Valsartan reduces combination of mortality and morbidity in CHF: Val-HeFT published

Susan Jeffrey

December 05, 2001

Boston, MA - Final results of the Valsartan Heart Failure Trial (Val-HeFT) show the addition of the angiotensin receptor blocker (ARB) valsartan (Diovan® - Novartis) to prescribed therapy for heart failure (HF) did not significantly affect all-cause mortality, but did significantly reduce the combined endpoint of mortality and morbidity, largely through a reduction in HF hospitalizations[1].

However, post hoc analysis suggested adverse trends on both of these primary endpoints when valsartan was given to patients already taking both ACE inhibitors and -blockers. The results, first presented at the American Heart Association Scientific Sessions 2000 and reported by heartwire , appear in the December 6, 2001 issue of the New England Journal of Medicine.

Regulatory decision on a subgroup analysis?

In October 2001, the FDA's Cardiovascular and Renal Drugs Advisory Committee came to a split decision of 4 votes to 4 on whether to recommend approval of valsartan in CHF. However, just 2 weeks later, Novartis announced they had received an approvable letter from the FDA for valsartan in the treatment of HF among patients not receiving an ACE inhibitor.

Subgroup analysis of the trial had shown that the small group of patients not receiving ACE inhibitors, about 7% of the overall population, appeared to reap preferential benefit from treatment with valsartan, with a 44% reduction in the combined endpoint, and a 33.1% reduction in mortality.

"Final approval is contingent on further analysis of existing data or possibly the submission of additional data," Novartis noted in a press release at that time.

Dr Jay N Cohn (University of Minnesota Medical School, Minneapolis, MN), the principal investigator of Val-HeFT, was disappointed by the split decision. Members of the committee who voted against approval were not those who treat patients, he said. "People who were clinically knowledgeable voted overwhelmingly for it," Cohn told heartwire . "They understand the need for valsartan and statisticians don't."

The addition of valsartan was beneficial to all the patients in the trial, he pointed out, except those already on both -blockers and ACE inhibitors. In those not on an ACE inhibitor, he added, it was "life-saving."

 
It's a very complicated issue, because we've never been faced with this sort of subgroup analysis in making regulatory decisions.
 

"Even though that's a relatively small subgroup, it's a very important observation and provides an alternative therapy for people who don't tolerate an ACE inhibitor," Cohn said. "And I think the committee recognized that, but they weren't asked to consider approval of the drug for patients not on an ACE inhibitor so that represents another direction."

"It's a very complicated issue, because we've never been faced with this sort of subgroup analysis in making regulatory decisions," Cohn added.

Further analysis, focusing on data relating to the effect of valsartan in patients not already on an ACE inhibitor, has recently been submitted to the FDA, Cohn said.

Blocking angiotensin II

Angiotensin II is a potent vasoconstrictor and growth-stimulating hormone, and is thought to contribute to the progression of HF through increased impedence of left ventricular emptying, adverse long-term effects on the vasculature, and the potentially deleterious activation of other hormones including norepinephrine, aldosterone, and endothelin, the researchers note in their paper.

Despite the use of ACE inhibitors, physiologically active levels of angiotensin II are found in patients with HF, they note. The rationale of this study was to see whether the addition of an angiotensin-receptor blocker to what the enrolling physicians considered optimal therapy could improve outcomes.

Val-HeFT included 5010 patients with NYHA class II, III, or IV HF, enrolled from 302 centers in 16 countries. Patients were randomized to receive 160 mg of valsartan or placebo twice a day.

Primary endpoints were all-cause mortality, and a combined endpoint of all-cause mortality and morbidity, including hospitalization for HF, resuscitated cardiac arrest, or the need for intravenous inotropic or vasodilator therapy for at least 4 hours.

Although all-cause mortality was not different between the groups, the combined endpoint was reduced by a statistically significant 13.2% with valsartan therapy.

Val-HeFT: Primary endpoints

Endpoint Valsartan (n=2511) Placebo (n=2488) RR (95% CI) p value
All-cause mortality 495 (19.7%) 484 (19.4%) 1.02
(0.88-1.18)
0.80
Combined all-cause mortality and morbidity* 723 (28.8%) 801 (32.1%) 0.87
(0.77-0.97)
0.009
*including hospitalization for HF, resuscitated cardiac arrest, need for intravenous therapy

The reduction in the combined endpoint was accounted for in large part by the reduction in the need for hospitalization for HF.

Hospitalization for HF

Endpoint Valsartan (n=2511) Placebo (n=2488) p value
Hospitalization for HF 348 (13.8%) 455 (18.2%) <0.001

NYHA class, ejection fraction, signs and symptoms of HF, and quality-of-life measures were also significantly improved with valsartan treatment (p<0.01).

Adverse events leading to discontinuation of therapy occurred in 9.9% of valsartan patients compared to 7.2% of the placebo group (p<0.001). Most common reasons for withdrawal with valsartan were dizziness, hypotension, and renal impairment.

Adverse effects of too much neurohormonal blockade?

Although findings from subgroup analyses should be interpreted with caution, Cohn et al point out, they did see differences in response to therapy based on background therapy at baseline. Treatment with valsartan appeared to benefit each subgroup - those on ACE inhibitors but not -blockers, those on -blockers but not ACE inhibitors, and those not on either of these therapies - except for those 1810 patients in whom valsartan was added to both -blocker and ACE-inhibitor therapy. "As previously noted, the apparent adverse effect of valsartan in this subgroup leads to the hypothesis that the extensive blockade of multiple neurohormonal systems in patients with heart failure could be deleterious," Cohn et al write.

Recent trials support this hypothesis, Cohn said. Moxonidine, a central inhibitor of norepinephrine of the sympathetic nervous system; endothelin-receptor antagonists; and cytokine inhibitors; all have been tested in trials given in addition to other therapies, he said, "and all three of those interventions in preliminary studies have failed."

Other trials are ongoing in which large numbers of patients are receiving these 3 classes of drugs, and their findings will provide more information about this potential interaction, Cohn added. For example, the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) trial examining the ARB candesartan (Atacand® - AstraZeneca) in HF is looking at that drug on a background of best medical therapy.

The suggestion of this safety concern in Val-HeFT did cause the safety committee for CHARM to examine their data, he said. "My understanding is they've found no reason to change the protocol or terminate the study, so in a way you might say that encourages us to think that this won't be replicated in another trial, but until the data are available we can't say that."

Adherence to guidelines

Finally, Cohn et al point out that despite the proven benefits of ACE inhibitor and -blocker therapy, only one third of patients enrolled in this trial were receiving both drugs at baseline, and suggest improved compliance with guidelines would reduce the numbers of "inadequately" treated patients. "Nonetheless," they conclude, "the benefit of valsartan in terms of the combined endpoint of mortality and morbidity that was found in all subgroups except those receiving both ACE inhibitors and -blockers suggests that the drug could have a role in the management of the syndrome."

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