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
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)
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
Two major targets for
CRT expansion
Advanced HF patients with narrow QRS
complexes (120ms)
Patients with mild HF (NYHA class I and II)
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
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
REVERSE:
Resynchronization reVErses
Remodeling in Systolic left vEntricular
dysfunction Linde C, et al. J Am Coll Cardiol 2008 52:1834-43
• 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
• 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
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
• 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
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
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)
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
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)
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
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
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
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
RAFT:
Resynchronization/defibrillation for
Ambulatory heart Failure Trial
Tang A et al. 2010 N Engl J Med 363(25):2385-2395
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
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
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
RAFT: Endpoints
Primary Endpoint
HF hospitalization or all-cause mortality
Key Secondary Endpoint
Mortality
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
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
RAFT: Primary Endpoint:
Significant Reduction in HF
Hospitalization or All-cause Death
RAFT: Secondary Endpoint:
Significant Reduction in Mortality
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.
RAFT: Primary endpoint: Subgroup Analysis
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
MADIT-CRT:
Multicenter Automatic
Defibrillator ImplanTation with
Cardiac Resynchronization
Therapy Moss AJ. et al. N Engl J Med 2009;361:1329-38.
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
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
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)
MADIT-CRT: Kaplan–Meier Estimates of the Probability of
Survival Free of Heart Failure
MADIT-CRT: Risk of Death or Heart Failure, according to Selected
Clinical Characteristics
MADIT-CRT: Changes in Mean Echocardiographic Left Ventricular
Volumes and Ejection Fraction between Baseline and
1-Year Follow-up
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
MADIT-CRT: Effect of LBBB across subgroups
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
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.
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
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
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
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
Hsu JC and Moss AJ et al. J Am Coll Cardiol 2012;59:2366–73
Hsu JC and Moss AJ et al. J Am Coll Cardiol 2012;59:2366–73
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%
2012 Device-Based Therapy Guideline Focused Update. JACC 60(14), 1297-1313, 2012
ESC Guidelines: NYHA III-IV HF
European Heart Journal doi:10.1093/eurheartj/ehs104
ESC Guidelines: NYHA class II HF
European Heart Journal doi:10.1093/eurheartj/ehs104
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
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
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
Thank You For Your Attention!
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