Elsevier

The Lancet

Volume 362, Issue 9386, 6 September 2003, Pages 767-771
The Lancet

Fast track — Articles
Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial

https://doi.org/10.1016/S0140-6736(03)14283-3Get rights and content

Summary

Background

Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements, neurohumoral activity, and left-ventricular remodelling when added to angiotensin-converting-enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). We aimed to find out whether these drugs improve clinical outcome.

Methods

Between March, 1999, and November, 1999, we enrolled 2548 patients with New York Heart Association functional class II–IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors. We randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). At baseline, 55% of patients were also treated with β blockers and 17% with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was done by intention to treat.

Findings

The median follow-up was 41 months. 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0·85 [95% CI 0·75–0·96], p=0·011; covariate adjusted p=0·010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for CHF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline β blocker treatment.

Interpretation

The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction.

Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7417web.pdf

Introduction

Mortality and morbidity among patients with chronic heart failure (CHF) and reduced left-ventricular ejection fraction remain high, despite the use of full conventional treatment, including angiotensin-converting-enzyme (ACE) inhibitors, β blockers, and spironolactone. The addition of an angiotensin II type 1 receptor blocker to an ACE inhibitor is a theoretically attractive treatment strategy in CHF. Angiotensin II can be produced by non-ACE enzymatic pathways in human cardiac tissue and blood vessels, and its generation seems to continue even during chronic, high-dose, ACE-inhibitor treatment in CHF.1, 2, 3, 4, 5 Angiotensin-receptor blockers should, therefore, provide more complete inhibition of the actions of angiotensin II. Conversely, ACE inhibitors also block the breakdown of bradykinin, mediated by kininase II, which is identical to ACE. Bradykinin has direct and indirect vasodilator, antimitotic, and antithrombotic actions that could be of benefit in CHF.6, 7 Consequently, treatment with combined ACE inhibitors and angiotensin-receptor blockers might have advantages over ACE-inhibitor monotherapy.

In several studies, including the Randomized Evaluation of Strategies for Left Ventricular Dysfunction pilot study,8 favourable effects on haemodynamic indices, left-ventricular remodelling, and neurohumoral activity in CHF have been reported with combined ACE inhibitors and angiotensin-receptor blockers.8, 9 This combination of treatment also increases exercise capacity and improves New York Heart Association functional class.10

In the prospective Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial, part of the CHARM programme,11, 12, 13 we investigated whether combining an angiotensin-receptor blocker, candesartan, with ACE inhibitors also improves clinical outcome. We compared the effect of candesartan with that of placebo among patients with CHF and reduced left-ventricular ejection fraction.

Section snippets

Methods

The design of the CHARM programme has been described in detail elsewhere, including randomisation, monitoring, and follow-up.11, 12, 13

Results

Of 2548 patients enrolled, 1276 were assigned candesartan and 1272 placebo (figure 1). Follow-up was concluded on March 31, 2003. The median duration of follow up was 41 months.

The baseline characteristics, including details of background medical treatment, are given in table 1. Enalapril, lisinopril, captopril, and ramipril were the most commonly used ACE inhibitors, together accounting for 74% of all ACE inhibitors used. The mean daily doses of these drugs in the candesartan group were 16·8,

Discussion

Among patients with CHF and a low left-ventricular ejection fraction, the addition of candesartan to an ACE inhibitor decreased the risk of cardiovascular death, and admission to hospital for CHF. This beneficial effect of candesartan was seen in all prespecified subgroups of patients, including those treated with β blockers and other treatments, with no evidence of treatment heterogeneity.

Our findings are consistent with the evidence that angiotensin II continues to be produced despite chronic

References (22)

  • RS McKelvie et al.

    Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study

    Circulation

    (1999)
  • Cited by (0)

    For CHARM investigators and committees see page 765

    View full text