Elsevier

The Lancet

Volume 362, Issue 9386, 6 September 2003, Pages 772-776
The Lancet

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Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial

https://doi.org/10.1016/S0140-6736(03)14284-5Get rights and content

Summary

Background

Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensin-receptor blocker, could improve outcome in such patients not taking an ACE inhibitor.

Methods

Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat.

Findings

The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33·7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0·77 [95% CI 0·67–0·89], p=0·0004; covariate adjusted 0·70 [0·60–0·81], p<0·0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups.

Interpretation

Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.

Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7418web.pdf

Introduction

Angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity among patients with chronic heart failure (CHF) and left-ventricular systolic dysfunction.1 However, more than one in five patients with left-ventricular systolic dysfunction are not receiving ACE inhibitors. In a registry in Europe and North America, 20% of patients with reduced left-ventricular ejection fraction were not receiving ACE inhibitors, and 9% had a history of ACE-inhibitor intolerance.2 In European registries, among patients with left-ventricular systolic dysfunction and heart failure, 20% at the time of hospital discharge3 and 29% in primary care4 were not receiving ACE inhibitors. Although the use of ACE inhibitors has been steadily and appropriately increasing, intolerance to these drugs frequently prevents their use. The most common manifestation of ACE-inhibitor intolerance leading to discontinuation is cough, representing around 30% to 65% of those people stopping.2, 5, 6 The most consistent predictors in patients of non-use of ACE inhibitors are older age and female sex.2, 3, 4

The use of angiotensin-receptor blockers for patients intolerant to ACE inhibitors is an alternative approach to inhibiting the renin-angiotensin-aldosterone system in CHF. Although short-term treatment with angiotensin-receptor blockers seems to be well tolerated in CHF patients intolerant to ACE inhibitors6 and may improve symptoms and exercise tolerance in patients not taking ACE inhibitors,7 their long-term clinical effectiveness on cardiovascular outcomes is not well established.

In the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Alternative study, part of an overall CHARM programme,8, 9 we investigated whether an angiotensin-receptor blocker, candesartan, improves clinical outcome in a population of patients intolerant to ACE inhibitors. The primary objective was to assess the effects of candesartan on the risk of cardiovascular death or hospital admission for heart failure in patients with reduced left-ventricular ejection fraction and symptomatic heart failure not currently treated with an ACE inhibitor because of previous intolerance.

Section snippets

Patients and methods

The design of the CHARM programme has been described in detail elsewhere, including randomisation, monitoring, and follow-up.8, 10

Results

2028 patients were randomised. Follow-up was concluded on March 31, 2003. The median duration of follow-up was 33·7 months and the vital status at study closure was ascertained in all but three patients (two candesartan and one placebo, figure 1).

The baseline characteristics, including details of background medical treatment, have been previously published10 and were generally balanced between the treatment groups (table 1). The most common manifestation of ACE-inhibitor intolerance before

Discussion

Among patients with CHF and left-ventricular systolic dysfunction clinically judged unable to tolerate an ACE inhibitor, candesartan significantly reduced cardiovascular death and hospital admission for heart failure. The effect appeared early and was sustained throughout the 3 years of the trial. Candesartan was well tolerated, without a significant excess in need for discontinuation compared with placebo, despite this population's history of intolerance to another inhibitor of the

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For CHARM investigators and committees see page 765

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