CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative Purpose To determine whether the angiotensin.

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CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative Purpose To determine whether the angiotensin II receptor blocker candesartan is beneficial in patients with chronic heart failure (CHF) who are intolerant to angiotensin converting enzyme (ACE) inhibitors Reference Granger CB, McMurray JJV, Yusuf S, et al. for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–6.

CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - TRIAL DESIGN - Design Multicenter, multinational, randomized, double-blind, placebo-controlled Patients 2028 patients aged >18 years with symptomatic CHF (NYHA class II–IV) and left ventricular ejection fraction <40%, who were not receiving ACE inhibitors because of previous intolerance due to cough (72%), hypotension (13%), renal dysfunction (12%), angioedema or anaphylaxis (4%), or other reasons Follow up and primary endpoint Primary endpoint: cardiovascular death or hospital admission for CHF. Median 33.7 months follow up. Treatment Placebo or candesartan titrated to 32 mg once daily

CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - TRIAL DESIGN - Baseline characteristics (%) 66.8 130.3 68 47 49 4 67 20 7 Placebo (n=1015) 66.3 129.9 68 48 4 70 19 6 Candesartan (n=1013) 61 55 23 59 40 74 12 10 4 Placebo (n=1015) 62 55 25 57 43 70 14 13 4 Candesartan (n=1013) Age (years)a History of MI Male Medications Beta-blocker NYHA class: Spironolactone II Aspirin III Lipid-lowering drug IV Reason for Systolic BP (mmHg)a intolerance Heart failure cause Cough Ischemic Hypotension Idiopathic Renal dysfunction Hypertensive Angioedema/anaphylaxis aMean Granger et al. Lancet 2003;362:772–6.

CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - RESULTS - Primary outcome of cardiovascular death or hospital admission for CHF significantly reduced in candesartan group compared with placebo (33.0 vs. 40.0%, hazard ratio 0.77, 95% CI 0.67–0.89, P=0.0004): each component was reduced but cardiovascular death nonsignificantly Secondary outcomes – composites of primary outcome and MI, nonfatal stroke and coronary revascularization – also significantly reduced All-cause mortality not significantly different (26.2 vs. 29.2%, hazard ratio 0.87, 95% CI 0.74–1.03, P=0.11) Permanent discontinuation similar for candesartan and placebo (30 vs. 29%, P=0.53)

CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - RESULTS continued - Cardiovascular death or hospital admission for CHF Proportion 50 with event (%) 40 30 20 Hazard ratio 0.77 (95% CI 0.67–0.89) P = 0.0004 10 Placebo Candesartan 1 2 3 3.5 Years after randomization Granger et al. Lancet 2003;362:772–6.

CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - RESULTS continued - Primary and secondary outcomes Placebo Candesartan (n=1015) (n=1013) Hazard ratio P (95% CI) No. (%) No. (%) Cardiovascular death or 406 (40.0) 334 (33.0) 0.77 (0.67–0.89) 0.0004 hospital admission for CHF Cardiovascular death 0.85 (0.71–1.02) 0.072 219 (21.6) 252 (24.8) Hospital admission for CHF 0.68 (0.57–0.81) < 0.0001 207 (20.4) 286 (28.2) Cardiovascular death, hospital admission for CHF, or MI 0.78 (0.68–0.90) 0.0007 353 (34.8) 420 (41.4) Cardiovascular death, hospital admission for CHF, MI, or stroke 0.80 (0.69–0.91) 0.001 369 (36.4) 432 (42.6) Cardiovascular death, hospital admission for CHF, MI, stroke, or coronary revascularization 0.81 (0.71–0.92) 0.002 396 (39.1) 456 (44.9) Granger et al. Lancet 2003;362:772–6.

CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - SUMMARY - In patients with symptomatic CHF and intolerant to ACE inhibitors, candesartan reduced: Cardiovascular death or hospitalization for CHF Secondary outcomes that combined these with MI, stroke and coronary revascularization procedures Despite prior intolerance to another inhibitor of the renin- angiotensin-aldosterone system, candesartan was well tolerated in this patient group