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

STICH Financial Disclosures 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 Duke University Medical Center Daniel B. Mark EQOL Core Laboratory Univ of Alabama-Birmingham Gerald M. Pohost CMR Core Laboratory Mayo Clinic Jae K. Oh ECHO Core Laboratory University of Pittsburgh Arthur M. Feldman NCG Core Laboratory Northwestern University Robert O. Bonow RN Core Laboratory Washington Hospital Center Julio A. Panza DECIPHER Substudy Baylor University Medical Ctr Paul Grayburn MR TEE Substudy Funding Sources: National Heart, Lung and Blood Institute 98% Abbott Laboratories 2%

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 NNumerous studies have suggested that identification of viable myocardium also predicts improved survival after CABG

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

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.

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 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

STICH Revascularization Hypothesis Viability testing: 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 using established SPECT and DE viability protocols.Viability testing was optional at enrolling sites using established SPECT and DE viability protocols.

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

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

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

SPECT n=471 Dobutamine echo n= Nonviable 487 Viable Patients with no usable myocardial viability test Patients with usable myocardial viability test Patients randomized in STICH Revascularization Hypothesis 601

Variable Viable (n=487) Non-Viable (n=114)P value Age61 ± ± 9 NS Multivessel CAD73% NS Proximal LAD stenosis64%70%NS Risk score12.4 ± ± 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 ± ± 53<0.001 LV end-systolic volume index (ml/m 2 ) 86 ± ± 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

Baseline Characteristics Patients With and Without Myocardial Viability Percent 0 Ejection Fraction (%) LV Volume Index (ml / m 2 ) With myocardial viability Without myocardial viability p<0.001 Previous MI LVEFLVEDVILVESVI

Myocardial Viability and Mortality Mortality Rate Years from Randomization Without viability With viability HR 95% CI P , 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

VariableNo. Univariate Multivariable Chi-squarep valueChi-squarep value SPECT and/or DE SPECT alone DE alone Myocardial Viability and Mortality

Years from Randomization HR 95% CI P , Cardiovascular Mortality Rate Without viability With viability Without viability With viability Myocardial Viability and Cardiovascular Mortality UnivariateMultivariable Chi-squarep valueChi-squarep value

Years from Randomization Without viability With viability Mortality and CV Hospitalization Rate HR 95% CI P ,0.44 <0.001 Without viability With viability Myocardial Viability and Mortality + CV Hospitalization UnivariateMultivariable Chi-squarep valueChi-squarep value 20.27< HR 95% CI P ,0.44 <0.001

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

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 ± ± 9.3NS LV EF (percent)23 ± 9 NS LV EDVI (ml/m 2 )151 ± ± 54NS LV ESVI (ml/m 2 )121 ± ± 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 ± ± 903NS LV EF (percent)28 ± 827± 8NS LV EDVI (ml/m 2 )118 ± ± 35NS LV ESVI (ml/m 2 ) 86 ± ± 32NS *

Myocardial Viability and Mortality Mortality Rate Years from Randomization MED (33 deaths) CABG (25 deaths) MED (95 deaths) CABG (83 deaths) MED CABG With ViabilityWithout Viability

Myocardial Viability and Mortality Mortality Rate Years from Randomization 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 , , CABG better MED better Without ViabilityWith Viability Interaction P value 0.528

EndpointEventsTreatmentp value Mortality236 As randomized0.528 As treated0.962 Mortality or CV hospitalization 422 As randomized0.390 As treated0.975 CV mortality187 As randomized0.697 As treated0.261 Interaction of Viability and Treatment on CV Outcomes

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

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

STICH Revascularization 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:

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