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RCTs in Cardiac Resynchronization
Therapy
Study
Pt
NYHA
LVEF
LVEDD
Rhythm
QRS
ICD
PATH-CHF
41
III,IV
≤35%
Any
SR
≥120
N
MUSTIC
58
III
≤35%
≥60
SR
≥150
N
MIRACLE
453
III,IV
≤35%
≥55
SR
≥130
N
MUSTIC AF
43
III,IV
≤35%
≥60
AF
≥200
N
MIRACLE ICD
369
III,IV
≤35%
≥55
SR, AF
≥130
Y
CONTAK CD
227
II-IV
≤35%
Any
SR
≥120
Y
MIRACLE ICD II
186
II
≤35%
≥55
SR
≥130
Y
PATH-CHF II
101
II-IV
≤35%
Any
SR
≥120
Y/N
COMPANION
1520
III,IV
≤35%
Any
SR
≥120
Y/N
CARE-HF
814
III,IV
≤35%
≥30
indexed
SR
≥120
N
3812
Reverse remodeling in CRT Pts:
Importance of etiology
Left Ventricular End-Diastolic Volume
(ml)
340
280
Left Ventricular End-Systolic
Volume (ml)
260
320
240
300
280
220
*
*
*
200
*
*
*
180
260
160
240
140
220
120
200
100
Ischemic Pts
35
30
Non-Ischemic Pts
Left Ventricular Ejection
Fraction (%)
*
*
*
Ischemic Pts
Non-Ischemic Pts
Baseline
6 Month
12 Month
Left Ventricular Mass (g)
*
380
360
320
25
*
340
300
*
*
280
20
260
240
15
220
10
200
Ischemic Pts
Non-Ischemic Pts
Ischemic Pts
Non-Ischemic Pts
St.John Sutton Circ. 2006
LVEF change at 6 month predicts long-term
outcome independently from etiology
Kaplan-Meier survival estimates
Kaplan-Meier survival estimates
1.00
1.00
0.75
0.75
LVEF >=11
LVEF >=6
0.50
0.50
LVEF = <11
LVEF =<6
0.25
P < 0.0001
0.25
P < 0.0001
0.00
0.00
0
12 24 36 48 60 72 84 96
Kaplan Meier Event-free survival
0
12 24 36 48 60 72 84 96
Kaplan Meier Event-free survival
1.00
1.00
0.75
0.75
LVEF >=11
LVEF >=6
0.50
0.50
0.25
P < 0.0001
LVEF =<6
P < 0.0001
LVEF = <11
0.00
0.00
0
0.25
12 24 36 48 60 72 84 96
Follow-up (months since response)
0
12 24 36 48 60 72 84 96
Follow-up (months since response)
Di Biase, Auricchio et al. EHJ 2008
Effect of CRT on Death,
Hospitalization, and i.v. Medications
Hazard Ratio
N=461
MIRACLE
[QRS >130 ms, EF<0.35, NYHA >III]
0.58
N=362
MIRACLE ICD
[QRS >130 ms, EF<0.35, NYHA >III, ICD
Indication]
0.69
N=1520
COMPANION (CRT-P)
[QRS >120 ms, EF<0.30, NYHA >III, recent
Hospitalization]
0.65
COMPANION (CRT-D)
0.60
N=813
CARE-HF
[QRS >160 ms or IntraVD, EF<0.30, NYHA
>III, recent Hospitalization]
0.63
0.4
0.6
CRT Better
0.8
1.0
1.2
1.4
1.6
1.8
Consistency in Survival Rate
COMPANION
CARE-HF (x-phase)
8.5 %/yr
10-12 %/yr
MILOS
Registry
(Magdeburg)
(Brescia)
8%/yr
(Rozzano)
(BadOeynhausen)
Auricchio et al. AJC 2007
Marginal Benefit in AF Patients
MUSTIC AF. Leclercq et al Eur Heart J 2002: 23: 1780
Role of underlying rhythm
All-cause mortality
LVEF
Upadhyay GA et al JACC 2008
Effect of Ablation and CRT in HF
patients with AF
Peak Oxygen Consumption
(ml/min/Kg)
Left Ventricular Ejection
Fraction (%)
60
50
40
30
20
10
0
25
20
15
10
0
Baseline
6
12
24
36 months
Baseline
6
12
24
36 months
Changes of Left Ventricular
End-Diastolic Diameter from
Baseline (%)
5
0
-5
-10
Sinus Rhythm
Atrial Fibrillation with AVJ Ablation
Atrial Fibrillation without AVJ Ablation
N=687
-15
Gasparini M, et al. JACC 2006
Device Therapy for Advanced HF:
Cardiac Resynchronization Therapy
Class I
ESC/EHRA
2007
Guidelines on pacing and CRT
ESC/HFA/ESICM
2008
Guidelines for the diagnosis and
treatment of acute and chronic
heart failure
ACC/AHA/HRS
2008
Cardiac Pacemakers &
Antiarrhythmia devices
LVEF ≤35%
QRS ≥120 ms
NYHA III - NYHA IV
OMT
LV Dilatation
Sinus rhythm
LVEF ≤35%
QRS ≥120 ms
NYHA III - NYHA IV
OMT
LVEF ≤35%
QRS ≥120 ms
NYHA III - NYHA IV ambulatory
OMT
Sinus rhythm
A
A (CRT-P)
B (CRT-D)
As above
Class I for an ICD
(upgrade or replacement)
Class IIa
A (CRT-P)
B (CRT-D)
B
As above
Permanent pacing
(upgrade or replacement)
As above
Frequent dependence on
ventricular pacing
C
C
As above
Permanent atrial fibrillation and
indication for AV junction
C
ablation
Vardas et al. EHJ 2007
As above
Atrial fibrillation
B
Dickstein et al. EHJ 2008
Epstein et al. Circulation 2008
Mode of Death in COMPANION
Time to Heart Failure Death
Time to Sudden Cardiac Death
CRT-D
CRT
OPT
Bristow et al. Circulation 2006
Effect of CRT-P on SCD (CARE-HF)
Definitive SCD
Probable SCD
Possible SCD
Uretsky et al. J Cardiac Fail 2008
Mode of Death in CRT-D and CRT-P
Patients (n=1298): The MILOS Registry
0,06% per year
2,5% per year
Multicenter
Longitudinal
Observational
Study
(MILOS)
Auricchio
et al. (MILOS
Study) Am
J Cariol
2006
Effect of CRT on Time to SCD or to HF
Death in Stable NYHA IV Patients
Time to Sudden Cardiac Death
Time to Heart Failure Death
CRT-D
CRT
OPT
CRT
CRT-D
OPT
• No difference in 2-year survival between CRT and CRT-D patients.
• In patients with Class IV symptoms in whom resynchronization is inadequate to restore clinical
stability, the presence of a ICD often complicates the impending transition to end-of-life care.
Lindenfeld et al. Circulation 2007
No reliable criteria to predict clinical
responders
MIRACLE: Functional NYHA Class
100%
10%
5%
80%
51%
60%
40%
20%
0%
90%
IV
III
II
I
10%
5%
35%
90%
52%
38%
6%
8%
Baseline 6-Months
Baseline 6-Months
Control (n = 123)
CRT (n = 131)
PROSPECT study: Selected
echocardiographic methods and cut-offs
Chung et al. Circulation 2008
PROSPECT study:
End-points
Chung et al. Circulation 2008
Predictive Value of Echo Dyssynchrony
Measures
The presence of single MD measures added
11-13% response to CCS and 13-23% to LVESV
Chung et al. Circulation 2008
ASE Expert Consensus Statement:
Conclusion
JASE 2008
COMPANION Trial: All subgroups
equally benefited
Bristow et al. NEJM 2005
CARE-HF: All subgroups equally
benefited
Cleland et al. NEJM 2005
Specific situations
Patients with RBBB
Aged patients
Patients with diabetes
Patients with chronic renal failure
CRT in RBBB Patients: COMPANION Study
Is CRT delivery suboptimal in these patients ?
Are these patients sicker ?
Bristow et al. NEJM 2005
RBBB vs LBBB
Fantoni et al. JCE 2005
RCTs and Registry (Age Issue)
MIRACLE
(2002)
COMPANION
(2005)
CARE-HF
(2005)
Piccini et al.
(2008)
64
66
67
71
Gender (W)
32%
33%
26%
31%
Race (W/B/I)
90/NA/NA
NA
NA
82/12/3
NA
40%
25%
16%
CAD
50%
55%
67%
57%
LVEF
0.22
0.22
0.25
0.25
QRS
167 ms
160 ms
160 ms
NA
Age
Diabetes
Comparison of end point after 6
months in young and aged patients
Kron et al. J Interv Cardioll 2009
Outcome of young and aged patients
Delnoy et al AHJ 2008
Incremental Cost Per QALY Gained €
Effect of Starting Age and Device
Longevity on Cost per QALY – Base case
80,000
7 Years
70,000
5 Years
60,000
50,000
40,000
8 Years
30,000
20,000
10,000
0
55
60
65
70
75
Age at Starting Treatment
CRT+MT vs MT
CRT+ICD+MT vs CRT + MT
CRT+ICD+MT vs MT
Freemantle N. on behalf of CARE-HF Investigators
Diabetes and CRT
No Diabetes
No Diabetes
Diabetes
Diabetes
No Diabetes
Diabetes
Diabetes
No Diabetes
Fantoni et al. EHFJ 2008
Diabetes and CRT
Diabetes Care 2007
Renal dysfunction
CRT-D both BB and no-BB
Normal renal function
CRT-D and BB
Normal renal function
Chronic renal failure
Chronic renal failure
Bai et al JCE 2008
Survival from cardiovascular death
Dyssynchrony-Scar-Creatinine Index
DSC index <3 (3/83 [4%])
HR: 30.5 (9.15 to 101.8), p<0.0001
1
.8
.6
DSC index 3 to 5 (9/30 [30%])
HR: 11.1 (3.00 to 41.1), p=0.0003
.4
DSC index ≥5 (25/35 [71%])
.2
Log rank p <0.0001
0
0
250
500
750 1000 1250 1500 1750 2000 2250
Time (days)
Posterolateral scar location
CMR-TSI , ms*
Creatinine, µmol/L
β coefficient (95% CI)
HR (95% CI)
Z-score
p
2.50 (1.60 to 3.40)
0.01 (0.00 to 0.02)
0.01 (0.00 to 0.02)
12.2 (4.97 to 30.1)
1.01 (1.00 to 1.02)
1.01 (1.00 to 1.02)
5.46
3.26
2.83
<0.0001
0.0011
0.0046
Model LR χ2: 73.4, p<0.0001
Leyva et al in press
Device Therapy for Advanced HF:
Cardiac Resynchronization Therapy
Class I
ESC/EHRA
2007
Guidelines on pacing and CRT
ESC/HFA/ESICM
2008
Guidelines for the diagnosis and
treatment of acute and chronic
heart failure
ACC/AHA/HRS
2008
Cardiac Pacemakers &
Antiarrhythmia devices
LVEF ≤35%
QRS ≥120 ms
NYHA III - NYHA IV
OMT
LV Dilatation
Sinus rhythm
LVEF ≤35%
QRS ≥120 ms
NYHA III - NYHA IV
OMT
LVEF ≤35%
QRS ≥120 ms
NYHA III - NYHA IV ambulatory
OMT
Sinus rhythm
A
A (CRT-P)
B (CRT-D)
As above
Class I for an ICD
(upgrade or replacement)
Class IIa
A (CRT-P)
B (CRT-D)
B
As above
Permanent pacing
(upgrade or replacement)
As above
Frequent dependence on
ventricular pacing
C
C
As above
Permanent atrial fibrillation and
indication for AV junction
C
ablation
Vardas et al. EHJ 2007
As above
Atrial fibrillation
B
Dickstein et al. EHJ 2008
Epstein et al. Circulation 2008