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

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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 .

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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 .

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Test: p=0.87

Event-free SurvivalIn patients with a Normal RTMCE vs CSE

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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

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CSE- Resting Wall Motion Abnormality

Test result CENSORFAIL TOTALMEDIANNormal RTMCE or CSE 571 34 605 .

Abnormal RTMCE or CSE 183 12 195 .

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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 .

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YearsTechnique used CENSOR FAIL TOTAL MEDIAN

CSE 178 45 223 .RTMPE 211 95 306 .

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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