The Val-HeFT trial: Valsartan reduces morbidity in chronic heart failure [Classics Series]

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1. Valsartan, an angiotensin-receptor blocker, significantly reduces morbidity, but not mortality, in heart failure patients when added to background therapy.

2. As an exception, valsartan was associated with increased morbidity and mortality in patients already receiving both an angiotensin-converting-enzyme inhibitor and beta-blocker.

Original Date of Publication: December 6, 2001

Study Rundown: Angiotensin II contributes to cardiac remodeling that leads to decreased left ventricular function and progressive heart failure. At the time of the study in 2001, angiotensin-converting-enzyme (ACE) inhibitors and beta-blockers were the standard therapies for heart failure. This study notably demonstrated that treatment with the angiotensin-receptor blocker (ARB) valsartan in addition to previously prescribed therapy could further decrease patient morbidity. Patient mortality, however, was not significantly different when compared to placebo, and valsartan increased morbidity and mortality in the subgroup of patients already receiving both an ACE inhibitor and beta-blocker.

The study’s results do not generalize to patients already receiving ARBs, who were excluded from this study. Additionally, approximately 90% of the study’s participants were white. In the study’s black population, consisting of African-American and South African patients, the effect of valsartan was not statistically significant. Finally, valsartan was associated with only a moderate increase in ejection fraction when compared with other prior trials involving ACE inhibitors and beta-blockers.

In summary, the Val-HeFT trial demonstrated an important role for ARBs in the management of heart failure.

Please click to read study in NEJM

Lead Study Investigator, Dr. Jay N. Cohn, MD, talks to 2 Minute Medicine: University of Minnesota, Professor of Medicine, Cardiovascular Division.

“Val-HeFT established that high dose ARB is a suitable substitute for an ACE inhibitor in the management of heart failure and may even provide additive benefit, especially in those on lower doses of ACE inhibitors. The fact that the ARB slowed the left ventricular remodeling process is further support for the use of inhibition of remodeling as a guide to long-term efficacy. This raises the possibility that all therapy for heart failure with a reduced ejection fraction should be aimed at LV remodeling, and that a benefit on this measurement should serve as a guide to individualized therapy.”

In-Depth [randomized, controlled study]: Published in NEJM in 2001, the Val-HeFT trial was a randomized, double-blinded, placebo-controlled, trial involving 302 centers in 16 countries.  A total of 5,010 patients with documented left ventricular dilatation and at least two weeks of treatment with ACE inhibitors, diuretics, digoxin, or beta-blockers were stratified according to previously prescribed beta-blocker treatment and randomized to receive valsartan or placebo.  Two primary endpoints were measured: 1) mortality alone, and 2) the combined endpoint of mortality and morbidity (defined as cardiac arrest with resuscitation, hospitalization for heart failure, etc.).  The combined endpoint of mortality and morbidity was significantly lower with valsartan (RR 0.87; 97.5%CI 0.77-0.97) than placebo, largely due to a decreased number of hospitalizations for heart failure (p < 0.001). There was no significant difference in mortality alone (RR 1.02; 98%CI 0.88-1.18).

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