Combination Therapy With ACE Inhibitors and ARBs in the Treatment of Heart Failure
Several studies have evaluated combination therapy on exercise tolerance and symptoms in heart failure. One study was a randomized, double-blind, placebo-controlled trial that evaluated the effect of adding an ARB on symptoms and exercise tolerance in patients with severe congestive heart failure being treated with maximal ACE inhibition. Patients were randomized to either placebo or 50 mg per day of losartan. Patients had an evaluation of peak aerobic capacity and NYHA class at 0, 3, and 6 months. The losartan-treated group had significant improvement in peak aerobic capacity and alleviation of their symptoms.
Another combination trial was the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. This study randomized 768 heart failure patients to candesartan, candesartan plus enalapril, or enalapril alone for 43 weeks. There were no differences among the groups in NYHA functional class, quality of life indices, or 6-minute walk distance. There was a trend toward increased ejection fraction in the candesartan plus enalapril group, as compared to either therapy alone. There also was a significant benefit with combination therapy in blood pressure control and less of an increase in end-diastolic volume and end-systolic volume in the combination group. The investigators concluded that most patients tolerated combination therapy with ACE inhibitors and ARBs, and that there may be some benefits to using combination therapy in patients with heart failure.
The Valsartan Heart Failure Trial (Val-HeFT) was undertaken to determine if there is clinical benefit to adding an ARB to ACE inhibitors in patients with heart failure. Val-HeFT was a double-blind, placebo-controlled trial with 5010 patients that examined the effect of the ARB valsartan vs. placebo in patients on traditional therapy for heart failure (ACE inhibitors, diuretics, digoxin, and blockers). Patients were stratified for blocker use and randomized to receive valsartan 40 mg twice daily titrated to 160 mg twice daily or placebo. The primary end points were time to death and combined all-cause morbidity and mortality.
The trial found no difference in all-cause mortality, with 495 deaths (19.7%) in the valsartan-treated group and 484 deaths (19.4%) in the placebo-treated group. However, there was a significant 13.3% reduction in the combined end point of all-cause mortality and morbidity in the group taking valsartan. Further analysis of the data showed that this difference was almost entirely derived from a reduction in the number of hospitalizations for heart failure, with a 27.5% risk reduction for heart failure hospitalizations in the valsartan group compared to placebo. Beneficial effects also were seen in a number of secondary end points, including NYHA class, ejection fraction, and quality of life measurements.
An interesting observation from Val-HeFT was that much of the benefit from ARB therapy was observed in those patients who were not on either an ACE inhibitor or a blocker. Only 7% of the patients enrolled in Val-HeFT were not on ACE inhibitors, but these patients showed significant improvement with addition of valsartan. Only 35% of enrolled patients were on blockers, and patients who were not on blockers also had significant improvement when treated with valsartan. However, there was an important finding in patients who were taking all three neurohumoral blockers (ACE inhibitor, ARB, and blocker). Though it was not statistically significant, these patients tended to have a negative outcome. This raises the question of whether it might be possible to have "too much" neurohormonal blockade in treating patients with heart failure.
Another trial that will further delineate the role of ARBs in heart failure is the Candesartan in Heart Failure: Assessment of Reduction in Morbidity and Mortality (CHARM) study. This multicenter, randomized, placebo-controlled trial has enrolled 7572 patients with NYHA class II-IV heart failure, and includes patients with ejection fractions both greater and less than 40%. The less than 40% ejection fraction group is divided into ACE inhibitor (combination)-treated and ACE inhibitor-intolerant groups, and each of these groups has been randomized to either candesartan or placebo. All patients will be followed for 42 months, and the primary overall end point is all-cause mortality. The trial is scheduled to finish in 2003.
CHF. 2002;8(5) © 2002 Le Jacq Communications, Inc.
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