Interim Chair, Medicine Brigham and Women’s Hospital Boston, MA Core Efficacy (CE) CHARM Program Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Efficacy Marc A. Pfeffer, MD, PhD Interim Chair, Medicine Brigham and Women’s Hospital Boston, MA DRAFT

Patients With Symptomatic CHF CHARM Program Core Efficacy (CE) Patients With Symptomatic CHF CHARM Program 3 component trials comparing candesartan to placebo Pooled CSR S 5.1 P 58, S 5.4.5 P 69-70, S 8.2 P 160 CHARM Alternative CHARM Added CHARM Preserved n = 2028 LVEF ≤ 40% ACE inhibitor intolerant n = 2548 LVEF ≤ 40% ACE inhibitor treated n = 3023 LVEF > 40% ACE inhibitor treated/not treated Primary endpoint for each trial: CV death or CHF hospitalization DRAFT

CHARM Program Recruitment Core Efficacy (CE) CHARM Program Recruitment Study close 8000 Total = 7599 6000 4000 Patients, n Preserved 3023 First patient 3/22/99 Added 2548 2000 Alternative 2028 Jan June Dec June Dec Mar Mar 1999 2000 2001 2003 DRAFT

Primary and Secondary Endpoints for Each CHARM Trial† Core Efficacy (CE) Primary and Secondary Endpoints for Each CHARM Trial† CSR SH-AHS-pooled P 3 Primary endpoint CV mortality or CHF hospitalization‡ Secondary endpoints All-cause mortality or CHF hospitalization CV mortality or CHF hospitalization or nonfatal MI † Protocol specified endpoints for the confirmatory analysis. ‡ Hospitalization for CHF defined as hospital admission primarily for worsening of CHF requiring IV diuretic and overnight stay, CEC adjudicated. DRAFT

Dose-Titration and Visit Schedule CHARM Added Core Efficacy (CE) CSR SH-AHS-pooled F 1 Dose-Titration and Visit Schedule CHARM Added Candesartan or matching placebo once daily 32 mg 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg Every 4 mo for minimum 24 mo (maximum 48 mo) Study close 31 March 2003 Time 0 w 2 w 4 w 6 w 6 m Visit 1 2 3 4 5 Mean dose 24 mg candesartan and 27 mg placebo qd. Target dose at 6 months - 61% on candesartan and 73% on placebo. DRAFT

Statistical Analysis Plan CHARM Program Core Efficacy (CE) Statistical Analysis Plan CHARM Program CSR SH-AHS-pooled P 5 Intent-to-treat (ITT) population Time to first event for 1° and 2° endpoints Log rank test for comparisons Cox proportional hazards models for effect size estimates Kaplan Meier estimates of distribution function Confirmatory strategy, primary and secondary analyses using a hierarchical closed test procedure Each individual trial Pooled analyses DRAFT

Patient Inclusion and Exclusion Criteria CHARM Program Core Efficacy (CE) CSR SH-AHS-pooled P 61, 63 Patient Inclusion and Exclusion Criteria CHARM Program Inclusion criteria Age ≥ 18 years Symptomatic HF for at least 4 weeks (NYHA class II - IV) CHARM Added: if NYHA class II, history of cardiac hospitalization in previous 6 months CHARM Preserved: history of cardiac hospitalization Key exclusion criteria Serum creatinine ≥ 3 mg/dL (≥ 265 µmol/L) Serum potassium ≥ 5.5 mmol/L Bilateral renal artery stenosis Symptomatic hypotension ARB within 2 weeks . DRAFT

Baseline Characteristics CHARM Added Core Efficacy (CE) 1 Baseline Characteristics CHARM Added Placebo n = 1272 Candesartan n = 1276 Mean age ± SD, yr 64.1 ± 11.3 64.0 ± 10.7 ≥ 75 yr, n (%) 245 (19.3) 212 (16.6) Female 272 (21.4) 270 (21.2) NYHA class, n (%) II 302 (23.7) 312 (24.5) III 925 (72.7) 931 (73.0) IV 45 (3.5) 33 (2.6) Mean heart rate ± SD, bpm 73.7 ± 12.9 73.4 ± 13.3 Mean blood pressure ± SD, mm Hg Systolic 125.6 ± 18.6 124.7 ± 18.6 Diastolic 75.2 ± 10.7 75.0 ± 10.8 Diabetes mellitus 382 (30.0) 376 (29.5) Hypertension 619 (48.7) 609 (47.7) Atrial fibrillation 341 (26.8) 346 (27.1) Myocardial infarction 703 (55.3) 714 (56.0) DRAFT

Baseline Medical Treatment CHARM Added Core Efficacy (CE) 1 SH-AHS-0006 T20 Baseline Medical Treatment CHARM Added Patients, n (%) Medical treatment Placebo n = 1272 Candesartan n = 1276 β-blocker 711 (55.9) 702 (55.0) Spironolactone 215 (16.9) 222 (17.4) Digoxin/digitalis glycoside 753 (59.2) 735 (57.6) Diuretic 1146 (90.1) 1148 (90.0) Aspirin 659 (51.8) 652 (51.1) Lipid-lowering drug 521 (41.0) 528 (41.4) DRAFT

Primary Endpoint CV Death or CHF Hospitalization CHARM Added Core Efficacy (CE) CSR SH-AHS-0006 F 4 Primary Endpoint CV Death or CHF Hospitalization CHARM Added Placebo (42.3%) 50 45 40 Candesartan (37.9%) 35 30 % 25 20 15 Relative risk reduction = 15% HR = 0.85 (95% CI: 0.75, 0.96) p = 0.011 10 5 6 12 18 24 30 36 42 48 Time, mo At risk, n Placebo 1272 1017 852 735 338 Candesartan 1276 1074 914 793 395 Median follow-up 41.0 mo. DRAFT

Primary Endpoint and Components CHARM Added 49 Core Efficacy (CE) CSR SH-AHS-0006 T 24, 30 Primary Endpoint and Components CHARM Added Patients, n Placebo N = 1272 Candesartan N = 1276 Hazard ratio (95% CI) p value (log-rank) Primary endpoint CV death or CHF hospitalization 538 483 0.85 (0.75, 0.96) 0.011 Components CV death 347 302 0.84 (0.72, 0.98) 0.029 CHF hospitalization 356 309 0.83 (0.71, 0.96) 0.013 Candesartan better Placebo better 0.5 1 1.5 Hazard ratio (95% CI) DRAFT

CV and Non-CV Death CHARM Added Core Efficacy (CE) CV and Non-CV Death CHARM Added 30 CV Death Relative risk reduction = 16% HR = 0.84 (95% CI: 0.72, 0.98) p = 0.029 Placebo Candesartan 25 20 % 15 Non-CV Death HR = 1.11 (95% CI: 0.80, 1.55) 10 Candesartan 5 Placebo 6 12 18 24 30 36 42 48 Time, mo At risk, n Placebo 1272 1136 1013 906 422 Candesartan 1276 1176 1063 948 458 Median follow-up 41.0 mo. DRAFT

CHF Hospitalization CHARM Added Core Efficacy (CE) CSR SH-AHS-0006 F 18 CHF Hospitalization CHARM Added 35 Placebo 30 Candesartan 25 20 % 15 10 Risk reduction = 17% HR = 0.83 (95% CI: 0.71, 0.96) p = 0.013 5 6 12 18 24 30 36 42 48 Time, mo At risk, n Placebo 1272 1017 852 735 338 Candesartan 1276 1074 914 793 395 Median follow-up 41.0 months. DRAFT

Secondary Endpoints and Components CHARM Added (n = 2548) Core Efficacy (CE) 49 CSR SH-AHS-0006 T S2, 27, 25, 26, 28, 12.1.9.4.43 Secondary Endpoints and Components CHARM Added (n = 2548) Patients, n Placebo n = 1272 Candesartann = 1276 HR (95% CI) p value All-cause mortality or CHF hospitalization 587 539 0.87 (0.78, 0.98) 0.021 All-cause mortality 412 377 0.86 (0.77, 1.02) 0.086 CHF hospitalization 356 309 0.83 (0.71, 0.96) 0.013 CV mortality or CHF hospitalization or nonfatal MI 550 495 0.85 (0.76, 0.96) 0.010 Candesartan better Placebo better 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 Hazard ratio (95% CI) DRAFT

CV Mortality or CHF Hospitalization Subgroup Analysis CHARM Added 20 Core Efficacy (CE) CV Mortality or CHF Hospitalization Subgroup Analysis CHARM Added DV CSR SH-AHS-0006 T 101, 102 Patients, n/N Placebo Candesartan Age < 65 211/636 192/632 ≥ 65 < 75 193/391 176/432 ≥ 75 134/245 115/212 Gender Male 427/1000 387/1006 Female 111/272 96/270 NYHA II 104/302 93/312 III / IV 434/970 390/964 LVEF < 25 203/382 186/388 ≥ 25 335/890 297/888 Medical history Diabetes No 334/890 291/900 Yes 204/382 192/376 Hypertension 261/653 248/667 277/619 235/609 Previous MI 224/569 188/562 314/703 295/714 Atrial fibrillation 375/931 335/929 163/341 148/346 Diuretic 27/126 26/128 511/1146 457/1148 Digitalis 185/519 172/541 353/753 311/735 Aspirin 264/613 240/624 274/659 243/652 Lipid lowering 336/751 294/748 202/521 189/528 US 410/970 355/981 128/302 128/295 All patients (N = 2548) 538/1272 483/1276 Candesartan better Placebo better All interaction p values not significant 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 Hazard ratio (95% CI) DRAFT

Outcomes by Beta-Blocker Therapy CHARM Added 52 Core Efficacy (CE) Outcomes by Beta-Blocker Therapy CHARM Added Briefing Document F7. Placebo Candesartan p value for interaction CV death or CHF hospitalization ACEi + β-B No 264/563 260/574 0.13 Yes 274/709 223/702 All patients 538/1272 483/1276 All-cause mortality 218/563 202/574 0.989 194/709 175/702 412/1272 377/1276 Candesartan better Placebo better 1.0 1.2 Hazard ratio (95% CI) 0.6 0.8 DRAFT

Outcomes by Spironolactone Use CHARM Added Core Efficacy (CE) Outcomes by Spironolactone Use CHARM Added Table 102, App 12.1.9.4.73,74,77,78 Group N Events placebo candesartan CV mortality or CHF hospitalization ACEi + spironolactone No: 2112 441/1058 378/1054 Yes: 436 97/214 105/222 ACEi + β-B + spironolactone No: 2311 487/1144 444/1167 Yes: 237 51/128 39/109 All patients 2548 538/1272 483/1276 All-cause mortality 324/1058 304/1054 88/214 73/222 368/1144 350/1167 44/128 27/109 412/1272 377/1276 Candesartan better Placebo better 0.5 1 1.5 Hazard ratio (95% CI) DRAFT

Core Efficacy (CE) Summary CHARM Added In patients with symptomatic CHF and left ventricular systolic dysfunction on an ACE inhibitor, the addition of candesartan to standard therapy, including a beta-blocker, provides incremental benefit by: Reducing CV mortality or CHF hospitalization Reducing all-cause mortality or CHF hospitalization DRAFT

CHARM Added and Val-HeFT Morbidity/Mortality Core Efficacy (CE) CHARM Added and Val-HeFT Morbidity/Mortality Placebo Candesartan Placebo Valsartan RRR = 15.0% 13.2% p = 0.011 0.009 DRAFT

Use of ACE Inhibitors CHARM Added Core Efficacy (CE) Use of ACE Inhibitors CHARM Added Stable dose of ACEi for ≥ 30 days Investigators were provided list of recommended doses of ACEi based on target doses in positive trials Individualized optimum doses of ACEi at baseline 96% of patients were determined to be on an individualized optimum dose of ACEi at baseline DRAFT

FDA-Approved ACE Inhibitors For Heart Failure Core Efficacy (CE) FDA-Approved ACE Inhibitors For Heart Failure ACE inhibitor CHARM Added Proportion of patients at baseline, % FDA labeled HF dose Baseline mean dose mg/d Enalapril 27 5 - 20 (40) 17 Lisinopril 19 5 - 40 (40) 18 Captopril 150 - 300 (450) 83 Ramipril 11 10 7 Trandolapril 6 4 2 Perindopril NA† Quinapril 5 20 - 40 25 Fosinopril 20 Benazepril 3 26 Cilazapril, Moexipril 1 – † NA = Not FDA approved for heart failure. DRAFT

Outcomes in CHARM Added According to ACE Inhibitor Used at Baseline Core Efficacy (CE) Outcomes in CHARM Added According to ACE Inhibitor Used at Baseline Candesartan better Placebo better N p value for interaction FDA approved No 258 Yes 2290 0.929 All patients 2548 0.4 0.6 0.8 1.0 1.2 1.4 Hazard ratio (95% CI) DRAFT

Recommended and Actual Doses of ACEi Core Efficacy (CE) Recommended and Actual Doses of ACEi ACE inhibitor CHARM Added Proportion of patients at baseline, % Recommended† HF Baseline mean Dose, mg/d Enalapril 27 20 17 Lisinopril 19 18 Captopril 150 83 Ramipril 11 10 7 Trandolapril 6 2 Perindopril 4 Quinapril 5 25 Fosinopril Benazepril 3 26 Other 1 – † Adapted from ESC Guidelines. DRAFT

Dosing and Visit Schedule CHARM Added Core Efficacy (CE) CSR SH-AHS-pooled F 1 Dosing and Visit Schedule CHARM Added Candesartan/ placebo 32 mg 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg Time 0 w 2 w 4 w 6 w 6 m 14 m 26 m 38 m Visit 1 2 3 4 5 7 10 13 ACEi mean daily dose, mg Enalapril 17 17 17 17 17 16 17 17 Lisinopril 18 18 18 17 18 17 18 18 Captopril 83 82 82 81 80 79 78 78 Ramipril 7 7 7 7 7 7 8 7 Trandolapril 2.5 2.4 2.5 2.4 2.5 2.5 2.5 2.5 DRAFT

Prespecified Subgroup CV Death or CHF Hospitalization CHARM Added 37 Core Efficacy (CE) DV CSR SH-AHS-0006 T 101, 102 Prespecified Subgroup CV Death or CHF Hospitalization CHARM Added Candesartan better Placebo better Patients, n/N Placebo Candesartan Recommended dose of ACEi No 263/624 251/633 Yes 275/648 232/643 All patients 538/1272 483/1276 p value for interaction 0.26 0.6 0.7 0.8 0.9 1 1.1 1.2 Hazard ratio (95% CI) DRAFT

≥ Recommended (CHARM) n = 1291 Core Efficacy (CE) Proportion of Patients on Recommended Dose or FDA Defined Maximum Dose of ACEi at Baseline CHARM Added ACE inhibitor ≥ Recommended (CHARM) n = 1291 ≥ Maximum (FDA)† n = 721 Dose, mg/d Patients, % Enalapril 20 52 Lisinopril 40 15 Captopril 150 21 Ramipril 10 39 Trandolapril 2 90 4 27 Perindopril 83 16 1 Quinapril 60 80 7 Fosinopril 59 Benazepril 62 5 Other – All 50.7 28.3 † FDA communication 12-17-04. DRAFT

p value for interaction Core Efficacy (CE) 36 Follow-up to Dec 17 discussion with FDA T 3 CV Death or CHF Hospitalization— Recommended or Maximum ACEi Doses at Baseline CHARM Added CSR SH-AHS-0006 T 102 Candesartan better Placebo better Patients, n Recommended dose of ACEi No 1257 (CHARM) Yes 1291 Maximum dose of ACEi 1827 (FDA)† 721 All patients 2548 p value for interaction 0.26 0.78 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 Hazard ratio (95% CI) † FDA communication 12-17-04. DRAFT

≥ Recommended (CHARM) n = 1291 ≥ Maximum (FDA)‡ revised n = 529 Core Efficacy (CE) Proportion of Patients on Recommended Dose or FDA Defined Maximum Dose of ACEi at Baseline CHARM Added ACE inhibitor % on Rx ≥ Recommended (CHARM) n = 1291 ≥ Maximum (FDA)† n = 721 ≥ Maximum (FDA)‡ revised n = 529 Dose, mg/d Patients, % Enalapril 27 20 52 40 10 Lisinopril 19 15 Captopril 17 150 21 300 2 Ramipril 11 39 Trandolapril 6 90 4 Perindopril 83 16 1 Quinapril 5 60 80 7 Fosinopril 59 Benazepril 3 62 Other All 100 50.7 28.3 20.8 † FDA communication 12-17-04. ‡ FDA communication 01-24-05. DRAFT

p value for interaction 36 Core Efficacy (CE) Follow-up to Dec 17 discussion with FDA T 3 CV Death or CHF Hospitalization—Recommended or Maximum ACEi Doses at Baseline CHARM Added CSR SH-AHS-0006 T 102 Candesartan better Placebo better Patients, n Recommended dose of ACEi No 1257 (CHARM) Yes 1291 Maximum dose of ACEi 1827 (FDA)† 721 2019 (FDA)‡ revised 529 All patients 2548 p value for interaction 0.26 0.78 0.29 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 † FDA communication 12-17-04. ‡ FDA communication 01-24-05. Hazard ratio (95% CI) DRAFT

CV Death or CHF Hospitalization—Maximum Range of ACEi Doses 36 Core Efficacy (CE) Follow-up to Dec 17 discussion with FDA T 3 CV Death or CHF Hospitalization—Maximum Range of ACEi Doses CSR SH-AHS-0006 T 102 Candesartan better Placebo better p value for interaction Patients, n Recommended dose of ACEi No 1257 (CHARM) Yes 1291 Maximum dose of ACEi 1827 (FDA)† 721 2019 (FDA)‡ revised 529 CHARM Added 2548 CHARM Alternative 2028 2 Pooled Low LVEF 4576 0.26 0.78 0.29 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 † FDA communication 12-17-04. ‡ FDA communication 01-24-05. Hazard ratio (95% CI) DRAFT

Core Efficacy (CE) Summary CHARM Added In patients with symptomatic CHF and left ventricular systolic dysfunction, the addition of candesartan to an ACE inhibitor provides incremental benefit. There was no evidence of modification of the beneficial effect of candesartan on CV death or CHF hospitalization based on ACE inhibitor dose or choice of ACE inhibitor DRAFT