Fast track — ArticlesEffects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial
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
References (19)
- et al.
Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey
Lancet
(2002) - et al.
Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD): SOLVD Investigators
Am Heart J
(1996) - et al.
Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors
Am Heart J
(2000) - et al.
Candesartan in Heart Failure-Assessment of Mortality and Morbidity (CHARM): rationale and design
J Cardiac Failure
(1999) - et al.
Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme
Lancet
(2003) - et al.
Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients
Lancet
(2000) - et al.
Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors
J Am Coll Cardiol
(2002) - et al.
Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure: Collaborative Group on ACE Inhibitor Trials
JAMA
(1995) - et al.
Contemporary management of patients with left ventricular svstolic dysfunction: results from the study of patients intolerant of converting enzyme inhibitors (SPICE) registry
Eur Heart J
(1999)
Cited by (0)
For CHARM investigators and committees see page 765