1. Coronary Artery Bypass Graft Surgery in Patients with Ischemic Heart Failure Eric J. Velazquez, MD on behalf of the STICH Investigators April 4, 2011

2. 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 Center Paul Grayburn MR TEE Substudy Funding Sources: National Heart, Lung and Blood Institute97.7% Abbott Laboratories2.3%

3. Background — I Coronary artery disease (CAD) is a major substrate for heart failure (HF) and left ventricular dysfunction (LVD).Coronary artery disease (CAD) is a major substrate for heart failure (HF) and left ventricular dysfunction (LVD). The role of coronary artery bypass graft surgery (CABG) in patients with CAD and HF has not been clearly established.The role of coronary artery bypass graft surgery (CABG) in patients with CAD and HF has not been clearly established.

4. Background — II In the 1970s, RCTs of CABG vs. medical therapy for chronic stable angina excluded patients with severe LVDIn the 1970s, RCTs of CABG vs. medical therapy for chronic stable angina excluded patients with severe LVD  Only 4.0% symptomatic with HF Major advances in surgical care and medical therapy (MED) render previous data obsolete for clinical decision makingMajor advances in surgical care and medical therapy (MED) render previous data obsolete for clinical decision making Observational analyses suggest a role for CABG for HF and LVDObservational analyses suggest a role for CABG for HF and LVD  CABG is increasingly utilized for these patients  Yet, substantial clinical uncertainty remains

5. Surgical Treatment for Ischemic Heart Failure Trial (STICH) Surgical Revascularization Hypothesis In patients with HF, LVD and CAD amenable to surgical revascularization, CABG added to intensive MED will decrease all-cause mortality compared to MED alone.

6. Study Design Randomized controlled trial, non-blindedRandomized controlled trial, non-blinded Investigator-initiated and ledInvestigator-initiated and led National Heart, Lung and Blood Institute fundedNational Heart, Lung and Blood Institute funded Duke Clinical Research Institute managedDuke Clinical Research Institute managed Independent Data and Safety Monitoring CommitteeIndependent Data and Safety Monitoring Committee Clinical Events Adjudication CommitteeClinical Events Adjudication Committee Blinded Core LaboratoriesBlinded Core Laboratories

7. Endpoints Primary Endpoint  All-cause mortality Major Secondary Endpoints  Cardiovascular mortality  Death (all-cause) + cardiovascular hospitalization

8. Statistical Assumptions and Analyses Statistical Assumptions MED mortality of 25% at 3 yearsMED mortality of 25% at 3 years CABG would reduce mortality by 25%CABG would reduce mortality by 25% 20% or fewer crossovers from MED to CABG20% or fewer crossovers from MED to CABG 400 or more deaths400 or more deaths 90% power90% power Planned Analyses Intention to treat (as randomized)Intention to treat (as randomized) Covariate-adjustedCovariate-adjusted As treatedAs treated  Time-dependent Per protocolPer protocol

9. Important Inclusion Criteria LVEF ≤ 0.35 within 3 months of trial entryLVEF ≤ 0.35 within 3 months of trial entry CAD suitable for CABGCAD suitable for CABG MED eligibleMED eligible  Absence of left main CAD as defined by an intraluminal stenosis of ≥ 50%  Absence of CCS III angina or greater (angina markedly limiting ordinary activity)

10. Major Exclusion Criteria Recent acute MI (within 30 days)Recent acute MI (within 30 days) Cardiogenic shock (within 72 hours of randomization)Cardiogenic shock (within 72 hours of randomization) Plan for percutaneous interventionPlan for percutaneous intervention Aortic valve disease requiring valve repair or replacementAortic valve disease requiring valve repair or replacement Non-cardiac illness with a life expectancy of less than 3 years or imposing substantial operative mortalityNon-cardiac illness with a life expectancy of less than 3 years or imposing substantial operative mortality

11. 1212 Randomized CABG Randomized MED only 610602 STICH Revascularization Hypothesis 99 clinical sites in 22 countries99 clinical sites in 22 countries Enrollment: July 2002 – May 2007Enrollment: July 2002 – May 2007

12. Selected Baseline Characteristics VariableMED (N=602)CABG (N=610) Age, median (IQR), yrs59 (53, 67) 60 (54, 68) Female, %12 Diabetes, %4039 Prior Myocardial infarction, %7876 Prior Heart Failure within 3 months, %9594 Prior PCI or CABG, %1516 LVEF (%) — median2827 Multi-vessel disease (>50%), %91 Proximal LAD stenosis (>75%), %6967

13. Medical Therapy MED (N=602)CABG (N=610) Medication, %Baseline Latest Follow-upBaseline Latest Follow-up Aspirin85848084 Aspirin or warfarin91938492 ACE inhibitor or ARB88899189 Beta-blocker88908390 Statin83877990 K+ sparing diuretic46534654 ICD219215

14. CABG Conduct Variable CABG (N=610) CABG received — no (%)555 (91) Time to CABG, days — Median (IQR)10 (5, 16) Performed electively, %95 Arterial conduits ≥ 1, %91 Venous conduits ≥ 1, %86 Total grafts ≥ 2, %88 Length of stay, days — Median (IQR)9 (7, 13)

15. Patient Follow-up Last follow-up period: August – November 2010Last follow-up period: August – November 2010 Final follow-up ascertained: 1207 (99.6%)Final follow-up ascertained: 1207 (99.6%)  Only 5 patients were not evaluable with median follow-up of 40 months Overall duration of follow-up: 56 monthsOverall duration of follow-up: 56 months

16. All-Cause Mortality — As Randomized HR 0.86 (0.72, 1.04) P = 0.123 HR 0.86 (0.72, 1.04) P = 0.123 0.46 0.41

17. All-Cause Mortality — As Randomized HR 0.86 (0.72, 1.04) P = 0.123 Adjusted HR 0.82 (0.68, 0.99) Adjusted P = 0.039 HR 0.86 (0.72, 1.04) P = 0.123 Adjusted HR 0.82 (0.68, 0.99) Adjusted P = 0.039 0.46 0.41

18. HR 0.81 (0.66, 1.00) P = 0.050 Adjusted HR 0.77 (0.62, 0.94) Adjusted P = 0.012 HR 0.81 (0.66, 1.00) P = 0.050 Adjusted HR 0.77 (0.62, 0.94) Adjusted P = 0.012 Cardiovascular Mortality — As Randomized 0.39 0.32

19. HR 0.74 (0.64, 0.85) P < 0.001 Adjusted HR 0.70 (0.61, 0.81) P < 0.001 HR 0.74 (0.64, 0.85) P < 0.001 Adjusted HR 0.70 (0.61, 0.81) P < 0.001 Death or Cardiovascular Hospitalization — As Randomized 0.58 0.68

20. Time-varying Hazard Ratios — As Randomized

21. STICH Revascularization Hypothesis Treatment As Received As treated MED (592) vs. CABG (620) 1212 Randomized CABG Randomized MED only 610602 Received MED only Received CABG 555537 55 65 17% 9%

22. All-Cause Mortality — As Treated HR 0.70 (0.58 – 0.84) P < 0.001 HR 0.70 (0.58 – 0.84) P < 0.001 0.49 0.38

23. STICH Revascularization Hypothesis Treatment Per Protocol Per protocol: MED (537) vs. CABG (555) 1212 Randomized CABG Randomized MED only 610602 Received MED only Received CABG 555537 55 65 17% 9%

24. All-Cause Mortality — Per Protocol HR 0.76 (0.62, 0.92) P = 0.005 HR 0.76 (0.62, 0.92) P = 0.005 0.37 0.48

25. Limitations The adjusted, as treated and per protocol analyses of the primary endpoint although informative should be considered provisionalThe adjusted, as treated and per protocol analyses of the primary endpoint although informative should be considered provisional The STICH trial was not blinded and non- fatal outcomes could have been influenced by the knowledge of the treatment receivedThe STICH trial was not blinded and non- fatal outcomes could have been influenced by the knowledge of the treatment received

26. Summary We compared CABG with contemporary evidence-based MED alone among high-risk patients with CAD, HF and LVDWe compared CABG with contemporary evidence-based MED alone among high-risk patients with CAD, HF and LVD Despite the medical adherence and operative results achieved, STICH-like patients remain at substantial riskDespite the medical adherence and operative results achieved, STICH-like patients remain at substantial risk  5-year mortality risk with MED only = 40%

27. Conclusions In patients randomized to STICH, there was no statistically significant difference in all- cause mortality between medical therapy alone and medical therapy with CABGIn patients randomized to STICH, there was no statistically significant difference in all- cause mortality between medical therapy alone and medical therapy with CABG Medical therapy with CABG reduces cardiovascular mortality and morbidity compared to medical therapy aloneMedical therapy with CABG reduces cardiovascular mortality and morbidity compared to medical therapy alone When randomized to CABG, patients are exposed to an early riskWhen randomized to CABG, patients are exposed to an early risk

28. Clinical Implications CAD should be assessed and medical therapy optimized for all patients presenting with HF.CAD should be assessed and medical therapy optimized for all patients presenting with HF. Decision making for CABG is complex, should be individualized and take into account the short-term risk for long-term benefit.Decision making for CABG is complex, should be individualized and take into account the short-term risk for long-term benefit. The STICH Extension Study will test the durability of these results at 10 years.The STICH Extension Study will test the durability of these results at 10 years.

29. THANK YOU Thank you to the STICH Investigators and Coordinators …and the STICH patients without whose participation in clinical research the STICH trial would never have been completed

30. Full report available online at NEJM.org