Importance of CHARM in relation to other heart failure trials with ARBs

Abstract

Angiotensin-converting-enzyme (ACE) inhibitors, beta-blockers, and spironolactone (for patients with severe heart failure) have substantially improved survival in chronic heart failure. Because angiotensin-receptor blockers (ARBs) provide specific and potent inhibition of the angiotensin type-1 receptor, there has been hope that they might extend the benefits of ACE inhibitors. ELITE-II found no benefit with losartan 50 mg a day compared with captopril. In retrospect, losartan may have been less effective than other ARBs or under-dosed. In Val-HeFT, valsartan 160 mg twice daily was beneficial in a population where 93% were on an ACE inhibitor, although subgroup analysis led to speculation that this benefit was largely restricted to patients not on ACE inhibitors and that addition of valsartan may have been harmful in patients treated with both ACE inhibitors and beta-blockers. However, no such safety concern with valsartan plus beta-blockers was found in the subsequent VALIANT trial. CHARM directly addressed the major questions raised by Val-HeFT. In CHARM. candesartan titrated to 32 mg a day reduced mortality and morbidity both in patients who were receiving ACE inhibitors and in those intolerant to ACE inhibitors. There was also substantial benefit in adding candesartan to the combination of ACE inhibitors and beta-blockers. Among patients with low ejection fraction, candesartan resulted in highly significant reductions in cardiovascular death and heart-failure hospitalization, and in all-cause mortality. Thus, in patients with low ejection fraction, candesartan improves survival, regardless of background therapy. Candesartan should now be considered as another important treatment to further improve outcome in patients with chronic heart failure. (C) 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.