The salutary effect of angiotensin-converting enzyme (ACE) inhibitors and beta blockers in congestive heart failure (CHF) has been well established in clinical studies. Previous studies have shown that physiologically active levels of angiotensin II persist despite long-term ACE inhibitor therapy. Cohn and Tognoni conducted a randomized, placebo-controlled, double-blind study of 5,010 CHF patients currently receiving either placebo or the angiotensin-receptor blocker (ARB) valsartan in addition to their standard therapy to determine if valsartan could further reduce mortality and morbidity.
ACE inhibitors were being used by 93 percent of study participants, while 35 percent were taking a beta blocker, and 5 percent were taking spironolactone. All patients had CHF documented by echocardiography. Valsartan was initiated at a dosage of 40 mg twice daily, and the dosage was doubled every two weeks until the target dosage of 160 mg twice daily was reached. Dosage increases were stopped if the systolic blood pressure was less than 90 mm Hg while the patient was standing, symptoms of hypotension were present, or the serum creatinine level was greater than 2 mg per dL (180 μmol per L). Patients returned for follow-up visits at two, four, and six months, and every three months thereafter to compare overall mortality rates and the combined outcomes of mortality and morbidity (e.g., hospitalization for heart failure, cardiac arrest with resuscitation, and need for intravenous inotropic or vasodilator drugs for four or more hours without hospitalization).
Overall mortality was not significantly improved by the addition of valsartan. When mortality and morbidity outcomes were combined, 28.8 percent of the valsartan group had an adverse outcome compared to 32.1 percent of participants receiving placebo, giving a relative risk reduction of 13.2 percent. The beneficial effect of valsartan was most pronounced in patients not currently receiving an ACE inhibitor as part of their standard CHF therapy. In the group receiving an ACE inhibitor and a beta blocker at initiation of the study, valsartan had an adverse effect on mortality and was associated with an increase in the combined end points of mortality and morbidity.
The authors concluded that even though there was a relative risk reduction of 13.2 percent in adverse outcomes when valsartan was added to standard CHF therapy, this therapy was potentially harmful in patients receiving an ACE inhibitor and a beta blocker.