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 beta-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 beta-blocker
therapy.