1. Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction Robert O. Bonow, MD On behalf of the STICH Trial Investigators Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction Robert O. Bonow, MD On behalf of the STICH Trial Investigators

2. STICH Financial Disclosures Funding Sources: National Heart, Lung and Blood Institute 98% Abbott Laboratories 2% Original Recipient Institution Principal Investigator Activity Duke University Medical Center Robert H. Jones Clinical Coordinating Ctr Duke University Medical Center Kerry L. Lee Statistical and Data CC Northwestern University Robert O. Bonow Radionuclide Core Lab Washington Hospital Center Julio A. Panza Dobutamine Echo Core Mayo Clinic Jae K. Oh Echo Core Laboratory Univ of Alabama-Birmingham Gerald M. Pohost CMR Core Laboratory University of Pittsburgh Arthur M. Feldman NCG Core Laboratory Baylor University Medical Ctr Paul Grayburn MR TEE Substudy Duke University Medical Center Daniel B. Mark EQOL Core Laboratory

3. Background LV dysfunction in patients with CAD is not always an irreversible process, as LV function may improve substantially after CABGLV dysfunction in patients with CAD is not always an irreversible process, as LV function may improve substantially after CABG Assessment of myocardial viability is often used to predict improvement in LV function after CABG and thus select patients for CABGAssessment of myocardial viability is often used to predict improvement in LV function after CABG and thus select patients for CABG Numerous studies have suggested that identification of viable myocardium also predicts improved survival after CABGNumerous studies have suggested that identification of viable myocardium also predicts improved survival after CABG

4. Limitations of Cohort Studies Decision for CABG may have been influenced by viability statusDecision for CABG may have been influenced by viability status No (or inadequate) adjustment for key baseline variables (age, comorbidities)No (or inadequate) adjustment for key baseline variables (age, comorbidities) Cohort studies carried out before modern aggressive medical therapyCohort studies carried out before modern aggressive medical therapy

5. STICH Revascularization Hypothesis The first prospective randomized trial testing the hypothesis that CABG improves survival in patients with ischemic LV dysfunction compared to outcome with aggressive medical therapyThe first prospective randomized trial testing the hypothesis that CABG improves survival in patients with ischemic LV dysfunction compared to outcome with aggressive medical therapy Provides the first opportunity to assess the interaction between myocardial viability and survival in randomized patients who were all eligible for medical management alone and also eligible for CABG.Provides the first opportunity to assess the interaction between myocardial viability and survival in randomized patients who were all eligible for medical management alone and also eligible for CABG.

6. STICH Viability Hypothesis In this prospective substudy, we tested the hypothesis that assessment of myocardial viability identifies patients with CAD and LV dysfunction who have the greatest survival benefit with CABG compared to aggressive medical therapy In this prospective substudy, we tested the hypothesis that assessment of myocardial viability identifies patients with CAD and LV dysfunction who have the greatest survival benefit with CABG compared to aggressive medical therapy

7. STICH Viability Hypothesis All randomized patients were eligible for viability testing with SPECT myocardial perfusion imaging or dobutamine echo.All randomized patients were eligible for viability testing with SPECT myocardial perfusion imaging or dobutamine echo. Viability testing was optional at enrolling sites and was not a prerequisite for enrollment.Viability testing was optional at enrolling sites and was not a prerequisite for enrollment.

8. STICH Viability Hypothesis SPECT protocols: Thallium-201 stress-redistribution-reinjection Thallium-201 stress-redistribution-reinjection Thallium-201 rest-redistribution Thallium-201 rest-redistribution Nitrate-enhanced Tc-99m perfusion imaging Nitrate-enhanced Tc-99m perfusion imaging Dobutamine echo protocols: Staged increase in dobutamine starting at Staged increase in dobutamine starting at 5 μg/kg/min 5 μg/kg/min

9. STICH Viability Hypothesis Criteria for myocardial viability were prospective and pre-specified SPECT: 17 segment model17 segment model ≥11 segments manifesting viability based on relative tracer activity≥11 segments manifesting viability based on relative tracer activity Dobutamine echo: 16 segment model16 segment model ≥5 segments with dysfunction at rest manifesting contractile reserve with dobutamine≥5 segments with dysfunction at rest manifesting contractile reserve with dobutamine

10. STICH Viability Hypothesis Primary endpoint: ▪ All-cause mortality ▪ All-cause mortality Secondary endpoints: ▪ Mortality plus cardiovascular hospitalization ▪ Mortality plus cardiovascular hospitalization ▪ Cardiovascular mortality ▪ Cardiovascular mortality Intention-to-treat analysis

11. Patients randomized in STICH Revascularization Hypothesis 1212 Patients with no myocardial viability test 594 Patients with myocardial viability test 611 Patients with usable myocardial viability test Patients with no usable myocardial viability test 17 Unusable test Timing Poor quality 601 618

12. 1212 150321130 611 SPECT n=471 Dobutamine echo n=280 114 Nonviable 487 Viable Patients with no usable myocardial viability test Patients with usable myocardial viability test Patients randomized in STICH Revascularization Hypothesis 601

13. Variable Viable (n=487) Non-Viable (n=114)P value Age61 ± 10 61 ± 9 NS Multivessel CAD73% NS Proximal LAD stenosis64%70%NS Risk score12.4 ± 8.712.9 ± 9.3NS Previous MI76.6%94.7%<0.001 LV ejection fraction (percent)28 ± 823 ± 9<0.001 LV end-diastolic volume index (ml/m 2 )117 ± 37147 ± 53<0.001 LV end-systolic volume index (ml/m 2 ) 86 ± 33116 ± 50<0.001 Baseline Characteristics Patients With and Without Myocardial Viability * * Significant covariates in risk model: Age, renal function, heart failure, ejection fraction, CAD index, mitral regurgitation, stroke

14. Myocardial Viability and Mortality 1.0 0.8 0.6 0.4 0.2 0.0 Mortality Rate Years from Randomization 01 2 3 456 Without viability With viability 114 99 85 80 63 36 16 487 432 409 371 294 188 102 HR 95% CI P 0.64 0.48,0.86 0.003 Without viability With viability Variables associated with mortality Chi-squarep Risk score33.26<0.001 LV ejection fraction24.80<0.001 LV EDVI35.36<0.001 LV ESVI33.90<0.001 Myocardial viability 8.54 0.003 50% 33%

15. VariableNo. UnivariateMultivariableChi-square p value Chi-square SPECT and/or DE 6018.540.0031.570.210 SPECT alone 4717.350.0070.580.444 DE alone 2801.180.2770.420.518 Myocardial Viability and Mortality

16. 1.0 0.8 0.6 0.4 0.2 0.0 Years from Randomization 01 2 3 456 HR 95% CI P 0.61 0.44,0.84 0.003 Cardiovascular Mortality Rate Without viability With viability Without viability With viability Myocardial Viability and Cardiovascular Mortality UnivariateMultivariable Chi-squarep valueChi-squarep value 8.810.0030.910.339 114 99 85 80 63 36 16 487 432 409 371 294 188 102 43% 29%

17. 1.0 0.8 0.6 0.4 0.2 0.0 Years from Randomization 01 2 3 456 Without viability With viability Mortality and CV Hospitalization Rate 114 56 41 34 22 14 5 487 327 284 238 166 94 41 HR 95% CI P 0.59 0.47,0.44 <0.001 Without viability With viability Myocardial Viability and Mortality + CV Hospitalization UnivariateMultivariable Chi-squarep valueChi-squarep value 20.27<0.0018.600.003 HR 95% CI P 0.59 0.47,0.74 0.001 82% 63%

18. Patients with viability tests 601 Patients without myocardial viability Patients with myocardial viability 487114 244243 CABG50.1% CABG47.4% MED49.9% 54 MED52.6% 60

19. Baseline Characteristics * * Significant covariates in risk model: Age, renal function, heart failure, ejection fraction, CAD index, MR, stroke Variable Non-Viable (n=114) P value MED (n=60) CABG (n=54) Age62 ± 9 60 ± 9 NS Gender (% male)92%93%NS Previous MI93%96%NS Multivessel CAD68%78%NS Proximal LAD70% NS Risk score13.7 ± 9.812.9 ± 9.3NS LV EF (percent)23 ± 9 NS LV EDVI (ml/m 2 )151 ± 51140 ± 54NS LV ESVI (ml/m 2 )121 ± 50111 ± 51NS Variable Viable (n=487) P value MED (n=243) CABG (n=244) Age60 ± 1062 ± 9 NS Gender (% male)84%86%NS Previous MI78%75%NS Multivessel CAD72%73%NS Proximal LAD65%63%NS Risk score11.9 ± 8.412.8 ± 903NS LV EF (percent)28 ± 827± 8NS LV EDVI (ml/m 2 )118 ± 38116 ± 35NS LV ESVI (ml/m 2 ) 86 ± 34 86 ± 32NS *

20. Myocardial Viability and Mortality 1.0 0.8 0.6 0.4 0.2 0.0 Mortality Rate Years from Randomization 0123456012 3 4 5 6 MED (33 deaths) CABG (25 deaths) MED (95 deaths) CABG (83 deaths) MED CABG 60 51 44 39 29 14 4 243 219 206 179 146 94 51 54 48 41 41 34 22 12 244 213 203 192 148 94 51 With ViabilityWithout Viability 56% 42% 35% 31%

21. Myocardial Viability and Mortality 1.0 0.8 0.6 0.4 0.2 0.0 Mortality Rate Years from Randomization 0123456012 3 4 5 6 MED (33 deaths) CABG (25 deaths) MED (95 deaths) CABG (83 deaths) Subgroup Subgroup Without viability Without viability With viability With viability N Deaths HR 95% CI N Deaths HR 95% CI 114 58 0.70 0.41, 1.18 487 178 0.86 0.64, 1.16 1 20.50.25 CABG better MED better Without ViabilityWith Viability Interaction P value 0.528 56% 42% 35% 31%

22. EndpointEventsTreatment p value Mortality236 As randomized 0.528 As treated 0.962 Mortality or CV hospitalization 422 As randomized 0.390 As treated 0.975 CV mortality 187 As randomized 0.697 As treated 0.261 Interaction of Viability and Treatment on CV Outcomes

23. Lack of viability data in all patients; patients represent a subpopulation of STICH Analysis limited to SPECT and dobutamine echo, not PET or cardiac MRIAnalysis limited to SPECT and dobutamine echo, not PET or cardiac MRI STICH Viability Hypothesis Limitations:

24. STICH represents the largest report to date relating myocardial viability to clinical outcomes of patients with CAD and LV dysfunctionSTICH represents the largest report to date relating myocardial viability to clinical outcomes of patients with CAD and LV dysfunction … and is the first to assess these relationships prospectively among patients who were all eligible for CABG as well as optimal medical management alone… and is the first to assess these relationships prospectively among patients who were all eligible for CABG as well as optimal medical management alone

25. STICH Viability Hypothesis …demonstrate a significant association between myocardial viability and outcome, but this association is rendered non-significant when subjected to a multivariable analysis that includes other prognostic variables. …fail to demonstrate a significant interaction between myocardial viability and medical versus surgical treatment with respect to mortality, whether assessed according to treatment assigned (intention to treat) or to the treatment actually received. STICH results:

26. STICH Viability Hypothesis Implications: In patients with CAD and LV dysfunction, assessment of myocardial viability does not identify patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy Full report available at www.NEJM.org