Fast track — ArticlesEffects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme
Introduction
In patients with chronic heart failure (CHF) and reduced left-ventricular ejection fraction (LVEF), results of clinical randomised trials have shown the life-saving and symptomatic benefits of angiotensin-converting-enzyme inhibitors,1, 2, 3 β blockers,4, 5, 6, 7 and, in more selected patients, spironolactone.8 These findings have led to widespread use of these treatments in appropriate populations.9 The results have been translated into benefits in clinical practice, since in epidemiological studies and large registries substantial temporally related reductions have been seen in the age-adjusted mortality of patients with heart failure.10, 11, 12 Despite these major successes, the prevalence of heart failure continues to increase, mainly as a consequence of ageing populations, many patients having hypertension, ischaemic heart disease, or both, the two main predisposing disorders for heart failure.13, 14, 15 Indeed, heart failure is the most common reason for hospital admission in patients older than 65 years.16, 17 About 35–50% of patients with signs and symptoms attributed to heart failure do not have substantially reduced LVEF.17 Irrespective of the cause or presence of left-ventricular dysfunction, once clinically recognised, patients with heart failure are at heightened risk for subsequent hospital admissions and death from cardiovascular causes.
The development of angiotensin II type 1 receptor blockers provides a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system. Angiotensin-receptor blockers offer the potential to improve clinical outcomes for patients with heart failure beyond those seen with angiotensin-converting-enzyme inhibitors, as well as providing an alternative for patients with previous intolerance of angiotensin-converting-enzyme inhibitors.18 The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme was specifically designed as three parallel, independent, integrated, randomised, double-blind, placebo-controlled, clinical trials comparing candesartan with placebo in three distinct but complementary populations of patients with symptomatic heart failure.19 Dependent on background use of angiotensin-converting-enzyme inhibitors or LVEF, patients were eligible for one of the three component trials. We designed each trial to find out whether the use of candesartan would reduce the risk of cardiovascular death or hospital admission for CHF management in the specific population. The overarching hypothesis of the CHARM programme prespecified that use of candesartan would reduce the risk of death from any cause in the broad spectrum of patients with heart failure. The population was appropriate to test for consistency of benefits in subgroups and potential safety issues.
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Patients
Eligible patients were women and men aged 18 years or older who had symptomatic heart failure (New York Heart Association class II–IV) for at least 4 weeks' duration. Major exclusion criteria included serum creatinine 265 μmol/L or more, serum potassium 5·5 mmol/L or more, known bilateral renal artery stenosis, symptomatic hypotension, women of childbearing potential not using adequate contraception, critical aortic or mitral stenosis, myocardial infarction, stroke, or open-heart surgery in the
Results
7601 patients were randomised, although no data were available on two patients incorrectly assigned randomisation numbers and, therefore, the results are based on 7599 patients (3803 candesartan, 3796 placebo, figure 1). The programme was completed as planned with follow-up concluding on March 31, 2003, 2 years after the last patient was randomised. The median duration of follow-up was 37·7 months and the vital status of all but ten (0·1%) patients was ascertained at study closure. The baseline
Discussion
Our results show that treatment of a broad spectrum of patients with symptomatic heart failure with candesartan resulted in a reduction in deaths, albeit of borderline significance, notably because of a significant 12% reduction in cardiovascular deaths. In the overall CHARM programme, the risk of death and, particularly, death attributed to cardiovascular causes was strongly affected by left-ventricular systolic function. The annual cardiovascular death rate among the placebo group who had
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For the CHARM investigators and committees see end of paper