CR-1 Candesartan in HF Benefit/Risk James B. Young, MD Cleveland Clinic Foundation

CR-2 CHARM Program of Clinical Trials Studied a broad patient population Comprehensively characterized the risks associated with the treatment, particularly the combination of ACE inhibitor and candesartan Clearly delineated net benefits for the chronic heart failure (CHF) patient with LV systolic dysfunction treated with candesartan and combination ACE inhibitor/candesartan

CR-3 CHARM Added Addressed the previously unresolved question whether adding the ARB candesartan to ACE inhibitor therapy in CHF patients with LV systolic dysfunction: Provides incremental benefit by reducing the risk of CV death or CHF hospitalization Provides benefit in patients receiving evidence-based doses of ACE inhibitors proven effective in previous HF trials Has a favorable benefit to risk profile

CR-4 Benefit to Risk Profile For Candesartan CHARM Added 15% relative risk reduction (p = 0.011) for the primary endpoint, CV death or CHF hospitalization with a 41-month median follow-up Per 1000 patient-years Absolute risk reduction of 25 patients having a primary endpoint No increased risk for all-cause mortality or all-cause hospitalization Events, per 1000 follow-up yr PlaceboCandesartan Events prevented CV death or CHF hospitalization CV mortality First CHF hospitalization All-cause hospitalization All-cause mortality All-cause mortality or all-cause hospitalization

CR-5 CHF With LV Systolic Dysfunction CHARM Added Candesartan, at a target dose of 32 mg once daily, significantly reduces the risk for CV death or CHF hospitalization Net benefit was demonstrated when candesartan was added to an ACE inhibitor Net benefit was demonstrated independent of ACE inhibitor dose or choice of ACE inhibitor

CR-6 Recommended Monitoring Hypotension, hyperkalemia, and abnormal renal function are expected events in this population Proposed instructions for use are consistent with those provided to the CHARM investigators and with good clinical management of CHF patients Emphasizes attention to volume status, BP, serum creatinine, and serum potassium prior to treatment Recommended monitoring of these measures with initiation of candesartan, with dose titration, and periodically thereafter

CR-7 Conclusions Addition of candesartan to the ACE inhibitor treatment of CHF patients results in a substantial cardiovascular morbidity/mortality benefit The adverse event profile of candesartan in heart failure patients is consistent with the pharmacology of the drug and the health status of the patients A positive benefit-risk profile is further supported by numerical reductions in both all-cause hospitalization and all-cause mortality These findings support the use of candesartan with or without an ACE inhibitor for the routine management of heart failure in patients with LV systolic dysfunction