ACE Inhibitor Intolerance and Lessons Learned From the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Trials

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials looked at the effects of candesartan in addition to best possible treatment for heart failure in 7601 patients. CHARM encompassed three studies in discrete populations, including patients with left ventricular dysfunction taking angiotensin-converting enzyme (ACE) inhibitors (CHARM-Added), patients with maintained left ventricular function (CHARM-Preserved), and patients with left ventricular dysfunction and an intolerance to ACE inhibitors (CHARM-Alternative). CHARM-Alternative was considered a success in that its participants experienced a significant reduction in each component of the study's primary end point, which was a composite of cardiovascular death or hospitalization for heart failure, over a median follow-up of 34 months. Candesartan was by and large well tolerated in these ACE-inhibitor intolerant patients; thus, the findings of this study provide additional support for the effectiveness of angiotensin receptor blocker therapy in heart failure patients poorly tolerant of an ACE inhibitor; however, candesartan was not convincingly shown to improve the incidence/severity of hypotension, hyperkalemia, and glomerular filtration rate reductions that were the basis for ACE inhibitor intolerance in approximately 25% of the study population.