the 56th cardiac resynchronization therapy in mild heart

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Cardiac Resynchronization Therapy in Mild Heart Failure Dong-Gu Shin, MD, PhD Yeungnam Univ Hospital, Daegu, S Korea The 56 th Annual Scientific Meeting of the Korean Society of Cardiology Nov 16-17 2012 DCC

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Page 1: The 56th Cardiac Resynchronization Therapy in Mild Heart

Cardiac Resynchronization

Therapy in Mild Heart

Failure

Dong-Gu Shin, MD, PhD

Yeungnam Univ Hospital, Daegu, S Korea

The 56th Annual Scientific Meeting of the Korean Society of Cardiology

Nov 16-17 2012 DCC

Page 2: The 56th Cardiac Resynchronization Therapy in Mild Heart

Introduction HF remains a significant health concern; a HF event is

associated with a five-fold increase in mortality in 5 years.

Cardiac resynchronization therapy with defibrillation

(CRT-D) has been demonstrated to reduce mortality and

hospitalizations, improve symptoms, and increase

exercise capacity in advanced HF.

CRT for the treatment of patients with the following

conditions:

Moderate to severe heart failure (NYHA Class III/IV) despite optimal pharmacological therapy

Reduced systolic function (LVEF 35%)

Wide QRS (QRS duration ≥ 120 ms)

Page 3: The 56th Cardiac Resynchronization Therapy in Mild Heart

ACC/AHA/HRS 2008 Guidelines for

Device-Based Therapy of Cardiac

Rhythm Abnormalities

Epstein et al. JACC 2008; 51(21):e1–62

Indications for CRT in NYHA I/II not in need of PM or ICD

Page 4: The 56th Cardiac Resynchronization Therapy in Mild Heart

Two major targets for

CRT expansion

Advanced HF patients with narrow QRS

complexes (120ms)

Patients with mild HF (NYHA class I and II)

Page 5: The 56th Cardiac Resynchronization Therapy in Mild Heart

CRTP/D Reimbursement Criteria in Korea1

Persistent HF symptoms despite 3 months’

optimal medical therapy including ACEI/ARB +

Diuretics -Blocker

• NYHA functional class III or ambulatory IV

• QRS duration 120msec

• LVEF ≤ 35%

• Sinus rhythm

1. relevant to Class I indications of 2008 ACC/AHA/HRS Guidelines for

Device-Based Therapy of Cardiac Rhythm Abnormalities

Page 6: The 56th Cardiac Resynchronization Therapy in Mild Heart

CRT Experiences in

Mildly Symptomatic HF

2003 Contak CD

6months, n=263

2004 MICDII

6months, n=186

2008 REVERSE

12 months, n=610

24 months, n=262

2009 MADI T CRT

Avg 29 months

n=1820

2010 RAFT

Avg 40 months

N=1438

•Reverse

remodelling

•Improved

CCR

•Reduced HF

Hospitalizations

•Reverse

remodelling

•Reverse

remodelling

•Reverse

remodelling

•Mortality

benefit

•More improvement,

Less worsening

CCR

•Reduced HF

Hospitalizations

•Reduced HF

Hospitalizations •Mortality

benefit in LBBB

population

Contak CD Higgins et al. JACC 2003, 42:1454-9

MICD II Abraham et al. Circulation 2004110:2864-8

MADIT CRT MossAJ et al. N EnglJ Med 2009 361(14):1329=38

Page 7: The 56th Cardiac Resynchronization Therapy in Mild Heart

REVERSE:

Resynchronization reVErses

Remodeling in Systolic left vEntricular

dysfunction Linde C, et al. J Am Coll Cardiol 2008 52:1834-43

Page 8: The 56th Cardiac Resynchronization Therapy in Mild Heart

• To determine the effects of CRT with or

without an ICD on disease progression over

12 months in patients with asymptomatic and

mildly symptomatic heart failure and

ventricular dysynchrony

• Randomized, double-blind, parallel-controlled

clinical trial

REVERSE: Purpose and Design

Page 9: The 56th Cardiac Resynchronization Therapy in Mild Heart

• NYHA Class II or I (previously symptomatic)

• QRS 120 ms; LVEF 40%; LVEDD 55

mm

• Optimal medical therapy (OMT)

• Without permanent cardiac pacing

• With or without an ICD indication

REVERSE: Inclusion Criteria

Page 10: The 56th Cardiac Resynchronization Therapy in Mild Heart

Baseline Assessment

Successful

CRT Implant

Randomized 1:2

CRT OFF (OMT ± ICD)

CRT ON (OMT ± ICD)

U.S., Canada: at 12 Months, all patients recommended CRT ON

Europe: at 24 Months, all patients recommended CRT ON

1

2

12 Months

REVERSE: Study Schematic

Page 11: The 56th Cardiac Resynchronization Therapy in Mild Heart

• Primary: HF Clinical Composite Response,

comparing the proportion of patients worsened

in CRT OFF vs. CRT ON groups

• Composite includes: all-cause mortality, HF hospitalizations,

crossover due to worsening HF, NYHA class, and the patient

global assessment assessed in double blind manner

• Prospectively Powered Secondary: Left

Ventricular End Systolic Volume Index (LVESVi)

comparing CRT OFF vs. CRT ON subjects • LVESVi is assessed by two core labs (1 in Europe, 1 in U.S)

REVERSE: End Points

Page 12: The 56th Cardiac Resynchronization Therapy in Mild Heart

684 Enrolled (2004-2006)

642 Implant Attempts

610 Patients Randomized

U.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)

CRT OFF 191 Patients CRT ON 419 Patients

- 594/598 completed 12 month follow-up

- 12 deaths (2%) - 0 lost to follow-up, 0 exits

-21 unsuccessful implant

621 Successful CRT Implants

(97%)

-42 ineligible or withdrew

-11 exits after successful implant

REVERSE: Enrollment and Randomization

Page 13: The 56th Cardiac Resynchronization Therapy in Mild Heart

CRT OFF

N=191

CRT ON

N=419 P-value

Age (mean) yrs 61.8 ± 11.6 62.9 ± 10.6 0.26

NYHA II 83% 82% 0.82

ICD 85% 82% 0.41

Beta-blockers 94% 96% 0.32

ACE-i/ ARB 97% 96% 0.63

Diuretics 77% 81% 0.33

EF 26.4 ± 7.0 26.8 ± 7.0 0.50

LVEDD (mm) 70 ± 9 69 ± 9 0.34

QRS (ms) 154.4 ± 24.1 152.8 ± 21.0 0.41

Ischemic 51% 56% 0.22

REVERSE: Baseline Characteristics of Randomized Cohort

(n=610)

Page 14: The 56th Cardiac Resynchronization Therapy in Mild Heart

40% 54%

39%

30%

16% 21%

0%

20%

40%

60%

80%

100%

CRT OFF CRT ON

Improved /

Unchanged

Pre-Specified Analysis Proportion Worsened

Conventional Analysis Distribution Worsened/Unchanged

/Improved

Worsened

Unchanged

Improved

P=0.004

REVERSE: Primary End Point:Clinical Composite Response

79% 84%

16% 21%

0%

20%

40%

60%

80%

100%

CRT OFF CRT ON

P=0.10

Worsened

Page 15: The 56th Cardiac Resynchronization Therapy in Mild Heart

70

75

80

85

90

95

100

105

110

115

Baseline 12 Months

LV

ES

Vi (m

l/m

2 )

CRT OFF

D = -1.3

CRT ON

D = -18.4

P<0.0001

n=487

REVERSE: Powered Secondary End Point: LVESVi (ml/m2)

Page 16: The 56th Cardiac Resynchronization Therapy in Mild Heart

REVERSE: Other Remodeling Parameters

12 Months Baseline

LVEDVi (ml/m2)

P<0.0001

LVEF (%)

P<0.0001

12 Months Baseline

CRT OFF

∆ = 0.6

CRT ON

∆ = 3.8

CRT OFF

∆ = -1.4

CRT ON

∆ = -20.5

n=487

20

22

24

26

28

30

32

34

90

100

110

120

130

140

150

Page 17: The 56th Cardiac Resynchronization Therapy in Mild Heart

360

370

380

390

400

410

420

430

440

Baseline 12 Mo

CRT OFF

D=18.7

CRT ON

D=12.7

15

17

19

21

23

25

27

29

31

33

35

Baseline 12 Mo

CRT OFF

D=-6.7

CRT ON

D=-8.4

MN LWHF

P=0.26 6-Min Walk Test

P=0.26

NYHA

P=0.06

REVERSE: Other Secondary Endpoints

32%

65%

57%

13% 11%

22%

0%

20%

40%

60%

80%

100%

CRT OFF CRT ON

Improved

Same

Worse

Page 18: The 56th Cardiac Resynchronization Therapy in Mild Heart

0%

5%

10%

15%

0 3 6 9 12% o

f P

ati

en

ts H

osp

italized

fo

r H

F

Number at Risk

CRT OFF 191 187 181 176 119

CRT ON 419 415 411 409 251

P=0.03 Hazard Ratio=0.47

CRT OFF

CRT ON

Months Since Randomization

REVERSE: Time to First HF Hospitalization

Page 19: The 56th Cardiac Resynchronization Therapy in Mild Heart

REVERSE is the first large, randomized, double-blind study

to show that CRT in asymptomatic and mildly symptomatic

heart failure patients on optimal medical therapy:

• Reverses LV remodeling

• Reduces the risk of heart failure hospitalization

• May improve clinical outcome as assessed by the

clinical composite response measure

REVERSE: Conclusion

Page 20: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT:

Resynchronization/defibrillation for

Ambulatory heart Failure Trial

Tang A et al. 2010 N Engl J Med 363(25):2385-2395

Page 21: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Purpose

To determine whether the addition of CRT to ICD and optimal medical therapy reduces mortality of HF hospitalization, as compared with an ICD and optimal medical therapy,

NYHA class II or III / systolic dysfunction / wide QRS

Muti-national, randomized, parallel, double-blinded

Page 22: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Study Design

Prospective, randomized, double-blind, multicenter

1798 enrolled and randomized patients

34 international centers 24 Canada, 8 Western Europe, Turkey, 2 Australia

Randomization 1:1 (ICD : CTR-D)

Enrollment

January 2003 through February 2009

Follow-up

40±20 months

Page 23: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Key Inclusion / Exclusion Criteria

Inclusion Criteria NYHA Class II or III (changed to NYHA Class II only

as of February 2006)

QRS ≥ 120 ms or Paced QRS ≥ 200 ms

LVEF ≤ 30%

Optimal medical therapy

ICD indication

With or without persistent atrial tachycardia

Exclusion Criteria NYHA Class I or IV

Existing ICD

Page 24: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Endpoints

Primary Endpoint

HF hospitalization or all-cause mortality

Key Secondary Endpoint

Mortality

Page 25: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Study Schematic

Enrollment

(n=1798)

Randomization 1:1

All patients included

In the primary analysis

ICD (n=904) CRT-D (n=894)

Device Implant

(n=899)

Device Implant

(n=888)

18-month

Minimum follow-up

95%

Successful

LV implants

(n=841)

Mean follow-up 40 months ± 20 months

Page 26: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Baseline characteristics

ICD

n=904

CRT-D

N=894 P-value

Age (yrs) 66.2 ± 9.4 66.1 ± 9.3 0.83

Male 81% 85% 0.03

NYHA II 81% 79% 0.41

LVEF (%) 22.6 ± 5.1 22.6 ± 5.4 0.76

QRS (ms) 158 ± 24 157 ± 24 0.28

LBBB 71% 73% 0.40

Ischemic 65% 69% 0.10

Permanent AF 13% 13% 1.00

Beta blockers 89% 90% 0.39

ACE-i/ARB 97% 96% 0.24

Page 27: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Primary Endpoint:

Significant Reduction in HF

Hospitalization or All-cause Death

Page 28: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Secondary Endpoint:

Significant Reduction in Mortality

Page 29: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Kaplan-Meier Estimates of the Primary Outcome

and Death by NYHA II Patients

Death or Hospitalization for HF Death from any cause

Tang A, et al. N Engl J Med 2010;363:2385-95.

Page 30: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Primary endpoint: Subgroup Analysis

Page 31: The 56th Cardiac Resynchronization Therapy in Mild Heart

RAFT: Conclusions

Among ICD-indicated patients with mildly

symptomatic HF/systolic dysfunction/QRS

prolongation, CRT-D;

Reduces heart failure hospitalization

or all-cause mortality

Reduces mortality alone

Findings support expanded use of CRT-D in

mildly symptomatic heart failure

Page 32: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT:

Multicenter Automatic

Defibrillator ImplanTation with

Cardiac Resynchronization

Therapy Moss AJ. et al. N Engl J Med 2009;361:1329-38.

Page 33: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT: Primary/Secondary

Effectiveness Hypotheses

Primary:

CRT-D would reduce the risk of the combined endpoint of

all-cause mortality or heart failure event, when compared

with ICD in patients with asymptomatic or mildly

symptomatic HF with LVD and wide QRS

Secondary:

Evaluate the effects of CRT-D, relative to ICD, on the

patient-specific rates of recurrent heart failure events over

the full study period

Page 34: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT:Main Inclusion Criteria

Ischemic heart disease (NYHA Class I or II) or

non-ischemic heart disease (NYHA Class II) for

at least three months prior to entry

Optimal pharmacologic therapy

Beta blockers, ACE/ARB, and statins (ischemic

patients) unless not tolerated or contraindicated

Left ventricular ejection fraction ≤ 30%

QRS duration ≥ 130 ms

Sinus rhythm

Page 35: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT: Methods Led by Dr. Arthur J. Moss

Largest randomized NYHA

Class I/II CRT-D trial to

date

Enrollment

1820 patients, 110

centers, 14 countries

Average follow-up

34.3 months

Commercially available

devices provided by

Boston Scientific were

used

Baseline Evaluation

To document inclusion/exclusion criteria and

establish baseline heart statusa

Randomization (3:2 CRT-D:ICD)

Stratified by center and ischemic status

Clinic Follow-up Visits

1 month post-enrollment/randomization, 3

months post-randomization, and quarterly

thereafter to a common study

closure dateb

CRT-D + OPT

(1089 patients)

ICD + OPT

(731

patients)

Page 36: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT: Kaplan–Meier Estimates of the Probability of

Survival Free of Heart Failure

Page 37: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT: Risk of Death or Heart Failure, according to Selected

Clinical Characteristics

Page 38: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT: Changes in Mean Echocardiographic Left Ventricular

Volumes and Ejection Fraction between Baseline and

1-Year Follow-up

Page 39: The 56th Cardiac Resynchronization Therapy in Mild Heart

Moss AJ et al. N Engl J Md. 2009 Oct 1;361(14):1329-38. Epub 2009 Sep 1.

34% 57%

MADIT-CRT: Kaplan–Meier Estimates of the Probability of

Survival Free of Heart Failure with LBBB

Page 40: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT: Effect of LBBB across subgroups

Page 41: The 56th Cardiac Resynchronization Therapy in Mild Heart

41

MADIT-CRT: Results

In asymptomatic or mild heart failure, patients

with wide QRS, LV dysfunction, and LBBB on

stable optimal heart failure pharmacologic

therapy, CRT-D, as compared to ICD, was

significantly associated with:

41% reduction in risk of HF events in pts with QRS

duration of 150 msec.

Reduction in Lt vent volumes and Improvement in

the ejection fraction

No significant difference in death rates

Page 42: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT Substudy: Probability of ventricular tachyarrhythmia by treatment and

echocardiographic response

Alon Barsheshet, et al. J Am Coll Cardiol 2011;57:2416–23

1. Patients with high echocardiographic response to CRT-D (≥25% reduction in LVESV) exhibit a significant reduction in the risk of VTA events.

2. The magnitude of reverse remodeling is inversely related to VTA risk:

10% reduction in LVESV → 20 % reduction in the risk of VTA.

Page 43: The 56th Cardiac Resynchronization Therapy in Mild Heart

MADIT-CRT Substudy: Effect of CRT on the Risk of First and Recurrent VTE

Ouellet G et al. J Am Coll Cardiol 2012;60: 1809–16

First VTE or Death Second VTE or Death

LBBB

Non-LBBB

Page 44: The 56th Cardiac Resynchronization Therapy in Mild Heart

Concordant Results for CRT

in Patients with Mild Symptoms

REVERSE Lind e C et al.J Am Coll Cardiol 2008, 52:1834-43

RFAT Tang A, et al NEJM 2010;363:2385-95

MADIT CRT Moss AJ et al. MEJM 2009;361(14):1329-38

Death or Heart Failure Hospitalization/Event

Hazard Ration with 95% CI

REVERSE

RAFT NYHA II

MADIT CRT

CRT-D Better 0.1 1 10

P=0.004

P=0.001

P<0.001

0.49

0.73

0.66

Page 45: The 56th Cardiac Resynchronization Therapy in Mild Heart

Consistent Benefit of CRT for

Patients with LBBB within Study

Cohorts

Death or Heart Failure Hospitalization/Event

LBBB REVERSE

RAFT NYHA II

MADIT CRT

Non-LBBB REVERSE

RAFT class II

MADIT-CRT

Hazard Ratio with 95% CI

CRT Better 0.1 1 10

0.48

0.63

0.43

0.53

1.06

1.32

Page 46: The 56th Cardiac Resynchronization Therapy in Mild Heart

Predictors of Response to CRT in

MADIT-CRT

7 Factors contributing to a Favorable

Echocardiographic Response: Reduction in LVEDV

•Female sex

•Nonischemic origin

•Left bundle-branch block

•QRS 150 milliseconds

•Prior hospitalization for heart failure

•Left ventricular end-diastolic volume 125 mL/m2

•Left atrial volume <40 mL/m2

Goldenberg I et al. Circulation. 2011;124:1527-1536

Conclusion—Combined assessment of factors associated with reverse

remodeling can be used for improved selection of patients for CRT

Page 47: The 56th Cardiac Resynchronization Therapy in Mild Heart

Hsu JC and Moss AJ et al. J Am Coll Cardiol 2012;59:2366–73

Page 48: The 56th Cardiac Resynchronization Therapy in Mild Heart

Hsu JC and Moss AJ et al. J Am Coll Cardiol 2012;59:2366–73

Page 49: The 56th Cardiac Resynchronization Therapy in Mild Heart

76/M NYHA ambulatory IV May 2003 dx as Dilated CM Sept 2005 CRT implant LVEDD 76mm, LVESD 68mm, LVEF 17% Oct 2010 LVEDD 50mm, LVESD 35mm, LVEF 61%

Page 50: The 56th Cardiac Resynchronization Therapy in Mild Heart

2012 Device-Based Therapy Guideline Focused Update. JACC 60(14), 1297-1313, 2012

Page 51: The 56th Cardiac Resynchronization Therapy in Mild Heart

ESC Guidelines: NYHA III-IV HF

European Heart Journal doi:10.1093/eurheartj/ehs104

Page 52: The 56th Cardiac Resynchronization Therapy in Mild Heart

ESC Guidelines: NYHA class II HF

European Heart Journal doi:10.1093/eurheartj/ehs104

Page 53: The 56th Cardiac Resynchronization Therapy in Mild Heart

Comparisons of the Guidelines

Korean Guideline1 2012 Updated2

LVEF 35% 35%

NYHA Functional status III, ambulatory IV II, III, and ambulatory IV

QRS Duration, ms 120 150

QRS Morphology NA LBBB

Rhythm status Sinus Rhythm Sinus Rhythm

1.`Class I indications of 2008 ACC/AHA/HRS Guidelines 2. 2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines

Current Korean Guideline

2012 ACCF/AHA/HR

S Guideline

Page 54: The 56th Cardiac Resynchronization Therapy in Mild Heart

2010 ICD/CRT Use in Asia-Pacific Zone

Underutilization in Korea

167

37

1

0

6.5

123

7

2

1

2.3

Australia & New Zealand

Japan

China

India

Korea

CRT ICD

n/million

Page 55: The 56th Cardiac Resynchronization Therapy in Mild Heart

Conclusions

• CRT in mild HF showed comparable morbidity

and mortality benefits, such as reverse

remodeling, and reductions in hospitalizations,

to those observed with more severe HF

• On the basis of these observations, CRT use

expanded to NYHA class II patients.

• A significant reduction in the risk of subsequent

life-threatening VTAs

• Careful selection of patients with wider QRS

durations and LBBB morphology for favorable

outcomes

Page 56: The 56th Cardiac Resynchronization Therapy in Mild Heart

Thank You For Your Attention!