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