Angiotensin II Receptor Blockers in the Treatment of Heart Failure

Ross C. Peterson, MD, Mark E. Dunlap, MD

Disclosures

CHF. 2002;8(5) 

In This Article

Clinical Benefits of ARB Therapy in the Treatment of Heart Failure

Improved Tolerance and Compliance. Although ACE inhibitors reduce morbidity and mortality among patients with heart failure and left ventricular systolic dysfunction, these agents are substantially underused.[32,33] A major reason for this is physician concern over possible adverse effects.[34] In fact, only 10% of patients with heart failure are intolerant of ACE inhibitors,[32] with cough, renal insufficiency, and symptomatic hypotension being the most common causes.

The use of ARBs has been proposed in those patients who are intolerant of ACE inhibitors, and they appear to be better tolerated. Adverse effects of ARBs are less frequent than with ACE inhibitors.[35] The incidence of cough is similar to that with placebo,[36,37] and significantly less than that with ACE inhibitors.[38] The Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE)[39] was a pilot study to evaluate the use of candesartan in a population of patients with heart failure and left ventricular systolic dysfunction with a history of intolerance to ACE inhibitors. The goal of the 12-week study was to determine the tolerability of candesartan in these patients. The investigators found that nearly 83% of patients completed the 12-week treatment period with candesartan, similar to the completion rate with placebo. Therefore, patients with heart failure who are intolerant of ACE inhibitors can tolerate another method of inhibiting the RAAS.

Several studies have examined the effects of ARBs on exercise tolerance and symptoms in patients with heart failure. Candesartan was given to 844 patients with mild to moderate heart failure in a double-blind, prospective, randomized, placebo-controlled trial.[40] All treatment groups experienced improvement in New York Heart Association (NYHA) functional class and dyspnea fatigue index scores. Increases in total exercise time were dose-related. Losartan has been found to be comparable to enalapril in terms of exercise tolerance over a 12-week period in patients with heart failure.[41] Irbesartan has been found to improve exercise tolerance to a magnitude similar to that of an ACE inhibitor.[42] These results all suggest that short-term ARB therapy is comparable to ACE inhibition in terms of exercise tolerance and symptoms of congestive heart failure.

Given the known benefits of ACE inhibitor therapy, any trial evaluating the effect of ARBs on mortality in heart failure needs to be randomized against ACE inhibitors. One of the first trials to look at this problem was the Evaluation of Losartan in the Elderly (ELITE)-I study.[43] In this randomized trial, 722 patients with heart failure were assigned to losartan titrated to 50 mg once daily or captopril titrated to 50 mg three times daily for 48 weeks. The trial was designed to compare the safety and efficacy of losartan and captopril. Although there was no difference between groups in renal dysfunction, the primary end point for the study, a mortality benefit from losartan was noted compared to captopril (4.8% vs. 8.7%, respectively).

Since this study was not designed as a mortality trial, a larger trial was initiated. The ELITE-II Losartan Heart Failure Survival Study[44] was a double-blind, randomized, controlled trial of 3152 patients, stratified for blocker use, in which patients were assigned to losartan 50 mg daily or captopril 50 mg three times daily. The primary end point was all-cause mortality. In contrast to ELITE-I, no improvement in survival was found in the losartan-treated group (total mortality, 17.7%) vs. captopril (mortality, 15.9%). ELITE-II did confirm the superior tolerability of losartan over captopril seen in ELITE-I. These findings suggest that ACE inhibitors should remain first-line therapy in the treatment of patients with heart failure and left ventricular systolic dysfunction, but that ARBs are well tolerated and could be considered in patients who cannot tolerate ACE inhibitors.

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