Elsevier

The Lancet

Volume 362, Issue 9386, 6 September 2003, Pages 777-781
The Lancet

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Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial

https://doi.org/10.1016/S0140-6736(03)14285-7Get rights and content

Summary

Background

Half of patients with chronic heart failure (CHF) have preserved left-ventricular ejection fraction (LVEF), but few treatments have specifically been assessed in such patients. In previous studies of patients with CHF and low LVEF or vascular disease and preserved LVEF, inhibition of the renin-angiotensin system is beneficial. We investigated the effect of addition of an angiotensin-receptor blocker to current treatments.

Methods

Between March, 1999, and July, 2000, we randomly assigned 3023 patients candesartan (n=1514, target dose 32 mg once daily) or matching placebo (n=1509). Patients had New York Heart Association functional class II–IV CHF and LVEF higher than 40%. The primary outcome was cardiovascular death or admission to hospital for CHF. Anaysis was done by intention to treat.

Findings

Median follow-up was 36·6 months. 333 (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0·89 [95% Cl 0·77–1·03], p=0·118; covariate adjusted 0·86 [0·74–1·0], p=0·051). Cardiovascular death did not differ between groups (170 vs 170), but fewer patients in the candesartan group than in the placebo group were admitted to hospital for CHF once (230 vs 279, p=0·017) or multiple times. Composite outcomes that included non-fatal myocardial infarction and non-fatal stroke showed similar results to the primary composite (388 vs 429; unadjusted 0·88 [0·77–1·01], p=0·078; covariate adjusted 0·86 [0·75–0·99], p=0·037).

Interpretation

Candesartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40%.

Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7419web.pdf

Introduction

Around 50% of patients with chronic heart failure (CHF) do not have low left-ventricular ejection fraction (LVEF).1 Although patients with LVEF of 40% or less have poorer outcomes than do patients with higher values, even those with heart failure and LVEF higher than 40% (preserved LVEF) have high rates of mortality and admission to hospital for CHF.1 In many studies researchers have assessed the effects of angiotensin-converting-enzyme inhibitors,2 β blockers,3, 4 and angiotensin-receptor blockers5 in patients with low LVEF but, other than digoxin in one trial,6 few treatments have been specifically assessed in CHF patients with LVEF higher than 40%. Consequently, many of the guidelines for the treatment of heart failure do not address this group of patients or simply extrapolate the findings from trials in individuals with low LVEF and heart failure. Whether such extrapolations are justified is unknown.

Inhibitors of angiotensin-converting enzyme reduce mortality and morbidity in patients at high risk of cardiovascular events with preserved LVEF and no CHF.7 Therefore, in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study, part of the CHARM programme,8 we tested the hypothesis that another inhibitor of the renin-angiotensin system, an angiotensin-receptor blocker, candesartan, would be of benefit in patients with CHF and preserved LVEF. The primary goal was to assess the effects of candesartan on the composite outcome of cardiovascular mortality or admission to hospital for worsening CHF.

Section snippets

Patients and methods

The design of the CHARM programme has been described in detail elsewhere, including randomisation, monitoring, and follow-up.8, 9, 10

Results

3025 patients were enrolled, including two patients who mistakenly received randomisation numbers but had no other data recorded and never received study medication. Therefore, 3023 patients were randomised—1514 were assigned candesartan and 1509 placebo. Two candesartan patients and one placebo patient were lost to follow-up (figure 1). Follow-up was concluded on March 31, 2003, with a median duration of 36·6 months. Baseline characteristics are presented in table 1. Several baseline

Discussion

We show a trend in favour of candesartan towards fewer cardiovascular outcomes among patients with preserved LVEF, although the difference in the composite of cardiovascular mortality or CHF hospital admissions between the candesartan and placebo group is moderate and of borderline significance. The numbers of individuals admitted one or more times for heart failure was reduced, which reinforces the fact that candesartan is of some clinical benefit in this population.

Heart failure at entry to

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For CHARM investigators and committees see page 765

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