1. Prospective Randomized Comparison of Conventional Stress Echocardiography with Real Time Perfusion Stress Echocardiography in Predicting Clinical Outcome University of Nebraska Medical Center, Omaha, NE

2. 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

3. 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

4. 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.

5. 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

6. 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.

7. Study Design Follow up Referring physician’s decision Intervention Consent & Randomization Consecutive patients referred to the echo lab CSE DSEESE RTMCE DSE Six Month Intervals

8. Exclusion Criteria Hypersensitivity to Ultrasound Contrast Agent Pregnant or breast feeding Low probability of CAD Ventricular Paced Rhythm/Pacemaker Dependent

9. 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

10. Real Time MCE –Siemens Acuson Sequoia (Contrast Pulse Sequencing) –Philips iE 33 or Sonos 5500 system (Power Modulation

11. Conventional Stress Echo CSE High mechanical Index Harmonic Imaging (60 Hz) Intermediate MI (If Reduced Visualization in Two Contiguous Segments

12. Image Analysis 17 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

13. A2C Pre Flash Immediate post flash 1 second post flash 2 second post flash

14. 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

15. 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

16. 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

17. Study Population Total Referred Patients Study Period Oct, 2007 - Dec, 2011 DSE - 5030 / ESE - 4298 Total - 9328 Total Patients Consented Oct 2007 - Dec 2011 2063 1035 Randomized to CSE 587 DSE448 ESE 1028 Randomized to RTMCE 627 DSE401 ESE

18. 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%) 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

19. 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

20. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 0 12345 Test result CENSORFAILTOTALMEDIAN Normal RTMCE or CSE 1451 62 1513. Abnormal RTMCE or CSE 497 36 5334.55 Test: p=0.038 Event-free Survival Death/Non Fatal MI CSE/RTMCE Combined

21. CSE 209 15 2244.55 RTMPE 288 21 309. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 012345 Technique used CENSORFAILTOTALMEDIAN Test: p=0.88 Event-free Survival In patients with an Abnormal RTMCE vs CSE

22. Technique used CENSORFAILTOTALMEDIAN CSE 769 33 802. RTMPE 682 29 711. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 01234 Test : p=0.87 Event-free Survival In patients with a Normal RTMCE vs CSE

23. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 012345 RWMACENSORFAILTOTALMEDIAN Negative 846 34 880. Positive 128 16 144. Test: p<0.001 RTMCE –Resting Wall Motion Abnormality

24. Years RWMACENSORFAILTOTALMEDIAN Negative 876 41 917. Positive 108 7 1154.55 Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 012345 Test: p=0.71 CSE- Resting Wall Motion Abnormality

25. Test resultCENSORFAILTOTALMEDIAN Normal RTMCE or CSE 571 34 605. Abnormal RTMCE or CSE 183 12 195. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 012345 Test: p=0.73 Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 01 2 34 5 Test: p=0.011 Test result CENSORFAILTOTAL Normal RTMCE or CSE 880 28 908. Abnormal RTMCE or CSE 314 24 338 Event-free survival, Less Experienced Reviewers Event-free survival, Experienced Reviewer Death/Non Fatal MI

26. Years Technique usedCENSORFAILTOTALMEDIAN CSE 732 50 782. RTMPE 658 41 699. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123 4 Test: p=0.85 Years Technique usedCENSORFAILTOTAL MEDIAN CSE 178 45 223. RTMPE 211 95 306. Proportion 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 01234 Test: p=0.0045 Normal CSE vs Normal RTMCE Abnormal CSE vs Abnormal RTMCE Secondary End Point

27. Univariate and multivariate models of EFS (death+MI) UnivariateFull Multivariate Backward selected model 95% CI Variable HRLowerUpper p-value HRLowerUpper p-value HRLowerUpper p-value RTMCE vs. CSE 1.120.751.670.571.010.661.550.951.060.711.580.77 Age >70 vs. <=70 1.480.962.300.0791.440.922.250.111.470.952.280.087 EF =50 1.700.982.940.0601.130.582.220.72 Prior revascularization1.550.982.460.0611.170.711.940.55 Diabetes 1.310.862.000.21 Resting WMA Yes vs No 2.011.253.240.0041.680.873.220.121.971.233.180.005 ECHO result Abnormal vs. Normal 1.551.022.340.040

28. 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.

29. 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

30. 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