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We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40-49%].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%.Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712.

Endothelial function is impaired in patients with coronary artery disease (CAD); in these patients plasma levels of C-reactive protein (CRP) and impaired endothelial function are related to future cardiac events. The aim of the present study was to evaluate the effects of medical therapy on endothelial function and CRP in patients with CAD.Seventy-three patients (52 men, 21 women, mean age 66 +/- 9 years) with CAD and 32 control subjects (25 men, 7 women, mean age 65 +/- 11 years) were enrolled in the study. The endothelial function was evaluated by means of flow-mediated dilation (FMD) of the brachial artery following ischemia and CRP by means of a high-sensitivity assay. After baseline evaluation of CRP and FMD all patients received full medical therapy for 3 months and were then again tested for endothelial function and CRP.Compared to healthy controls, patients had significantly more impaired endothelial function (FMD 3.6 +/- 3.2 vs 8 +/- 2.4%, p0.01) and higher CRP plasma levels (1.6 +/- 0.9 vs 0.9 +/- 0.56 mg/dl, p0.05). At baseline a significant negative correlation was found between CRP plasma levels and FMD in patients with CAD (r = -0.56, p0.05) while no correlation was found in controls. Medical therapy resulted in a significant improvement in endothelial function (3.64 +/- 3 vs 7.2 +/- 3.5%, p0.01), and a decrease of CRP (-0.26 +/- 0.19, p0.01); the changes in CRP and FMD were independent of the drug used. A positive correlation was found between the improvement in FMD and the degree of CRP reduction (r = 0.57, p0.01).In patients with CAD plasma levels of CRP are associated with an impaired endothelial function suggesting a correlation between inflammation and the integrity of the endothelium. Full medical therapy reduces CRP with a parallel improvement in endothelial function.