The Importance of Beta-Blockers in Patients with Heart Failure: A - PowerPoint PPT Presentation

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

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

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

BACKGROUND - 2 Resynchronization-defibrillation for Ambulatory heart Failure Trial (RAFT) • 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

BACKGROUND - 3 RAFT Results: Death or CHF Hospitalization ICD HR = 0.75 60 95% CI: 0.64 – 0.87 50 p < 0.001 Cumulative Incidence 40 CRT-ICD 30 20 10 0 0 1 2 3 4 5 6 Years of Follow-up Tang AS et al. N Engl J Med 363:2385-95, 2010

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

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

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 (dicotomized < 50% versus ≥ 50%). 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

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

RESULTS - 2 Beta-Blocker Use Distributions < 50% target 700 ≥ 50% target 629 600 p < 0.001 500 489 400 number 356 300 200 100 0 bisoprolol carvedilol metoprolol (39%) (67%) (34%)

RESULTS - 3 Population Differences by Beta-Blocker Dosage VARIABLE BB < 50% Target BB ≥ 50% Target P-value Age (years ± SD) 67.5 ± 9.0 64.6 ± 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 ± 16.5 85.3 ± 18.1 <0.0001 BMI (± SD) 27.1 ± 5.1 28.6 ± 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 ± 21.9 61.8 ± 19.1 0.0039 6 MWT distance (m ± SD) 346 ± 111 367 ± 107 0.0010

RESULTS - 4 Death / CHF Hospitalization by Beta-Blocker Dosage HR = 1.50 60 95% CI = 1.24 – 1.81 < 50% p < 0.001 50 Cumulative Incidence 40 30 ≥ 50% 20 10 0 0 1 2 3 4 5 6 Years of Follow-up

RESULTS - 5 Independent Predictors of Primary Outcome PARAMETER HR (95% CI) P-value previous CABG 1.63 (1.32-2.02) <0.0001 beta-blocker < 50% target 1.50 (1.24-1.81) <0.0001 ICD without CRT 1.50 (1.25-1.80) <0.0001 ischemic heart disease 1.39 (1.07-1.80) 0.01 peripheral vascular disease 1.36 (1.04-1.76) 0.02 lower estimated GFR (per 5 units) 1.10 (1.01-1.16) 0.0002

RESULTS - 6 Death / CHF Hospitalization by Beta-Blocker Dosage by bisoprolol dosage (N=489) by beta-blocker dosage (N=1474) 60 60 p < 0.0001 p < 0.0001 Incidence < 50% < 50% 40 40 20 20 ≥ 50% ≥ 50% 0 0 5 0 1 2 3 4 5 6 0 1 2 3 4 6 by carvedilol dosage (N=629) by metoprolol dosage (N=356) p < 0.0001 p = 0.006 60 60 Incidence < 50% < 50% 40 40 20 20 ≥ 50% ≥ 50% 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years of Follow-up Years of Follow-up

RESULTS - 7 Death / CHF Hospitalization by RAFT Randomisation Randomised to CRT-ICD (N=740) Randomised to ICD (N=734) p < 0.001 p = 0.07 60 60 Cumulative Incidence < 50% < 50% 40 40 20 20 ≥ 50% ≥ 50% 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years of Follow-up Years of Follow-up

INFERENCES In this subgroup analysis of CHF patients studied in RAFT: • 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

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