This article represents the overall summary of an international program of research, which was simultaneously presented at the Hot Topics session of the European Congress of Cardiology and concurrently published in four manuscripts in the Lancet. "Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)" was one of the largest and most inclusive randomized controlled trials evaluating a pharmacologic approach for patients with heart failure. Despite the major pharmacologic advances (angiotensin converting enzyme inhibitors, beta-adrenergic receptor blockers) in the management of patients with symptomatic heart failure, the incidence and health-care burden of heart failure continues to expand with the increasing proportion of elderly in developed nations.

CHARM was designed to ascertain whether the angiotensin receptor blocker candesartan could reduce the incidence of cardiovascular death or need for hospitalization for management of heart failure of the broadest range of patients identified as having symptomatic heart failure in spite of optimal medical management. Across the Program, patients were enrolled into one of three components trials based on either having reduced left ventricular ejection fraction (less than or equal to 40%) not being treated with an ACE inhibitor due to prior intolerance (CHARM Alternative), on an ACE inhibitor (CHARM Added), or perhaps the most unique group for clinical trials, those with a left ventricular ejection fraction greater than 40% regardless of ACE inhibitor use (CHARM Preserved). Each of these trials had its own hypotheses, sample size and objectives. The collective experience (CHARM Program) was prespecified to be analyzed for mortality, cardiovascular and non-cardiovascular causes of death, as well as provide the best tool for assessing subgroups and safety.

In patients with reduced left ventricular ejection fraction, randomization to candesartan reduced the risk of cardiovascular death or hospitalization for heart failure in both CHARM Alternative (risk reduction 23%) and CHARM Added (risk reduction 15%). All-cause mortality in the combined group of patients with low ejection fraction was also demonstrated. These benefits were independent and indeed additive to the use of both ACE inhibitor and beta-blockers, representing a new advance in the management of patients with symptomatic heart failure with reduced ejection fraction. Although significant benefits in this primary outcome were not achieved in CHARM Preserved, fewer patients on candesartan were hospitalized for heart failure. Overall, the risk of cardiovascular death, the composite outcome of CV death, and hospitalization for heart failure and new onset diabetes were reduced in the CHARM Program. Candesartan therapy was associated with higher rates of renal impairment and hyperkalemia, meaning additional laboratory monitoring will be required when candesartan is used to produce the clinical benefits.