1. Relationship of background ACEI dose to benefits of candesartan in the CHARM-Added trial

2. CHARM-Added: Study design McMurray JJV et al. Lancet. 2003;362:761-71. Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added Randomized, double-blind NYHA class II–IV, LVEF ≤40%, stable ACEI dose for ≥30 days N = 2548 Candesartan 32 mg qd n = 1276 Placebo n = 1272 Median follow-up: 41 months Primary outcome: CV death or hospitalization for HF ACEI = angiotensin-converting enzyme inhibitor

3. CHARM-Added: Baseline characteristics by ACEI dose <FDA maximum dose (n = 2019) ≥FDA maximum dose (n = 529) Male (%) Mean BP (mm Hg) NYHA class (%) II III IV Medical history (%) HF hospitalization MI Angina Hypertension Diabetes 78 125/75 25 72 3.2 77 57 53 46 29 81 126/75 22 76 2.5 76 50 52 56 34 McMurray JJV et al. Am Heart J. 2006;151:985-91.

4. CHARM-Added: Daily ACEI dose McMurray JJV et al. Am Heart J. 2006;151:985-91. *Based on European Society of Cardiology guidelines † Not indicated for heart failure ACEI (86% of patients) Mean dose (mg/day) % on Rx Mean dose (mg/day) Patients (%) Mean dose (mg/day) Patients (%) Enalapril172720524010 Lisinopril181920522052 Captopril8317150213002 Ramipril71110391039 Trandolapril2.56290427 Perindopril † 46483161 Subgroup analysis, most commonly used ACEIs ≥Recommended (CHARM prespecified)* (n = 1291) ≥Maximum (FDA) (n = 529) All patients (N = 2548)

5. CHARM-Added: Primary outcome of CV death or HF hospitalization N = 2548 McMurray JJV et al. Am Heart J. 2006;151:985-91. Recommended dose of ACEI CHARM prespecified Maximum dose of ACEI FDA 2005 CHARM-Added CHARM-Alternative Pooled results (low LVEF patients) No Yes No Yes 1257 1291 2019 529 2548 2028 4576 0.26 0.29 Patients (n) Candesartan better Placebo better P value for interaction 0.60.811.2 Hazard ratio (95% Cl)

6. CHARM-Added: Primary outcome in patients taking a  -blocker McMurray JJV et al. Am Heart J. 2006;151:985-91. n = 1413 CV death or HF hospitalization Recommended dose of ACEI CHARM prespecified Maximum dose of ACEI FDA 2005 All patients No Yes No Yes 692 721 1100 313 1413 0.69 0.64 Patients (n) Candesartan better Placebo better P value for interaction 0.60.811.2 Hazard ratio (95% Cl)

7. Summary: CHARM-Added Candesartan reduced CV death or HF hospitalization in patients taking no ACEI, a moderate ACEI dose, or a high ACEI dose Benefits of candesartan in HF patients were not modified by either ACEI dose or concomitant therapy with a  -blocker ACEIs and angiotensin receptor blockers (ARBs) have distinct and complementary mechanisms of action Combined use of an ACEI and the ARB, candesartan, improved outcomes in patients with HF vs ACE inhibition alone McMurray JJV et al. Am Heart J. 2006;151:985-91.