A Randomized Trial of the Angiotensin‐Receptor Blocker Valsartan in Chronic Heart Failure

Background. Actions of angiotensin II may contribute to the progression of heart failure despite treatment with currently recommended drugs. We therefore evaluated the long-term effects of the addition of the angiotensin receptor blocker valsartan to standard therapy for heart failure. Methods. A total of 5010 patients with heart failure of New York Heart Association (NYHA) class II, III, or IV were randomly assigned to receive 160 mg of valsartan or placebo twice daily. The primary outcomes were mortality and the combined end point of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least 4 hours. Results. Overall mortality was similar in the two groups. The incidence of the combined end point, however, was 13.2% lower with valsartan than with placebo (relative risk, 0.87; 97.5% confidence interval, 0.77–0.97; p=0.009), predominantly because of a lower number of patients hospitalized for heart failure: 455 (18.2%) in the placebo group and 346 (13.8%) in the valsartan group (p<0.001). Treatment with valsartan also resulted in significant improvements in NYHA class, ejection fraction, signs and symptoms of heart failure, and quality of life, as compared with placebo (p<0.01). In a post hoc analysis of the combined end point and mortality in subgroups defined according to baseline treatment with angiotensin-converting enzyme (ACE) inhibitors or β blockers, valsartan had a favorable effect in patients receiving neither or one of these types of drugs but an adverse effect in patients receiving both types of drugs. Conclusions. Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, an ACE inhibitor, and a β blocker raises concern about the potential safety of this specific combination.—Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667–1675. Comment. Angiotensin II has been associated with significant deleterious effects in heart failure patients. Previous investigations have examined interruptions of the renin-angiotensin-aldosterone system. This has been accomplished through various mechanisms. The most notable has been the use of ACE inhibitors. This drug class has been marketed for more than two decades and for the last 15 years or more, these agents have demonstrated significant benefits for heart failure patients. Working from previous information, the authors of this paper were involved in a trial to assess the use of angiotensin receptor blockers, specifically valsartan, in combination with standard heart failure regimens. They looked at the long-term effects of valsartan in more than 5000 patients with significant systolic dysfunction and clinical heart failure. Patients in the trial were randomly assigned to receive either 160 mg of valsartan or placebo in a twice-daily regimen. End points included mortality as well as a combined end point of mortality and morbidity, hospitalization, or need for intravenous inotropic or vasodilator therapy. The results of the trial showed that neither the treated nor the untreated group had a significant difference in mortality overall; however, in terms of the combined end points of mortality and morbidity, the valsartan group fared significantly better. The difference was noted predominantly in the need for hospitalization in the untreated group when compared to the treated group. Additional information gleaned from this trial showed that the use of valsartan was associated with functional improvements as well as an increase in the ejection fraction and improvement in quality of life. The authors of the trial therefore concluded that valsartan use can significantly reduce the combined end point of mortality and morbidity as well as confer improvement in functional status and clinical predictors. The data, however, suggested that there should be concern in patients who are receiving both ACE inhibitors and β blockers. In these patients, the addition of valsartan to the standard clinical regimen led to a worse outcome in this trial. While it seems very attractive to have another avenue to pursue in treating heart failure patients, due to their otherwise poor prognosis, this new regimen should be considered with great caution. In patients who cannot tolerate ACE inhibitors or β blockers, however, this regimen may prove very helpful. More studies are ongoing at this time and will likely elucidate this issue.