Valsartan reduces combined morbidity and mortality in CHF: Val-HeFT

Susan Jeffrey

November 15, 2000

New Orleans, LA - Results of the Valsartan Heart Failure Trial (Val-HeFT) show that among patients with heart failure, the addition of valsartan (Diovan® - Novartis) to usual therapy did not affect all-cause mortality, but there was a significant 13.3% reduction in the combined endpoint of all-cause mortality and morbidity, particularly CHF hospitalization[1]. The researchers, led by principal investigator Dr Jay N Cohn (University of Minnesota, Minneapolis, MN) released preliminary data at the American Heart Association's Scientific Sessions 2000 in New Orleans, LA.

However, while the overall message is positive, Cohn pointed out that in subgroup analysis, they found a trend toward a negative outcome among patients who were on valsartan against a background therapy of both ACE inhibitors and beta blockers.

"The bottom line is that valsartan is an effective drug to add to conventional therapy for heart failure, with a little flag waving that being on all three drugs - that is, an ACE inhibitor, beta blocker and angiotensin receptor blocker valsartan - may not be beneficial, and could potentially have an adverse effect," Cohn said. "We're going to be doing a good deal more analysis on these data to determine just what, if anything, that adverse trend means."

Overall positive effect, with a "little flag waving"

Val-HeFT was a large-scale, double-blind, placebo-controlled trial examining the effect on morbidity and mortality of the selective angiotensin receptor blocker valsartan versus placebo, in addition to usual therapy with ACE inhibitors, beta blockers, diuretics, and digoxin.

Primary endpoints included all-cause mortality (time to death) and combined all-cause mortality and morbidity, comprising all-cause mortality, hospitalization for heart faillure, resuscitated sudden death, and the need for therapeutic doses of an IV inotropic or vasodilating agent for at least 4 hours.

The study included 5010 patients from 300 centers in the US and Europe. The ratio of men to women was about 4:1, about 90% were white. Most were in NYHA class II (61.7%) or III (36.2%) at baseline. At baseline, 93% of patients were on ACE inhibitors, about 35% of patients were on beta blockers, higher numbers than might be expected in clinical practice, Cohn said. Most were receiving diuretics and about two-thirds were on digoxin, he added, "so these were very well-treated patients."

Patients were randomized to placebo or to valsartan. Valsartan was initiated at a dose of 40 mg twice daily, then was titrated up to a target dose of 160 mg twice daily. The drug was well-tolerated, Cohn noted, with an average dose achieved of 254 mg/day. After about 2 years of follow up, analysis of the data showed no effect of valsartan on the outcome of all-cause mortality. However, the combined endpoint of all-cause morbidity and mortality was reduced by 13.3%, a statistically significant finding.

Val-HeFT: primary endpoints

Primary endpoints Valsartan, N=2511 Placebo, N=2499 Relative Risk (95% CI) p value
All-cause mortality 495 (19.7%) 484 (19.4%) 1.02
Combined all-cause mortality and morbidity 723 (28.8%) 801 (32.1%) 0.87

A large proportion of the reduction in the combined endpoint was accounted for by a significant 27.5% reduction in hospitalizations for heart failure. Positive effects were seen on a variety of other secondary endpoints, including NYHA functional class, ejection fraction, and the signs and symptoms of heart failure, including dyspnea, shortage of breath, and edema. Valsartan patients also reported significantly better quality of life, as measured by the Minnesota Living With Heart Failure Questionnaire.

The investigators elected to carry out a variety of subgroup analyses, which Cohn acknowledged "one does with great trepidation in clinical trials such as these."

An attenuation of the beneficial effects of valsartan was seen in both patients taking ACE inhibitors and in patients taking beta blockers. For example, the 7% of patients who were not on ACE inhibitors had a benefit that approached a 45% reduction, he said. Those on an ACE inhibitor showed slightly less benefit, and the confidence intervals for these findings did not overlap.

This differential effect was even more dramatic in the beta blocker group, he said. Those not on beta blocker exhibited a "striking benefit" from valsartan treatment, but among those on beta blockers, the point estimate actually trended toward a negative effect with valsartan.

However, they found that the observation of a negative outcome seen among those taking a beta blocker and valsartan was present only in those also taking an ACE inhibitor in addition to the other agents. He acknowledged, however, that these numbers are small and the analysis constitutes "thin ice" statistically.

We don't want to oversell the concept that valsartan is good treatment - it is good treatment but there is that caveat.

A trial to define this potential interaction "is going to have to be done, because it's a question now that needs to be answered. It impacts upon all other trials in heart failure because it may be that when one has two neurohormonal inhibitors, one is really reaching the [peak] of benefit, and some of these newer drugs coming along may exhibit this problem, that you can't get further benefit once you're on two drugs," Cohn told heart wire in an interview.

"We now have three drugs that have proved to be effective, and my initial impression would be that all patients should be on two of those, but I'm not sure they should be on all three," he added. "We don't want to oversell the concept that valsartan is good treatment - it is good treatment - but there is that caveat."

Val-HeFT versus ELITE-II

Perhaps not surprisingly, the question of comparing the positive results of this trial with valsartan with disappointing results seen with another of this class of agents, losartan in the ELITE II trial[2], came up during a press conference here. There are a number of AT1 receptor blockers on the market, and differences among them in terms of pharmacologic effect may exist, Cohn said, but these have not yet been clearly defined.

"But the dosing is terribly important," he pointed out. "The ELITE trial was carried out with a dose of losartan of 50 mg, once daily. Val-HeFT used a dose of 160 mg, twice daily. So more important than class effect is knowing what dose of any drug to use to achieve the desired effect. We now know with valsartan that 160 mg twice daily has a favorable effect. We do not know that with any other drug, and indeed this is the first angiotensin receptor blocker that has been shown to be effective in heart failure."

Val-HeFT is part of a program of investigation with this drug by Novartis, who also supported this study. Among these is the Valsartan Antihypertensive Long-term Use Evaluation (VALUE), a morbidity and mortality trial comparing valsartan to the calcium channel blocker amlodipine in patients with high-risk hypertension. The Valsartan in Acute Myocardial Infarction (VALIANT) trial will assess valsartan in comparison to, and in combination with, captopril in post-MI patients with heart failure or LV dysfunction. Both are expected to report in 2003.



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