1. The Importance of Beta-Blockers in Patients with Heart Failure: A Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) Analysis. L. Brent Mitchell, Jean L. Rouleau, Gary E. Newton, Jonathon Howlett, Elizabeth Yetisir, George A. Wells, Anthony S.L. Tang

2. DECLARATION - 1 Beta-Blockers ACE-I / ARB Aldo Block CRT Declaration of Potential Conflict of Interest I have nothing to declare

3. BACKGROUND - 1 Beta-Blockers ACE-I / ARB Aldo Block ICD CRT CHF - Proven Effective Therapies on All-Cause Mortality

4. multicenter, randomized, two parallel-group, clinical trial 1798 patients with NYHA II/III congestive heart failure receiving optimal medical therapy with LVEF ≤ 0.30 and QRSd ≥ 120ms (≥ 200ms if V-paced) and with an independent indication for an ICD were randomized 1:1 to receive an ICD or a CRT-ICD Resynchronization-defibrillation for Ambulatory heart Failure Trial (RAFT) BACKGROUND - 2

5. RAFT Results: Death or CHF Hospitalization BACKGROUND - 3 0 10 20 40 50 30 Cumulative Incidence 123460 Years of Follow-up 5 60 ICD CRT-ICD HR = 0.75 95% CI: 0.64 – 0.87 p < 0.001 Tang AS et al. N Engl J Med 363:2385-95, 2010

6. BACKGROUND - 4 CHF - Proven Effective Therapies on All-Cause Mortality Beta-Blockers ACE-I / ARB Aldo Block ICD CRT

7. PURPOSE To assess the contemporary importance, independence, and dose-dependence of beta-blocker therapy in the congestive heart failure patients studied in RAFT.

8. METHODS PATIENT POPULATION: RAFT patients that were treated with one of bisoprolol, carvedilol, or metoprolol. BETA-BLOCKER TARGET DOSAGES: were as defined by ESC guidelines 1 - bisoprolol 10 mg/d, carvedilol 50 mg/d, metoprolol 200 mg/d. PRIMARY OUTCOME: death or CHF hospitalization. STATISTICS: Times to outcome displayed as KM curves. Sixteen variables were included in stepwise proportional hazards analyses. 1. McMurray JJV et al. Eur Heart J 33:1787-847, 2012

9. RESULTS - 1 The RAFT Patient Population: N = 1798, mean age 66 yrs, 83% male, 67% ischemic 80% NYHA Class II, mean LVEF 0.23 90% beta-blocker use, 97% ACE-I / ARB use 42% spironolactone use This Substudy Patient Population (82%): N = 1474, mean age 66 yrs, 83% male, 66% ischemic 82% NYHA Class II, mean LVEF 0.23 100% beta-blocker use, 97% ACE-I / ARB use 42% spironolactone use

10. RESULTS - 2 Beta-Blocker Use Distributions < 50% target ≥ 50% target number 489 356 629 (39%) (34%) (67%) p < 0.001

11. Population Differences by Beta-Blocker Dosage RESULTS - 3 VARIABLEBB < 50% TargetBB ≥ 50% TargetP-value Age (years ± SD)67.5 ± 9.064.6 ± 9.6<0.0001 Ischemic HD n(%)541 (73.2%)436 (59.3%)<0.0001 NYHA Class II n(%)568 (76.9%)621 (84.5%)0.0002 Weight (kg ± SD)79.6 ± 16.585.3 ± 18.1<0.0001 BMI (± SD)27.1 ± 5.128.6 ± 5.4<0.0001 Prior CABG n(%)288 (39.0%)214 (29.1%)<0.0001 PVD n(%)88 (11.9%)61 (8.3%)0.0216 CHF Hosp < 6mo n(%)211 (28.6%)166 (22.6%)0.0087 Beta-blocker use at baseline n(%)643 (87.0%)709 (96.3%)<0.0001 ASA use n(%)517 (70.0%)477 (64.9%)0.0381 Warfarin use n(%)231 (31.3%)266 (36.2%)0.0452 Clopidogrel use n(%)130 (17.6 %)96 (13.1%)0.0158 Amiodarone use n(%)114 (15.4%)78 (10.6%)0.0060 eGFR (ml/min/1.73m 2 ± SD)58.7 ± 21.961.8 ± 19.10.0039 6 MWT distance (m ± SD)346 ± 111367 ± 1070.0010

12. Death / CHF Hospitalization by Beta-Blocker Dosage RESULTS - 4 0 10 20 40 50 30 Cumulative Incidence 123460 Years of Follow-up 5 60 < 50% ≥ 50% HR = 1.50 95% CI = 1.24 – 1.81 p < 0.001

13. Independent Predictors of Primary Outcome RESULTS - 5 PARAMETERHR (95% CI)P-value previous CABG1.63 (1.32-2.02)<0.0001 beta-blocker < 50% target1.50 (1.24-1.81)<0.0001 ICD without CRT1.50 (1.25-1.80)<0.0001 ischemic heart disease1.39 (1.07-1.80)0.01 peripheral vascular disease1.36 (1.04-1.76)0.02 lower estimated GFR (per 5 units)1.10 (1.01-1.16)0.0002

14. 0 20 40 123460 5 60 0 20 40 123460 5 60 0 20 40 123460 5 60 RESULTS - 6 Death / CHF Hospitalization by Beta-Blocker Dosage Years of Follow-up < 50% ≥ 50% Incidence 0 20 40 123460 5 60 Incidence by beta-blocker dosage (N=1474) Years of Follow-up < 50% ≥ 50% by carvedilol dosage (N=629) by bisoprolol dosage (N=489) by metoprolol dosage (N=356) p < 0.0001 p = 0.006

15. 0 20 40 123460 5 60 0 20 40 123460 5 60 RESULTS - 7 Cumulative Incidence Years of Follow-up Death / CHF Hospitalization by RAFT Randomisation Randomised to CRT-ICD (N=740) Years of Follow-up p < 0.001 p = 0.07 Randomised to ICD (N=734) < 50% ≥ 50% < 50% ≥ 50%

16. independent predictors of death / CHF hospitalization were: beta-blockers use at < 50% (not ≥ 50%) of target dosage use of an ICD (not a CRT-ICD) ischemic heart disease and previous CABG peripheral vascular disease or impaired renal function with lower dosage these outcome were 50% more likely there were no efficacy differences among the beta-blockers carvedilol is more often used at ≥ 50% of target dosages the superiority of higher beta-blocker dosages are less evident in CRT-ICD patients than in ICD patients INFERENCES In this subgroup analysis of CHF patients studied in RAFT:

17. The Importance of Beta-Blockers in Patients with Heart Failure: A Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) Analysis. L. Brent Mitchell, Jean L. Rouleau, Gary E. Newton, Jonathon Howlett, Elizabeth Yetisir, George A. Wells, Anthony S.L. Tang