Transcript 8/08 LV Dyssnchrony and CRT

LV Dssynchrony and Cardiac
Resynchronization Therapy
in Heart Failure
Nisha I. Parikh MD MPH
August 13th 2008
Summary of Talk
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Background
CRT Rational and Evidence for Benefit
LV Dssynchrony by Echocardiography
Evidence for Ability of Echo to Predict CRT
Response
Discharges in Thousands
Hospital discharges for HF from 1979-2004
700
600
Male
500
Female
400
1,099,000
1,099,000
300
200
100
399,000
0
79 80
85
90
95
00
04
Years
American Heart Association. Heart Disease and Stroke Statistics — 2007 Update
HF Total Expenditures: $27.9 Billion
American Heart Association. Heart Disease and Stroke Statistics — 2007 Update
Percent Change in United States Crude Death Rates
from 1972 to 2000 by cause
NHLBI Morbidity and Mortality Chart Book. 2004
HF Therapy
Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: 2007-2018. Copyright 2002 Massachusetts Medical Society.
All rights reserved.
Electrical dyssynchrony
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Abnormal ventricular depolarization,
causing increased QRSd generates early
and delayed ventricular contraction
QRSd directly associated with EF
BBB present in 20% of HF patients and
35% of patients with severely impaired EF
BBB is an independent predictor of
mortality especially QRSd > 120 ms
Mechanical dyssynchrony
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Intraventricular- refers to delayed activation
of one LV region to another
Interventricular- refers to delayed activation
of LV relative to RV
CRT aims to correct both
Achieving Cardiac
Resynchronization
Goal: Atrial synchronous
biventricular pacing
Transvenous approach for left ventricular lead via
coronary sinus
Back-up epicardial approach
Right Atrial
Lead
Left Ventricular
Lead
Right Ventricular
Lead
From Dr. A. Goldman’s CRT Talk 2007
Cumulative Patients
Cumulative Enrollment in Cardiac
Resynchronization Randomized Trials
4000
CARE HF
MIRACLE ICD
3000
MIRACLE
MUSTIC AF
2000
1000
MIRACLE ICD II
MUSTIC SR
COMPANION
PATH CHF
PATH CHF II
CONTAK CD
0
1999
2000
2001
2002
2003
Results Presented
2004
2005
CRT benefits
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Reduced mitral regurgitation
Increased 6-minute hall walk distance
Improved NYHA functional class ranking
Increased peak VO2 and treadmill exercise time
Reduced QRS duration
Reversal of maladaptive remodeling
Fewer days in hospital over 6 months
Improved clinical composite response
Reduced morbidity and mortality
Improvement with CRT - MR
Regional Wall Motion With CRT:
Improved LVEF
Regional Fractional Area Change
Septum
0
Adapted from Kawaguchi M, et al. J Am Coll Cardiol. 2002;39:2052-2058.
0.4
Lateral
0
Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.
Seconds
Seconds
Pacing Off
Pacing On
0.4
CRT Promotes Reverse Remodeling in
Class II CHF
3
cm
400
Left Ventricular End
Diastolic Diameter
3
cm
400
Left Ventricular End
Systolic Diameter
%
Left Ventricular
Ejection Fraction
30
P=0.04
P=0.01
350
P=0.02
28
350
26
300
300
24
250
200
250
Base
6 Mo
200
22
Base
 Control (n=85)
6 Mo
 CRT (n=69)
Abraham et al., Circulation 2004; 110:2864-2868
20
Base
6 Mo
CRT Improves Quality of Life and
NYHA Functional Class
Average Change in Score
NYHA: Proportion Improving
1 or More Class
0
80%
-5
*
40%
-15
*
Control
20%
ICD
*
MI
RA
CL
E
NT
AK
C
CO
TIC
D
*
SR
*
MU
S
MI
RA
CL
E
*
60%
-10
-20
*
CRT
Abraham et al., 2003
0%
* P < 0.05
MIRACLE CONTAK MIRACLE
CD
ICD
Control
CRT
CRT Improves Exercise Capacity
Average Change in 6 Minute
Walk Distance
m
*
60
*
3
mL/kg/min
*
40
Average Change in Peak VO2
20
0
-20
*
2
*
*
1
0
CRT
Abraham et al., 2003
* P < 0.05
CL
E
ICD
D
Control
MI
RA
CO
NT
AK
C
SR
TIC
MU
S
CL
E
MI
RA
ICD
D
Control
MI
RA
CL
E
NT
AK
C
CO
MU
S
TIC
SR
0
MI
RA
CL
E
-40
*
CRT
Progressive Heart Failure Mortality
51% Relative Reduction with CRT
Overall odds ratio (95% CI) of 0.49 (0.25 - 0.93)
Favors CRT
Favors No CRT
CONTAK CD (n=490)
MIRACLE ICD
(n=554)
MIRACLE (n=532)
MUSTIC (n=58)
Overall (n=1634)
0.1
0.5
1.0
Odds Ratio (95% CI)
Bradley DJ, et al. JAMA 2003;289:730-740
10.0
Summary of Major Trials
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Significant clinical benefit of CRT in patients with class III-IV
HF, low EF, and QRS > 120
 Improvement in symptoms
 Improvement in objective standards of HF
Meta-analysis
 29% decrease in HF hospitalization (13% vs. 17.4%)
 51% decrease in deaths from HF (1.7% vs. 3.5%)
 Trend toward decrease in overall mortality (4.9% vs 6.3%)
BUT: >30% non-responders consistent through most trials
Bradley et al. JAMA 2003;289:730
How to best predict who will respond
to CRT?
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?Use of Echo/ imaging parameters
Intraventricular Dyssynchrony
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M-Mode Echo
Tissue Velocity
Strain Imaging
Three Dimensional Echo
M-Mode
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Septal to posterior wall delay
Measures time between maximal
displacement of septum and posterior wall
(SPWMD)
≥ 130 ms considered significant
Easy to perform
No specific equipment needed
M-mode echocardiography with color-coded tissue velocity. a, Timing of ventricular
septal (VS) wall motion is difficult to define because of its severe hypokinesis and
the lack of distinct peaks. b, Color coding of tissue velocity helps to identify the
exact wall motion timing as transition point of blue to red color for septal wall
(arrows) and red to blue color for posterior wall (arrowheads) (right)
Copyright ©2008 American Heart Association
Anderson, L. J. et al. Circulation 2008;117:2009-2023
M-Mode- SPWMD Disadvantages
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Can only be quantified in regions
perpendicular to U/S beam
Only feasible in half of patients studied
In several reports, septal-posterior wall
delay didn’t predict outcome after CRT
Only assesses motion of septal and
posterior walls
Tissue Velocity
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Measurement of either longitudinal tissue velocity
or deformation (strain)
- Opposing wall peak delay of > 60-65 ms1-2
- Yu index: global 12 segment Asynchrony Index ≥
33 ms3
High temporal resolution
Color-coded TDI- allows simultaneous processing
of multiple samples from the same image
Susceptible to translational motion or tethering
effect
Bax et al, Am J Card 2003
Bax et al, Am J Card 2004
Tissue velocity waveforms in a normal subject
from 4-chamber (left), apical long-axis (middle),
and 2-chamber views (right)
Anderson, L. J. et al. Circulation 2008;117:2009-2023
Copyright ©2008 American Heart Association
Color-coded tissue velocity recordings from 12 LV segments before (a) and
after (b) CRT in 65-year-old patient with nonischemic cardiomyopathy whose
LVEF improved by 17% at 6 months after CRT
Apical 4 Ch
Long axis
Before CRT
After CRT
Anderson, L. J. et al. Circulation 2008;117:2009-2023
Copyright ©2008 American Heart Association
2 Chamber
Tissue Velocity- Disadvantages
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Susceptible to translational motion or
tethering effect
Color coding can vary with time window
setting
Requires specific equipment
Strain Imaging
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TDI-derived and Speckle tracking
Abnormal strain pattern- premature early
systolic shortening of septum accompanied
by lateral prestretch and followed by
postsystolic lateral wall shortening
Less affected by tethering / translational
motion
Radial strain curves from short-axis view of speckle tracking
Echocardiography: Significant timing difference was found among
time to peak radial strain before CRT (a),
and it was reduced after CRT (b).
Anderson, L. J. et al. Circulation 2008;117:2009-2023
Copyright ©2008 American Heart Association
Strain imaging
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Dependent on image quality; not feasible in
all patients
Mixed results with respects to predicting
success after CRT
3-D Echo
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Only one image allows entire assessment
Short-term improvements in 3-D
dyssynchrony index noted after CRT
Three Dimensional Echocardiography
3-D Echo
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No study to date shows 3D Echo predicts
response to CRT
Highly dependent on image quality
Incomplete inclusion of the apex
Can’t perform in a-fib or rhythm with
several ectopic beats
Interventricular Dyssynchrony
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Difference in preejection period between PW
doppler in Ao and PA
Correlates with QRSd
Exceeds 40s in patients with QRDs>150 ms
Shown to be predictive of response post-CRT in
SCART and CARE-HF trials
TV delay between RV and LV free wall not
predictive of effect of CRT
Evidence for echo in predicting CRT
outcomes
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Limited echo-CRT studies with hard
endpoints
Thus far, trials have enrolled 4000 patients
based on ECG versus ~500 by
echocardiogram
PROSPECT Study- largest study
Enrollment and follow-up of patients in PROSPECT
Chung, E. S. et al. Circulation 2008;117:2608-2616
Copyright ©2008 American Heart Association
PROSPECT patient population
Mean age
Male
NYHA class III
Mean LVEF
Prior MI
Beta-blockers
Ace-I
68 years
71%
96%
23%
48%
85%
92%
Endpoints- Composite clinical score
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Worsened (died, hospitalized, worsened heart failure,
demonstrated worsening in NYHA class at last observation
carried forward, moderate or marked worsening of patient
global assessment score at last observation carried forward,
or permanently discontinued CRT because of or associated
with worsening heart failure
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Improved (not worsened as defined above and demonstrated
improvement in NYHA class at last observation carried
forward or had moderate or marked improvement in patient
global assessment score at last observation carried forward)
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Unchanged (the patient was neither improved nor worsened)
PROSPECT RESULTS: CCS and LVESV response rates
Chung, E. S. et al. Circulation 2008;117:2608-2616
Copyright ©2008 American Heart Association
Table 5. Sensitivity, Specificity, and Area Under the Curve for Primary End Points
CCS
LVESV
Evaluable
Echocardiography Dyssynchrony Echocardiograms, Sensitivity, Specificity,
P for Sensitivity, Specificity,
P for
Type
Measure
(yield) %
%
%
AUC AUC
%
%
AUC AUC
M mode
Pulsed Doppler
M mode+ Doppler
TDI, published
TDI+SRI
TDI, median value
used as cutoff
SPWMD
71.7
IVMD
92.4
LVFT/RR
85.3
LPEI
94.6
LLWC
60.7
Ts (Lat-Sep)
66.8
Ts-SD
50.0
PVD
81.4
DLC
81.1
Ts-peak
displacement
Ts-peak basal
37.4
82.0
55.4 (48.3–
62.3)
55.2 (48.9–
61.4)
36.3 (30.2–
42.7)
66.3 (60.2–
72.0)
6.3 (3.2–
11.0)
42.4 (34.4–
50.7)
74.1 (65.2–
81.8)
67.6 (60.3–
74.3)
41.7 (34.4–
49.2)
54.8 (43.5–
65.7)
51.9 (44.4–
50.0 (39.1–
60.9)
56.4 (46.9–
65.6)
76.6 (67.5–
84.3)
47.1 (38.0–
56.4)
91.7 (82.7–
96.9)
56.9 (44.7–
68.6)
35.3 (22.4–
49.9)
37.8 (27.8–
48.6)
60.4 (49.6–
70.5)
56.1 (39.7–
71.5)
53.8 (43.1–
0.54 0.27 63.6 (54.8–
71.8)
0.58 0.013 59.7 (51.5–
67.6)
0.57 0.032 41.0 (32.9–
49.5)
0.60 0.001 72.0 (64.3–
78.8)
0.52 0.63 9.5 (4.7–
16.8)
0.50 0.85 52.6 (42.1–
63.0)
0.60 0.034 77.5 (66.0–
86.5)
0.51 0.89 67.8 (58.6–
76.1)
0.51 0.75 43.6 (34.4–
53.1)
0.56 0.32 58.0 (43.2–
71.8)
0.55 0.19 52.1 (42.8–
52.1 (41.6–
62.4)
54.1 (44.8–
63.2)
74.1 (65.0–
81.9)
42.4 (33.6–
51.6)
92.9 (85.3–
97.4)
69.2 (57.8–
79.2)
30.6 (19.6–
43.7)
34.4 (25.0–
44.8)
59.4 (48.9–
69.3)
54.5 (38.8–
69.6)
55.7 (45.2–
0.62 0.003
0.59 0.009
0.60 0.007
0.59 0.014
0.50 0.98
0.61 0.012
0.55 0.35
0.55 0.30
0.51 0.75
0.57 0.25
0.57 0.10
Sensitivity
Area Under the Curve
Odds ratios for
a binary marker
1-Specificity
PROSPECT Conclusions
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Echocardiographic measures of dyssynchrony
aimed at improving patient selection criteria for
CRT did not have a clinically relevant impact on
improving response rates
Echocardiographic parameters assessing
dyssynchrony do not have enough predictive
value to be recommended as selection criteria for
CRT beyond current indications
Current ACC/AHA/NASPE 2005
Guideline Update
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Patients with LVEF 35%, sinus rhythm,
and New York Heart Association functional
class III or ambulatory class IV symptoms
despite recommended optimal medical
therapy and who have cardiac
dyssynchrony, which is currently defined as
a QRS duration >120 ms, should receive
CRT unless contraindicated (Class: I, Level
of Evidence: A).
Other roles for Echo in CRT
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Assess LVEF
Assess pre- and post-valvular regurgitation
Assess best location of lead placement
Future directions
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>30% non-responders consistent through most
trials
Studies should aim to characterize the nonresponders