% decrease in mortality and morbidity, whereas the morbidity and mortality benefit of valsartan observed in the overall trial was no longer significant in patients receiving background ACE inhibitor therapy (relative risk, 0.90; P.10). The larger subgroup of patients receiving both an ACE inhibitor and a β-blocker at baseline had a statistically significant 42% increase in mortality with valsartan (P.009) and a trend toward an increase in the mortality and morbidity composite (P.10). Conclusions: When added to standard therapy, valsartan has no overall effect on mortality and produces a modest (13.2%) reduction in morbidity and mortality. However, this benefit is much larger in patients not receiving concomitant ACE inhibitor therapy and statistically not significant in those who are taking ACE inhibitors. Somewhat troublesome is the finding of significant increase in mortality with valsartan in patients receiving both ACE inhibitor and β-blocker therapy. (Prepared by Journal of Cardiac Failure editors.) A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure (Val-HeFT). N Engl J Med 2001;345:1667-1675