[Clinical study of the month. The CHARM study]

Abstract

In parallel, randomized, double-blind, controlled clinical trials, candesartan (titrated to 32 mg once daily) was compared to placebo in 3 distinct populations: 1) patients with symptomatic heart failure (SHF) and left ventricular ejection fraction (LVEF) 40% or less who were not receiving an ACE inhibitor because of previous intolerance (CHARM-Alternative); 2) patients with SHF and LVEF 40% or less who were currently receiving an ACE inhibitor (CHARM-Added); 3) patients with SHF and LVEF higher than 40% (CHARM-Preserved). The primary outcome for the overall programme (CHARM-Overall) was all-cause mortality. For the component trials, it was a composite of cardiovascular death and hospital admission for CHF. Analysis was by intention to treat. In CHARM-Overall (placebo, n = 3796; candesartan, n = 3803; mean follow-up; 37.7 months), candesartan induced a 1.6% absolute reduction in all-cause mortality (unadjusted HR: 0.91; 95% CI 0.83-1.00; p = 0.055). In a prespecified analysis with covariate adjustment, this was statistically significant (HR: 0.90; 95% CI 0.82-0.94; p = 0;032). A highly significant reduction in the combined incidence of cardiovascular death and CHF hospital admission (HR: 0.84; 95% CI 0.77-0.91; p < 0.0001) was noted as well as a reduction of the number of patients developping a new diabetes (6% vs 7.4%: p = 0.02). In CHARM-Alternative, there were 1013 patients on candesartan and 1015 on placebo and the mean follow-up was 33.7 months. The combined incidence of cardiovascular death and CHF hospitalization was reduced by 23% (p = 0.0004). In CHARM-Added, 1276 patients received candesartan and 1272, placebo; mean follow-up was 41 months. The benefit induced by candesartan on the primary endpoint was 15% (p = 0.011). In those two studies the two components of the primary endpoint were significantly reduced. Candesartan was beneficial in all prespecified subgroups, including patients concomitantly treated by beta-blockers. In CHARM-Preserved (candesartan, n = 1514; placebo, n = 1509; mean follow-up: 36.6 months), neither the composite endpoint, nor cardiovascular death were reduced, but the number of admissions for heart failure was reduced. The clinical implications of these important results are discussed.