Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum

Aims
We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid‐range ejection fraction [HFmrEF; ejection fraction (EF) 40–49%].
Methods and results
In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow‐up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient‐years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient‐years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75–0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient‐years in HFmrEF (HR 0.76, 95% CI 0.61–0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient‐years in HFpEF (HR 0.95, 95% CI 0.79–1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58–0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33–0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59–1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%.
Conclusion
Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF.
ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712