Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction Robert O. Bonow, MD April 4, 2011 On behalf

1. Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction Robert O. Bonow, MD April 4, 2011 On behalf of the STICH Trial Investigators

2. STICH Financial Disclosures

3. Background • LV 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 CABG • Numerous 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 status • No (or inadequate) adjustment for key baseline variables (age, comorbidities) • Cohort 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 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 eligible for CABG.

6. STICH Revascularization Hypothesis • Hypothesis of viability testing: • In patients with CAD and LV dysfunction, assessment of myocardial viability will identify those patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy

7. STICH Revascularization Hypothesis Viability testing: • All randomized patients were eligible for viability testing with SPECT myocardial perfusion imaging or dobutamine echo. • Viability testing was optional at enrolling sites using established SPECT and DE viability protocols.

8. STICH Revascularization Hypothesis • SPECT protocols: • Thallium-201 stress-redistribution-reinjection • Thallium-201 rest-redistribution • Nitrate-enhanced Tc-99m perfusion imaging • Dobutamine echo protocols: • Staged increase in dobutamine starting at 5 μg/kg/min • Prespecified definition of viability: • SPECT: 17 segment model; ≥11 segments manifesting • viability based on relative tracer activity • DE: 16 segment model; ≥5 segments with dysfunction • at rest manifesting contractile reserve with dobutamine

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

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

11. Patients randomized in STICH Revascularization Hypothesis 1212 SPECT n=471 Dobutamine echo n=280 150 321 130 Patients with no usable myocardial viability test 611 Patients with usable myocardial viability test 601 114 Nonviable 487 Viable

12. 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

13. Baseline Characteristics Patients With and Without Myocardial Viability LVEF LVEDVI LVESVI Previous MI p<0.001 p<0.001 p<0.001 p<0.001 100 50 200 180 80 40 160 140 30 120 60 100 Percent Ejection Fraction (%) LV Volume Index (ml / m2) 40 20 80 60 20 10 40 20 0 0 0 With myocardial viability Without myocardial viability

14. Myocardial Viability and Mortality 1.0 Without viability With viability Variables associated with mortality 0.8 HR 95% CI P 0.64 0.48,0.86 0.003 0.6 Mortality Rate 0.4 0.2 0.0 0 1 2 3 4 5 6 Years from Randomization Without viability With viability 114 99 85 80 63 36 16 487 432 409 371 294 188 102

15. Myocardial Viability and Mortality

16. Myocardial Viability and Cardiovascular Mortality 1.0 Without viability With viability 0.8 HR 95% CI P 0.61 0.44,0.84 0.003 0.6 Cardiovascular Mortality Rate 0.4 0.2 0.0 0 1 2 3 4 5 6 Years from Randomization Without viability With viability 114 99 85 80 63 36 16 487 432 409 371 294 188 102

17. Myocardial Viability and Mortality + CV Hospitalization 1.0 Without viability With viability 0.8 HR 95% CI P 0.59 0.47,0.44 <0.001 0.6 Mortality and CV Hospitalization Rate 0.4 HR 95% CI P 0.59 0.47,0.44 <0.001 0.2 0.0 0 1 2 3 4 5 6 Years from Randomization Without viability With viability 114 56 41 34 22 14 5 487 327 284 238 166 94 41

18. Patients with viability tests 601 Patients with myocardial viability 487 114 Patients without myocardial viability 243 244 60 54 CABG 47.4% MED 49.9% CABG 50.1% MED 52.6%

19. Baseline Characteristics * * * Significant covariates in risk model: Age, renal function, heart failure, ejection fraction, CAD index, MR, stroke

20. Myocardial Viability and Mortality Without Viability With Viability 1.0 MED (95 deaths) CABG (83 deaths) MED (33 deaths) CABG (25 deaths) 0.8 0.6 Mortality Rate 0.4 0.2 0.0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years from Randomization Years from Randomization 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

21. Myocardial Viability and Mortality Without Viability With Viability 1.0 MED (95 deaths) CABG (83 deaths) MED (33 deaths) CABG (25 deaths) 0.8 0.6 Mortality Rate 0.4 0.2 0.0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Years from Randomization Years from Randomization Subgroup Without viability With viability N Deaths HR 95% CI 114 58 0.70 0.41, 1.18 487 178 0.86 0.64, 1.16 Interaction P value 0.528 0.25 0.5 1 2 CABG better MED better

22. Interaction of Viability and Treatment on CV Outcomes

23. Limitations • Lack of viability data on all patients; patients represent a subpopulation of STICH • Analysis limited to SPECT and DE, not PET or cardiac MRI • Fundamental differences in viability information provided by SPECT and DE, and differences in analytic methods between the two methods

24. STICH Revascularization Hypothesis • STICH 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

25. STICH Revascularization Hypothesis STICH results: • …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.

26. STICH Revascularization Hypothesis • Implications of STICH: • 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