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CRT WA Pres Acro2.pdf
1. Cardiac Resynchronization Therapy
William T. Abraham, MD, FACP, FACC
Professor of Medicine
Chief, Division of Cardiovascular Medicine
Associate Director, Davis Heart & Lung Research Institute
The Ohio State University
Columbus, Ohio
2. Goals of Heart Failure Therapy
in the Symptomatic Patient
• Relieve HF symptoms
• i.e., make patients feel better
• Improve overall clinical status
• Stabilize acute episodes of decompensation
• Decrease morbidity and mortality
• Slow and/or reverse disease progression
• Identify and treat reversible causes of
LV dysfunction
3. Despite Current Drug Therapies, Heart
Failure Morbidity and Mortality Remain High
• 30% to 40% of patients are in
NYHA class III or IV
• Re-hospitalization rates
• 2% at 2 days
• 20% at 1 month
• 50% at 6 months
• 5-year mortality ranges from
15% to more than 50%
• Asymptomatic LVD ≈ 15%
• Mild-moderate HF ≈ 35%
• Advanced HF >50%
End Show
4. Definitions
• Ventricular Dysynchrony:
• Effect of intra-ventricular conduction defects or
bundle branch block
• Non-synchronous ventricular activation associated
with abnormal ventricular filling and wall motion
• Usually manifested as left bundle branch block
• Cardiac Resynchronization:
• Therapeutic intent of biventricular pacing
• In patients with ventricular dysynchrony
End Show
5. Clinical Consequences of
Ventricular Dysynchrony
Reduced diastolic
filling times
Grines, et al. (1989);
Xiao, et al.
Br Heart J 1991;66:443-447
Prolonged MR duration
Grines, et al. (1989);
Xiao, et al. (1992)
Reduced dP/dt
Xiao H, et al.
Br Heart J 1992;68:403-407
Abnormal
interventricular
septal wall motion
Grines C, et al.
Circulation 1989;79:845-853
End Show
6. QRS Duration and Mortality:
The VEST Trial
• VEST study analysis
• NYHA Class II-IV patients
• 3,654 ECGs digitally
scanned
• Age, creatinine, LVEF,
heart rate, and QRS
duration found to be
independent predictors of
mortality
• Relative risk of widest QRS
group 5x greater than
narrowest 60%
70%
80%
90%
100%
0 60 120 180 240 300 360
Days in Trial
Cumulative
Survival
QRS
Duration
(msec)
<90
90-120
120-170
170-220
>220
Adapted from Gottipaty et al. JACC
1999; 33(2):145A (abstract 847-4)
End Show
7. Cardiac Resynchronization Therapy:
Weight of Evidence
• More than 4000 patients enrolled in
randomized controlled trials
• Consistent improvement in quality of life,
functional status, and exercise capacity
• Strong evidence for reverse remodeling
• ? LV volumes and dimensions
• ↑ LV ejection fraction
• ? Mitral regurgitation
• Reduction in heart failure (CRT) and all-
cause morbidity and mortality (CRT-D)
End Show
8. Cumulative Enrollment in Cardiac
Resynchronization Randomized Trials
• Actual • Projected
0
1000
2000
3000
4000
1999 2000 2001 2002 2003 2004 2005
Results Presented
Cumulative
Patients
PATH CHF
MUSTIC SR
MUSTIC AF
MIRACLE
CONTAK CD
MIRACLE ICD
PATH CHF II
COMPANION
MIRACLE ICD II
CARE HF
End Show
9. Cardiac Resynchronization Therapy:
Major Randomized Controlled Trials
In Press
No
Normal
≥120
III, IV
COMPANION (1520)
Enrolled
No
Normal
≥150
III
PACMAN (328)
Enrolling
No
Normal
≥140
II-IV
VecToR (420)
Presented
No
Normal
≥120
III, IV
PATH CHF II (89)
Presented
Yes
Normal
≥130
II
MIRACLE ICD II (186)
Enrolled
No
Normal
≥120†
III, IV
CARE HF (800)
Published
Yes
Normal
≥130
III-IV
MIRACLE ICD (362^)
Published
Yes
Normal
≥120
III-IV
CONTAK CD (581¥)
Published
No
Normal
≥120
III, IV
PATH CHF (42)
Published
No
AF
>200*
III
MUSTIC AF (43)
Published
No
Normal
>150
III
MUSTIC SR (58)
Published
No
Normal
≥130
III, IV
MIRACLE (524#)
Status
ICD?
Sinus
QRS
NYHA
Study (n random.)
LVEF ≤ 35% for all trials
#Includes 71 patients enrolled in 3-month pilot study; ^Excludes class II patients; ¥Includes 248 patients
enrolled in 3-month cross-over phase; *RV paced QRS; †Echo-based criteria for QRS < 150 msec
End Show
10. Primary and Secondary Endpoints of the
Major Randomized Controlled Trials
Mortality, Hospital.
Mortality + Hospital.
COMPANION (1520)
QoL, NYHA, Arrhythmias
6MW
PACMAN (328)
QoL, Echo, Mortality
6MW
VecToR (420)
Peak VO2
PATH CHF II (89)
Echo, NYHA, QoL, 6MW
Peak VO2
MIRACLE ICD II (186)
Mortality, Hospital.
Mortality + Hospital.
CARE HF (800)
CPX, Echo, Neurohormones
NYHA, QoL, 6MW
MIRACLE ICD (362^)
Peak VO2, NYHA, QoL, 6MW
Composite
CONTAK CD (581¥)
Peak VO2, 6MW, QoL, LVEF, NYHA
PATH CHF (42)
QoL, Peak VO2
6MW
MUSTIC AF (43)
QoL, Peak VO2
6MW
MUSTIC SR (58)
CPX, Echo, Neurohormones
NYHA, QoL, 6MW
MIRACLE (524#)
Secondary Endpoint(s)
Primary Endpoint(s)
Study (n random.)
#Includes 71 patients enrolled in 3-month pilot study; ^Excludes class II patients; ¥Includes 248 patients
enrolled in 3-month cross-over phase
End Show
11. Does CRT make heart failure
patients feel better?
End Show
12. CRT Improves Quality of Life and
NYHA Functional Class
Average Change in Score
(MLWHF)
-20
-15
-10
-5
0
M
I
R
A
C
L
E
M
U
S
T
I
C
S
R
C
O
N
T
A
K
C
D
M
I
R
A
C
L
E
I
C
D
Control CRT
* * * *
* P < 0.05
NYHA: Proportion Improving
1 or More Class
0%
20%
40%
60%
80%
MIRACLE CONTAK
CD
MIRACLE
ICD
Control CRT
*
*
*
Abraham et al., 2003
End Show
13. CRT Improves Exercise Capacity
Average Change in 6 Minute
Walk Distance
-40
-20
0
20
40
60
M
I
R
A
C
L
E
M
U
S
T
I
C
S
R
C
O
N
T
A
K
C
D
M
I
R
A
C
L
E
I
C
D
m
Control CRT
*
*
*
* P < 0.05
Average Change in Peak VO2
0
0
1
2
3
M
I
R
A
C
L
E
M
U
S
T
I
C
S
R
C
O
N
T
A
K
C
D
M
I
R
A
C
L
E
I
C
D
ml/kg/min
Control CRT
*
*
*
*
Abraham et al., 2003
End Show
14. CRT Benefits
Sustained Through 2 Years
MIRACLE Study Program
Baseline
Follow-up
Paired
Data
Displayed
0
100
200
300
400
500
Mean
distance
walked in
6 minutes
(m)
P<0.001 P<0.001 P<0.001 P=0.01
0
20
40
60
80
100
6 (N=1124) 12 (N=693) 18 (N=320) 24 (N=68)
Months of Active CRT
Mean
QoL
Score
P<0.001 P<0.001 P<0.001 P<0.001
1
2
3
4
Mean
NYHA
Functional
Class
P<0.001 P<0.001 P<0.001 P<0.001
Abraham et al.,
AHA 2003
End Show
15. Change from baseline in 6
minute walk distance
-30
-20
-10
0
10
20
30
40
Dig
(1)
BB
(2)
CRT
(6)
meters
Change from baseline in
CPX Duration
-30
0
30
60
90
Dig
(1)
ACE
(3)
CRT
(6)
seconds
Control Treatment
Change from baseline in
QoL (MLWHF) Score
-20
-15
-10
-5
0
5
ACE
(4)
BB
(5)
CRT
(6)
score
Improvement
*
NS
‡
‡
‡
†
* P≤.05 † P≤.01 ‡ P≤.001
†
*
*
1 NEJM 1993;329:1-7 (RADIANCE)
2 Circulation 1996;94:2793-2799 (PRECISE)
3 JAMA 1988;259:539-544
4 Am J Cardiol 1993;71:1106-1107 (SOLVD Treatment)
5 J Cardiac Failure 1997;3:173-179
6 NEJM 2002;346:1845-53 (MIRACLE)
Comparison with Drug Trials: Digoxin,
ACE-I and Beta-blocker Therapies
End Show
16. Does CRT reduce morbidity and mortality
in chronic heart failure?
End Show
17. CRT Improves
Cardiac Function & Structure
Change in MR Jet Area
-4
-3
-2
-1
0
1
Control
(n=118)
CRT
(n=116)
cm2
P<0.001 P=0.009
Change in LVEDD
-6
-4
-2
0
2
Control
(n=118)
CRT
(n=116)
mm
P<0.001
Absolute Change in
LVEF
-2
0
2
4
6
8
Control
(n=146)
CRT
(n=155)
%
Baseline (mm)
291
69 ± 10
70 ± 10
Baseline (cm2
)
291
7.2 ± 4.9
7.6 ± 6.4
Baseline (%)
291
22 ± 6
22 ± 6
Paired median change from baseline at 6 months. Error bars are 95% CI.
Abraham et al., N Engl J Med 2002; 346:1845-1853;
St. John Sutton et al., Circulation 2003
End Show
18. Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk
10
15
20
25
30
35
40
*
* †
*
*
*
†
†
Mitral
regurgitation
(%)
MR area
Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk
100
125
150
175
200
225
*
*
*
*
†
* *
*
†
Left
ventricular
volume
(mL)
*
LV End Systolic and
Diastolic Volumes
Time Course of LV Reverse
Remodeling after CRT
Pacing No pacing
N = 25
Yu CM, et al, Circulation 2002;105:438-445
End Show
19. Improved Cardiac Function
Without Oxidative Stress
0.14
0.16
0.18
0.20
0.22
0.24
500 600 700 800 900
dP/dtmax (mm/Hg/s)
MVO2/HR
(Relative
Units)
Dobutamine
LV Pacing
P<0.05
Nelson et al. Circulation 2000;102:3053-3059
Myocardial Oxidative
Metabolism
0
0.02
0.04
0.06
LV RV
k
mono
(min
-1
)
p=
0.86
p=
0.62
n=8
Myocardial Efficiency
(Work Metabolic Index)
0
2
4
6
8
10
12
mm
HG·L·m-2
Baseline CRT
p=
0.024
Ukkonen et al. Circulation 2003;107:28-31
n=7
End Show
20. 0 1 2
Hazard Ratio
MIRACLE: Clinical Events
During Double-Blind Period
Favors CRT Favors Control
P=0.40
P=0.03
P=0.02
P=0.02
P=0.004
Death for any reason
Death or worsening HF
requiring hospitalization
Death or worsening HF
with hospitaliz. or IV Rx
Hospitalized for
worsening HF
Worsening HF with use
of IV med for HF CRT (n=228)
Control (n=225)
Abraham et al., 2002
End Show
24. Proven Beneficial Effects of CRT in
Class III-IV Heart Failure
• Improved quality of life
• Increased 6-minute hall walk distance
• Improved NYHA functional class ranking
• Increased peak VO2 and treadmill
exercise time
• Reduced QRS duration
• Improved cardiac structure and function
• Fewer days in hospital over 6 months
• Improved Clinical Composite Response
• Reduced morbidity and mortality
End Show
25. NNTx years =
(%Mortality in Control Group – %Mortality in Treatment Group)
100
3.5 Yr
20
SAVE
1 Yr
25
CIBIS
II
1 Yr
29
MERIT
HF
1.5 Yr
29
CAPRICORN
2 Yr
37
Amiodarone
Drugs
14
CRT-D
1 Yr
25
CRT
COMPANION
CRT
5 Yr
3
MUSTT
2.4Yr
4
MADIT
3 Yr
11
MADIT
II
3 Yr
9
AVID
ICD
Years of
tested
treatment
0
5
10
15
20
25
30
35
40
45
50
Number
of
patients
needed
to
treat
to
save
one
life
4 Yr
56
HOPE
14
COPERNICUS
0.8 Yr
Comparison of CRT±D with Other Life
Prolonging Therapies in CVD
Auricchio and Abraham, Circulation 2004;109:300-307
End Show
26. Relative Cost of
Cardiac Resynchronization Therapy
with or without an ICD
Cost per patient
$0
$20
$40
$60
CRT+ICD
CRT
Hip/knee replace
PTCA
CABG
Dialysis
$ thousands
Total Annual Expenditures
$0 $5 $10 $15 $20
$ Billions
US data only. Data sources: All except dialysis: Weighted DRG payment for 2003 using the
# of discharges in 2000: HCUPnet, Healthcare Cost and Utilization Project. AHRQ.
www.ahrq.gov/data/hcup/hcupnet.htm. Dialysis: Medicare 2000 payment per patient: The
US Renal Data System (USRDS), 2002. www.usrds.org.
End Show
27. Who Responds to Cardiac
Resynchronization?
• Observational study;
• not confirmed by
MIRACLE
Correlated with improved
NYHA6
No MI, significant mitral
regurgitation
• Small studies, ≤ 30 pts;
• Varying techniques
• No clinical endpoint
Correlated with ↓
volumes 3,4,5
Difference in time to peak
systolic contraction
• Small studies, < 30 pts;
• No clinical endpoint
• not confirmed by
MIRACLE
Correlated with improved
dP/dt 1,2
QRS ≥ 150/155 and/or
dP/dt ≤ 700 mm Hg/s
• ~ 70% respond favorably
Confirmed in RCTs of
over 2,500 patients
NYHA III/IV, QRS≥ 130 ms,
EF≤ 35%, LVEDD≥ 55 mm
Limitation(s)
Finding
Responder
Parameter(s)
1. Circulation. 2000;101:2703-2709
2. Circulation 1999;99:2993-3001
3. Am J Cardiol 2002;91:684–688
4. J Am Coll Cardiol 2002;40:1615-1622
5. J Am Coll Cardiol 2002;40:723–730
6. Am J Cardiol 2002;89:346-350
End Show
28. Cardiac Resynchronization Therapy:
Patient Selection March 2004
• ≥ 18 years of age
• NYHA Functional Class III or IV
despite stable/optimal drug regimen
• QRS duration ≥ 120-130 msec
• LVEF ≤ 35%; LVEDD ≥ 55 millimeters
• With or without indication for ICD
End Show
29. Summary
• Large number of patients studied in RCTs
• Concordant proof that CRT improves quality
of life, functional status, and exercise capacity
• Improvements persist through = 1 year
• CRT reduces the risk of mortality and heart
failure due to worsening HF
• CRT + ICD reduces risk of all-cause mortality
• CRT improves cardiac function and structure
End Show
30. Future Directions
• Changing the definition of ventricular
dysynchrony (QRS duration → ECHO)
• Expanding the indication to less severe heart
failure (? asymptomatic LV dysfunction)
• Evaluating the effects of CRT versus right-
sided pacing in narrow QRS patients
• Evaluating prospective predictors of response
• Improvement of lead placement technologies
End Show
