Prospective Randomized Comparison of Prospective Randomized Comparison of Conventional Stress Echocardiography with Conventional Stress Echocardiography with Real Time Perfusion Stress Echocardiography Real Time Perfusion Stress Echocardiography in Predicting Clinical Outcome in Predicting Clinical Outcome
University of Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NEOmaha, NE
Disclosure
• Thomas R Porter, MD has the following conflict of interests to disclose:
• Grant Support – General Electric Global Healthcare; Astellas Pharma, Inc., Lantheus Medical Imaging, Philips Healthcare
• Equipment Support – Philips Healthcare• GE Global Healthcare
Background• Conventional Stress Echocardiography (CSE):
– Compares wall motion during rest and stress echocardiography
– Ultrasound contrast • Used for FDA Approved Indication• 2 or more contiguous segments not visualized
Real time Myocardial Contrast Echo (RTMCE)
• Improve left ventricular opacification• Real time myocardial perfusion
– Perfusion and Wall Motion• Improves Detection of CAD• Improves Predictive Power of Stress Echo
• No prospective comparison with conventional stress echo (CSE) performed.
Objective• Prospectively compare the ability of CSE and
RTMCE to predict outcome of patients referred for suspicion of coronary artery disease, and who are at intermediate risk
Secondary Objectives
• Determine what effect RTMCE and CSE had on prediction of revascularization, death, or non-fatal MI
• Determine what effect training experience with contrast imaging had on the predictive value of either CSE or RTMCE.
Study Design
Six Month Intervals
Exclusion Criteria
• Hypersensitivity to Ultrasound Contrast Agent• Pregnant or breast feeding• Low probability of CAD• Ventricular Paced Rhythm/Pacemaker
Dependent
Methods• For RTMCE and CSE (when indicated)
– Definity (Lantheus Medical )• 3% intravenous continuous infusion at 4 to 6 ml/min
under resting conditions and during stress
Real Time MCE– Siemens Acuson Sequoia (Contrast Pulse Sequencing)– Philips iE 33 or Sonos 5500 system (Power Modulation
Conventional Stress EchoCSE
High mechanical Index Harmonic Imaging (60 Hz)Intermediate MI (If Reduced Visualization in Two Contiguous Segments
Image Analysis17 segment model
• CSE and RTMCE– Wall motion (CSE)– Perfusion and wall motion (RTMCE)– analyzed simultaneously during the replenishment phase
of contrast following brief high MI impulses – Normal
• four seconds replenishment during rest• two seconds during stress
A2C
Pre Flash Immediate post flash 1 second post flash 2 second post flash
Five Independent Reviewers
• Experienced Reviewer (R1)-interpreted>1000 contrast studies for left ventricular opacification and perfusion
• Less Experienced Reviewers (R2; n=4) Interpreted >100 contrast studies for left ventricular opacification and perfusion
Study end point
• Primary end point: Death or non-fatal MI–Revascularization: Time Dependent Co-
variate• Secondary end point: death, non-fatal
MI, and subsequent revascularization
Statistical Analysis
• Patient characteristics – compared with chi-square tests, or t-tests as
appropriate• Survival distributions
– Kaplan and Meier estimates– log-rank test.
• Cox proportional hazards regression – univariate/multivariate predictors– Full multivariate and backward selected model
Study Population
Patient Characteristics Total (n=2063) CSE (n=1035) RTMCE (n=1028) P-value
Age: mean (SD) 59.6 (12.5) 59.4 (12.8) 59.8 (12.2) 0.43
Female 1069 (52%) 544 (53%) 525 (51%) 0.5
Family Hx of CAD 688 (33%) 344 (33%) 344 (33%) 0.91
Non smoker 1351 (65%) 681 (66%) 670 (65%) 0.84
Diabetes 533 (26%) 262 (25%) 271 (26%) 0.59
HTN 1268 (61%) 628 (61%) 640 (62%) 0.46
Patient Characteristics Total (n=2063) CSE (n=1035) RTMCE (n=1028) P-value
Hyperlipidemia 1112 (54%) 529 (51%) 583 (57%) 0.011
Previous PCI 241 (12%) 99 (10%) 142 (14%) 0.0027
Previous MI 192 (9%) 84 (8%) 108 (11%) 0.062
Ejection Fraction (%) 59.4 (9.2) 60.2 (9.0) 58.6 (9.3) <0.001
Anti-platelet (Plavix) 118 (6%) 53 (5%) 65 (6%) 0.24
Beta blockers 833 (40%) 394 (38%) 439 (43%) 0.032
Resting wall motion abnormality 250 (12%) 114 (11%) 146 (14%) <0.001
Abnormal Result 536 (26%) 225 (22%) 311 (30%) <0.001
Prop
ortio
n
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Years0 1 2 3 4 5
Test result CENSOR FAIL TOTAL MEDIANNormal RTMCE or CSE 1451 62 1513 .
Abnormal RTMCE or CSE 497 36 533 4.55
Test: p=0.038
Event-free SurvivalDeath/Non Fatal MI
CSE/RTMCE Combined
CSE 209 15 224 4.55
RTMPE 288 21 309 .
Prop
ortio
n
0.0
0.10.20.3
0.40.50.6
0.7
0.8
0.9
1.0
Years0 1 2 3 4 5
Technique used CENSOR FAIL TOTAL MEDIAN
Test: p=0.88
Event-free SurvivalIn patients with an Abnormal RTMCE vs CSE
Technique used CENSOR FAIL TOTAL MEDIAN
CSE 769 33 802 .RTMPE 682 29 711 .
Prop
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Years0 1 2 3 4
Test: p=0.87
Event-free SurvivalIn patients with a Normal RTMCE vs CSE
Prop
ortio
n
0.0
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Years0 1 2 3 4 5
RWMA CENSOR FAIL TOTAL MEDIAN
Negative 846 34 880 .Positive 128 16 144 .
Test: p<0.001
RTMCE –Resting Wall Motion Abnormality
Years
RWMA CENSOR FAIL TOTAL MEDIAN
Negative 876 41 917 .
Positive 108 7 115 4.55
Prop
ortio
n
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Test: p=0.71
CSE- Resting Wall Motion Abnormality
Test result CENSORFAIL TOTALMEDIANNormal RTMCE or CSE 571 34 605 .
Abnormal RTMCE or CSE 183 12 195 .
Prop
ortio
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Years0 1 2 3 4 5
Test: p=0.73Prop
ortio
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0.3
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0.6
0.7
0.8
0.9
1.0
Years0 1 2 3 4 5
Test: p=0.011
Test result CENSOR FAIL TOTAL
Normal RTMCE or CSE 880 28 908 .
Abnormal RTMCE or CSE 314 24 338
Event-free survival, Less Experienced ReviewersEvent-free survival, Experienced Reviewer
Death/Non Fatal MI Death/Non Fatal MI
YearsTechnique used CENSOR FAIL TOTAL MEDIAN
CSE 732 50 782 .RTMPE 658 41 699 .
Prop
ortio
n
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1.0
0 1 2 3 4
Test: p=0.85
YearsTechnique used CENSOR FAIL TOTAL MEDIAN
CSE 178 45 223 .RTMPE 211 95 306 .
Prop
ortio
n0.0
0.1
0.2
0.3
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0.6
0.7
0.8
0.9
1.0
0 1 2 3 4
Test: p=0.0045
Normal CSE vs Normal RTMCE Abnormal CSE vs Abnormal RTMCE
Secondary End Point
Univariate and multivariate models of EFS (death+MI)
Univariate Full MultivariateBackward selected
model
95% CI 95% CI 95% CI
Variable HR Lower Upper
p-value
HR Lower Upper
p-value
HR Lower Upper
p-value
RTMCE vs. CSE 1.12 0.75 1.67 0.57 1.01 0.66 1.55 0.95 1.06 0.71 1.58 0.77
Age >70 vs. <=70 1.48 0.96 2.30 0.079 1.44 0.92 2.25 0.11 1.47 0.95 2.28 0.087
EF < 50 vs. >=50 1.70 0.98 2.94 0.060 1.13 0.58 2.22 0.72
Prior revascularization 1.55 0.98 2.46 0.061 1.17 0.71 1.94 0.55
Diabetes 1.31 0.86 2.00 0.21
Resting WMA Yes vs No 2.01 1.25 3.24 0.004 1.68 0.87 3.22 0.12 1.97 1.23 3.18 0.005ECHO result Abnormal vs. Normal 1.55 1.02 2.34 0.040
Summary• Abnormal studies are more frequently detected
with RTMCE when compared to CSE, and more frequently lead to revascularization
• A resting wall motion abnormality during RTMCE is the most powerful predictor of outcome
• Negative predictive value of a dobutamine or exercise SE, when performed with RTMCE versus CSE, is not different.
Limitations• Reviewer experience/training
– Critical for contrast use for CSE and RTMCE• CSE results may be different if contrast not
utilized. – Contrast Use was >60% for CSE in this study
• Baseline Differences Between Groups
Conclusions
• Both RTMCE and CSE (with 60% contrast use) have excellent negative predictive value
• RTMCE –Combined Perfusion and WM–Can detect high risk patients–Potentially Alter Their Outcome