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 - 1
Beta-Blockers
ACE-I / ARB
Aldo Block
CRT
Declaration of Potential Conflict of Interest
• I have nothing to declare
BACKGROUND - 1
Beta-Blockers
ACE-I / ARB
Aldo Block
ICD
CRT
CHF - Proven Effective Therapies on All-Cause Mortality
• 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
RAFT Results: Death or CHF Hospitalization
BACKGROUND - 3
0
10
20
40
50
30
Cu
mu
lati
ve In
cid
ence
1 2 3 4 60
Years of Follow-up
5
60ICD
CRT-ICD
HR = 0.7595% CI: 0.64 – 0.87p < 0.001
Tang AS et al. N Engl J Med 363:2385-95, 2010
BACKGROUND - 4
CHF - Proven Effective Therapies on All-Cause Mortality
Beta-Blockers
ACE-I / ARB
Aldo Block
ICD
CRT
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 treatedwith one of bisoprolol, carvedilol, or metoprolol.
BETA-BLOCKER TARGET DOSAGES: were as defined byESC guidelines1 - 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 proportionalhazards 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
≥ 50% target
bisoprolol carvedilol metoprolol0
100
200
300
400
500
600
700
nu
mb
er
489
356
629
(39%) (34%)(67%)
p < 0.001
Population Differences by Beta-Blocker Dosage
RESULTS - 3
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/1.73m2 ± SD) 58.7 ± 21.9 61.8 ± 19.1 0.0039
6 MWT distance (m ± SD) 346 ± 111 367 ± 107 0.0010
Death / CHF Hospitalization by Beta-Blocker Dosage
RESULTS - 4
0
10
20
40
50
30
Cu
mu
lati
ve In
cid
ence
1 2 3 4 60
Years of Follow-up
5
60< 50%
≥ 50%
HR = 1.5095% CI = 1.24 – 1.81p < 0.001
Independent Predictors of Primary Outcome
RESULTS - 5
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
0
20
40
1 2 3 4 60 5
60
0
20
40
1 2 3 4 60 5
60
0
20
40
1 2 3 4 60 5
60
RESULTS - 6
Death / CHF Hospitalization by Beta-Blocker Dosage
Years of Follow-up
< 50%
≥ 50%Inc
ide
nc
e
0
20
40
1 2 3 4 60 5
60
Inc
ide
nc
e
by beta-blocker dosage (N=1474)
Years of Follow-up
< 50%
< 50%
< 50%
≥ 50%
≥ 50%
≥ 50%
by carvedilol dosage (N=629)
by bisoprolol dosage (N=489)
by metoprolol dosage (N=356)
p < 0.0001 p < 0.0001
p < 0.0001 p = 0.006
0
20
40
1 2 3 4 60 5
60
0
20
40
1 2 3 4 60 5
60
RESULTS - 7C
um
ula
tive
Inci
den
ce
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%
• 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:
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