Prospective Randomized Comparison of Conventional Stress Echocardiography with Real Time Perfusion Stress Echocardiography in Predicting Clinical Outcome University of Nebraska Medical Center, Omaha, 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 Follow up Referring physician’s decision Intervention Consent & Randomization Consecutive patients referred to the echo lab CSE DSEESE RTMCE DSE 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 Echo CSE High mechanical Index Harmonic Imaging (60 Hz) Intermediate MI (If Reduced Visualization in Two Contiguous Segments

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

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 Total Referred Patients Study Period Oct, Dec, 2011 DSE / ESE Total Total Patients Consented Oct Dec Randomized to CSE 587 DSE448 ESE 1028 Randomized to RTMCE 627 DSE401 ESE

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

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%) 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

Proportion Years Test result CENSORFAILTOTALMEDIAN Normal RTMCE or CSE Abnormal RTMCE or CSE Test: p=0.038 Event-free Survival Death/Non Fatal MI CSE/RTMCE Combined

CSE RTMPE Proportion Years Technique used CENSORFAILTOTALMEDIAN Test: p=0.88 Event-free Survival In patients with an Abnormal RTMCE vs CSE

Technique used CENSORFAILTOTALMEDIAN CSE RTMPE Proportion Years Test : p=0.87 Event-free Survival In patients with a Normal RTMCE vs CSE

Proportion Years RWMACENSORFAILTOTALMEDIAN Negative Positive Test: p<0.001 RTMCE –Resting Wall Motion Abnormality

Years RWMACENSORFAILTOTALMEDIAN Negative Positive Proportion Test: p=0.71 CSE- Resting Wall Motion Abnormality

Test resultCENSORFAILTOTALMEDIAN Normal RTMCE or CSE Abnormal RTMCE or CSE Proportion Years Test: p=0.73 Proportion Years Test: p=0.011 Test result CENSORFAILTOTAL Normal RTMCE or CSE Abnormal RTMCE or CSE Event-free survival, Less Experienced Reviewers Event-free survival, Experienced Reviewer Death/Non Fatal MI

Years Technique usedCENSORFAILTOTALMEDIAN CSE RTMPE Proportion Test: p=0.85 Years Technique usedCENSORFAILTOTAL MEDIAN CSE RTMPE Proportion Test: p= Normal CSE vs Normal RTMCE Abnormal CSE vs Abnormal RTMCE Secondary End Point

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 Age >70 vs. <= EF = Prior revascularization Diabetes Resting WMA Yes vs No ECHO result Abnormal vs. Normal

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