Report from the 94th Cardiovascular and Renal Drugs Advisory Committee Meeting, October 11, 2001

An orally active, competitive, angiotensin-II antagonist (at the level of the angiotensin II type 1 receptor), valsartan (Diovan), was first developed and approved by the US Food and Drug Administration 5 years ago for the treatment of hypertension alone or in combination with other antihypertensive agents.

Because angiotensin-converting enzyme (ACE) inhibitors do not block the formation of angiotensin II mediated by non-ACE enzymatic pathways, such as cardiac chymase, it has been argued that more complete inhibition of the renin-angiotensin system may be beneficial in the setting of congestive heart failure.

Five clinical, controlled studies of heart failure were submitted by Novartis for review. Hemodynamic effects were demonstrated, especially on pulmonary capillary wedge pressure and blood pressure, but in 2 trials, no improvement in exercise performance or symptom benefit was achieved.

The committee deliberations were directed primarily toward the large Valsartan Heart Failure Trial (Val-HeFT) of 5010 patients with class II to IV heart failure who all received some or all of currently accepted therapy, including ACE inhibitors, diuretics, digoxin, and β-blockers (randomization was stratified by β-blocker use) and were randomized to placebo or valsartan beginning at a dose of 40 mg BID with forced titration to 160 mg BID. The study assumed a placebo mortality of 12% per year and was powered to detect a 20% reduction in mortality. The trial had 2 coprimary end points, time to death and time to the first morbid event, which included death, sudden death with resuscitation, need for intravenous inotropic or vasodilator agents for worsening heart failure for at least 4 hours, or hospitalization for heart failure. All-cause mortality was 19.7% for valsartan-treated patients and 19.4% for those receiving placebo. Although morbidity was 28.8% for valsartan and 32.1% for placebo (hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P=0.009), the majority of the effect on morbidity was related to a reduction in heart failure hospitalizations from 18.2% to 13.8%, which translated to a reduction of ≈5 hospitalizations per 100 patients treated per year.

Of particular note in a major subgroup of 1750 patients receiving β-blockers, valsartan treatment was associated with excess mortality (16.4% versus 12.5% for placebo; hazard ratio, 1.357; 95% CI, 1.057 to 1.7422; P=0.018).

Other questions were raised regarding an unfavorable effect of valsartan in the modest-sized black population (7%) in Val-HeFT and an excess in hyperkalemia and renal failure associated with the small number of patients taking spironolactone at the time of entry.

Although there was little doubt in the minds of the Advisory Committee members that valsartan had a modest beneficial effect on the reduction of hospitalizations for heart failure, (especially in the small subgroup not receiving an ACE inhibitor), there was a division of opinion about the adequacy of information presented by this single trial (without other reproduction) on both efficacy and safety, especially among very elderly patients, blacks, and those taking adequate doses of ACE inhibitors, β-blockers and spironolactone. This division of opinion was reflected in a split vote of 4 for approval and 4 against approval.