The CHARM-Alternative trial: Angiotensin-receptor blockers in heart failure [Classics Series]

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1. Candesartan significantly reduced cardiovascular death and hospital admission for chronic heart failure in patients with heart failure and reduced ventricular function, who were intolerant to ACE inhibitors.

2. Candesartan was well-tolerated in patients with previous intolerance to ACE inhibitors.

Original Date of Publication: September 6, 2003

Study Rundown: Angiotensin-converting-enzyme (ACE) inhibitors have been shown to effectively reduce morbidity and mortality in patients with symptomatic heart failure, but intolerance to ACE inhibitors occurs frequently. Angiotensin-receptor blockers (ARB) are an alternative agent that may be used to inhibit the renin-angiotensin-aldosterone system but evidence of its effectiveness in reducing long-term clinical events was limited at the time this study was conducted. The CHARM-Alternative trial was one arm of the CHARM-Overall programme assessing the effectiveness of candesartan compared to placebo in patients with symptomatic heart failure and reduced left-ventricular systolic function, who could not tolerate ACE inhibitors. Results of the study showed a significant reduction in cardiovascular death and hospital admission due to heart failure in the candesartan group.

In sum, an angiotensin receptor blocker should be considered in patients with symptomatic chronic heart failure, reduced ventricular function, and an intolerance to ACE inhibitors.

Please click to read study in The Lancet

In-Depth [randomized, controlled study]: Published in The Lancet in 2003, this study randomized 2,028 patients to receive an ARB (i.e., candesartan) or placebo and investigated the long-term clinical outcomes. The CHARM-Alternative trial included patients with symptomatic chronic heart failure (CHF) and left-ventricular ejection fraction of 40% or less who had a previously documented intolerance to ACE inhibitors. The primary outcome of cardiovascular death or hospital admission for CHF occurred in 33% of patients in the candesartan group and 40% of patients in the placebo group. This reduction in the primary outcome in the candesartan group was significant and was maintained when non-fatal myocardial infarction, non-fatal stroke and coronary revascularization were included in the composite outcome. Study drug discontinuation was similar between the treatment and placebo groups suggesting that candesartan was well-tolerated in this population of patients in spite of previously documented intolerance to ACE-inhibitors.

By Adrienne Cheung, Andrew Cheung, M.D.

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