Results of the Predictors of Response to CRT
(PROSPECT) Trial
Chung ES, Leon AR, Tavazzi L, Sun J-P, Nihoyannopoulos P,
Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu C-M,
Gorcsan J 3rd, St John Sutton M, De Sutter J, Murillo J,
Circulation. 2008;117:2608-2616.
Introduction
– Cardiac Resynchronization Therapy (CRT) improves
quality of life and functional status, reduces heart
failure related hospitalizations, and prolongs survival
in systolic heart failure patients with NYHA Class III or
ambulatory NYHA Class IV symptoms and a wide
QRS.
• Strong clinical mandate for CRT in eligible patients by
practice guidelines
– Majority of patients treated with CRT show clinical
benefit, but some considered non-responders using
various measures of clinical responsiveness.
– Several echocardiographic measures of mechanical
dyssynchrony have identified responders pre-implant
Chung, E. Circulation. 2008;117:2608-2616.
PROSPECT Study
Purpose:
– Prospective, multi-center study designed to evaluate the ability of
selected, pre-defined baseline echocardiographic parameters to
predict clinical or echocardiographic response to CRT in a
prospective, multi center study
Primary Endpoints at 6 months:
– Clinical Composite Score
•
•
–
Subjective and objective measures of clinical status include:
Survival, heart failure hospitalization, change in NYHA Class and
change in Patient Global Assessment Score
Definition of Improved: Has not Worsened (death, HF
hospitalization, worsening NYHA Class) and demonstrates
improvement in NYHA Class and/or improvement in patient global
assessment score
Left Ventricular End-Systolic Volume
•
Definition of Improved: Reduction of ≥ 15%
Chung, E. Circulation. 2008;117:2608-2616.
12 Predefined Echo Measures of Dyssynchrony
(will report on measures with arrow)
Standard Echo
 SPWMD Septal to posterior wall motion delay (≥ 130 ms)
IVMD Interventricular mechanical delay (≥ 40 ms)
 LPEI LV pre-ejection interval (≥ 140 ms)
LVFT/RR LV filling time as % of cardiac cycle length (R-R interval) (≤40%)
LLWC Left lateral wall contraction (any overlap)
Tissue Doppler Imaging
 Ts- (lateral-septal) Time Δ between basal lateral and septal peak (≥60 ms)
 Ts-SD Standard deviation of time to peak systolic velocity (≥ 32 ms)
PVD Peak velocity difference (≥ 110 ms)
 DLC Delayed longitudinal contraction (≥ 2 segments)
TD Maximum difference in time to peak displacement (median)
Ts-peak Maximum Δ in time to peak systolic velocity (median)
Ts-onset Maximum Δ in time to onset of systolic velocity (median)
Chung, E. Circulation. 2008;117:2608-2616.
Echocardiography Equipment and
Core Labs
Philips
Core
labs
Equipment
GE
Siemens
Atlanta, US
London, UK
Pavia, IT
Atlanta, US
Pavia, IT
Atlanta, US
London, UK
Sonos 5500,
7500, or
IE33. TDI:
QLAB version
1.0, updated
throughout to
version 4.1
Echopac
standalone
workstation
V4.0.4 or
Vivid 7,
version
3.2.6
Utilization by Vendor
37%
GE
TDI
analyzed
with Tomtec
version 1.0,
but not used
in analysis
Siemens
12%
Aloka
Philips
50%
Chung, E. Circulation. 2008;117:2608-2616.
Training and Quality Control
Center
• Each enrolling center was trained on protocol and image acquisition,
and was accredited by core lab prior to patient enrollment.
• Any subsequent studies judged by core lab to be of insufficient
quality were censored and not included in the analysis
Core Lab
• Echo core labs followed internal echocardiographic measurement
guidelines created and reviewed by experts and the Steering
Committee.
• Echo core labs were blinded to CRT response
• Independent Echo Review Committee visited core labs to ensure
measurement consistency and adherence to protocols prior to
statistical analysis
Chung, E. Circulation. 2008;117:2608-2616.
Baseline Characteristics
Characteristic
Total Subjects
(N=426)
Age
68 ± 11yrs
Male
71%
NYHA (Class III)
96%
QRS duration
LVEF
163 ± 22 ms
24 ± 7 %
Ischemic
54%
LBBB
6 MHW
77%
274 ± 122 m
Using Diuretics
83 %
Using β-blocker
85 %
Using ACE-i/ARB
92 %
Chung, E. Circulation. 2008;117:2608-2616.
Primary Endpoint Results for All Patients
at 6 Months
Percent of Patients
100%
Clinical Composite
Response
N = 426
100%
Change in LVESV
N = 286
69%
50%
50%
56%
35%
15%
0%
16%
9%
0%
Improved
.
UnWorsened
changed
% Improved
Ischemic
Non-Ischemic
64%
75%
P = 0.01
.
≥ 15%
Reduction
Other
≥ 15%
Increase
% with ≥ 15% Reduction
Ischemic
Non-Ischemic
50%
63%
P = 0.03
Chung, E. Circulation. 2008;117:2608-2616.
Feasibility of Dyssynchrony Measures
Available Measurable
Images
Images
Method
Measure
Doppler
TDI
M-mode
LPEI
DLC
SPWMD
407
334
407
385
271
292
%
95
81
72
TDI
Ts Lat-Sep
334
223
67
TDI
Ts-SD
334
167
50
Chung, E. Circulation. 2008;117:2608-2616.
Primary Endpoint Results
Selected Echo Measures
Clinical Composite Response
72%
67%
SPWMD
P-value
0.44
73%
0.013
61%
LPEI
Ts LatSep (Bax)
67%
68%
1.00
72% 0.27
63%
Ts-SD
(Yu)
DLC
(Sogaard)
68%
66%
0%
50%
% Improved
LVESV
0.79
100%
■ Cut-off Met
65%
49%
61%
45%
68%
P-value
0.021
0.016
45%
0.005
56%
46%
0.33
57%
54%
0.68
0%
50%
100%
% with ≥ 15% Reduction
■ Cut-off Not Met
Chung, E. Circulation. 2008;117:2608-2616.
Inter-observer Variability
London
UK
Philips
10
10
LPEI
Pavia
Italy
6
Ts-SD (Yu)
96
280
Atlanta
US
GE
6
SPWMD (Pitzalis)
140
64
Lab 2 (ms)
Lab 2 (ms)
Lab 2 (ms)
260
32
0
0
0
140
280
0
0
32
64
96
Lab 1 (ms)
Lab 1 (ms)
Coef. of Variation: 6.5%
Kappa Coefficient: 0.67
Coef. of Variation: 33.7%
Kappa Coefficient: 0.15
Chung, E. Circulation. 2008;117:2608-2616.
130
0
130
260
Lab 1 (ms)
Coef. of Variation: 72.1%
(not displayed)
Kappa Coefficient: 0.35
Sensitivity and Specificity:
Area Under the ROC Curve
• Clinical Composite Response: Range from 0.50
to 0.60
• LVESV: Range from 0.51 to 0.62
ROC Curve
100.0
100.0
80.0
80.0
60.0
60.0
Sensitivity (%)
Sensitivity (%)
ROC Curve
40.0
20.0
0.0
0.0
40.0
20.0
20.0
40.0
60.0
80.0
1 - Specificity (%)
Clinical Composite Response
Ts-SD AUC = 0.60
100.0
0.0
0.0
20.0
40.0
60.0
80.0
100.0
1 - Specificity (%)
LVESV
SPWMD AUC = 0.62
Chung, E. Circulation. 2008;117:2608-2616.
Discussion
• Dyssynchrony is a complex issue, not a matter of one
single measurement. Echo parameters that may be
considered attractive candidates for further studies
point at different components of cardiac dyssynchrony
(inter-, intra-, and A-V dyssynchrony). A general
assessment might be warranted.
• PROSPECT data may be useful to understand how to
better standardize procedures and reduce variability of
echo assessment of dyssynchrony.
Chung, E. Circulation. 2008;117:2608-2616.
Conclusions
The results of the PROSPECT study indicate that no
single echocardiographic measure of dyssynchrony, as
applied in this multi-center study, may be recommended
to further improve patient selection among the CRT
candidates.
Current clinical criteria including electrocardiogram,
remain the standard for CRT patient selection.
Chung, E. Circulation. 2008;117:2608-2616.