1. Presenter Disclosure Information Robert E. Michler, M.D. Influence of Left Ventricular Volume Reduction on Outcome After Coronary Artery Bypass Grafting With or Without Surgical Ventricular Reconstruction Financial Disclosure: NIH STICH Grants NHLBI CT Surgery Network NHLBI CT Surgery Network Unlabeled/Unapproved Uses Disclosure: No

2. Influence of Left Ventricular Volume Reduction on Outcome After Coronary Artery Bypass Grafting With or Without Surgical Ventricular Reconstruction Robert E. Michler, Gerald M. Pohost, Krzysztof Wrobel, Robert O. Bonow, Jan Pirk, Jae K. Oh, Carmelo A. Milano, Patricia A. Pellikka, Francois Dagenais, Thomas A. Holly, Anne S. Hellkamp, Kerry L. Lee, Marisa Di Donato, on behalf of the STICH Investigators Late-Breaking Clinical Trial Update American College of Cardiology March 16, 2010

3. Introduction Ischemic cardiomyopathy resulting from progressive LV volume increase due to CAD and anterior-apical myocardial scar compromises clinical outcome. The objective of surgical ventricular reconstruction (SVR) is to create a smaller left ventricle with a more natural shape. One STICH (Surgical Treatment for Ischemic Heart Failure) Trial specific aim was to determine if adding SVR to CABG provided patient benefit beyond that of CABG alone.

4. SVR Hypothesis Question Does adding SVR to CABG in medically-treated ischemic heart failure patients decrease death/cardiac rehospitalization? 1000 patients randomized 2002-2006 CAD, EF 35% Anterior akinesia/dyskinesia amenable to SVR 499 CABG only 501 CABG + SVR Follow-up 99% complete at 48-months Randomized

5. Purpose To determine whether any magnitude of postoperative change in LV ESVI identified a subgroup of CABG + SVR patients who have increased survival when compared to patients undergoing CABG alone.

6. Analysis Design Cohort identified with paired core laboratory studies of fair to excellent quality permitting accurate assessment of end-systolic volume index (ESVI). Cohort identified with paired core laboratory studies of fair to excellent quality permitting accurate assessment of end-systolic volume index (ESVI). Individual preoperative and postoperative ESVI illustrated for patient groups with: Individual preoperative and postoperative ESVI illustrated for patient groups with: 1. ESVI <60 mL/m 2 1. ESVI <60 mL/m 2 2. ESVI 60-90 mL/m 2 2. ESVI 60-90 mL/m 2 3. ESVI >90 mL/m 2 3. ESVI >90 mL/m 2 Kaplan-Meier curves and hazard ratios calculated on cohorts to examine for a differential effect of adding SVR to CABG. Kaplan-Meier curves and hazard ratios calculated on cohorts to examine for a differential effect of adding SVR to CABG.

7. Paired Left Ventricular Studies Before and After Operation in 979 SVR Hypothesis Patients Operated Patients N = 979 86 died before 4 months Patients eligible for paired study analysis N = 893 13 Specific reasons provided for missing study 3 Unexplained Patients with baseline studies sent to core lab N = 877 64 Telephone follow-up only 22 Technical problem 21 Unexplained Patients with paired baseline and 4-month studies, N = 770 15 Pts with CMR assessment 14 Pts with SPECT assessment 146 Pts with ECHO assessment Patients analyzed in this report, N = 595 16 NO baseline study sent to core lab 107 NO 4-month study sent to core lab both paired studies of fair to excellent quality 175 patients without 86 (9%) of operated patients Observational cohort defined by ESVI taken from a Randomized population

8. Cumulative Distribution of 595 SVR Hypothesis Patients by Baseline ESVI

9. Preoperative to Postoperative Change in ESVI by Operation Received 160 Patients with Baseline ESVI < 60 mL/m 2 GROUP 1

10. Preoperative to Postoperative Change in ESVI by Operation Received 200 Patients with Baseline ESVI 60–90 mL/m 2 GROUP 2

11. Preoperative to Postoperative Change in ESVI by Operation Received 235 Patients with Baseline ESVI > 90 mL/m 2 GROUP 3

12. ESVI Change Lowest to Highest ESVI Group 1 <60 ml/m 2 (N=160) Group 2 60-90 ml/m 2 (N=200) Group 3 >90 ml/m 2 (N=235) Operation CABG (N=91) CABG+ SVR (N=69) CABG (N=111) CABG+ SVR (N=89) CABG (N=118) CABG+ SVR (N=117) % No Reduction55%43%48%20%32%21% % >30% Reduction23%28%20%38%24%44% Preop LVEF Median 0.370.280.220.360.300.21 Postop LVEF Median 0.380.310.250.400.350.27

13. Hazard Ratios and 95% Confidence Intervals All-Cause Mortality All Patients (n=1000) (as randomized) All Patients (n=979) (by operation received) Patients with Pre & Post Surgery Studies (n=595) Patients Excluded (n=384) CABG+SVR BetterCABG Only Better

14. Hazard Ratios and 95% Confidence Intervals All-Cause Mortality Patients with Pre & Post Surgery Studies (n=595) Baseline ESVI > 90 ml/m 2 (n=235) Baseline ESVI 60- 90 ml/m 2 (n=200) Baseline ESVI < 60 ml/m 2 (n=160) CABG+SVR BetterCABG Only Better

15. Kaplan-Meier Estimates: Cumulative Risk of Death Patients with Pre & Post Surgery Studies : Baseline ESVI 90 mL/m 2 (n=360) HR=0.59 (95% CI: 0.35 – 1.00; rank test: p=0.0475) Total events (63): 20 in CABG+SVR and 43 in CABG Only

16. Kaplan-Meier Estimates: Cumulative Risk of Death Patients with Pre & Post Surgery Studies : Baseline ESVI > 90 mL/m 2 (n=235) HR=1.24 (95% CI: 0.75 – 2.06; rank test: p=0.4071) Total events (60): 33 in CABG+SVR and 27 in CABG Only

17. Hazard Ratios and 95% Confidence Intervals All-Cause Mortality Baseline ESVI 90 mL/m 2 with Small or no Reduction (n=180) Baseline ESVI 90 mL/m 2 with Large Reduction (n=180) Baseline ESVI > 90 mL/m 2 with Small or no Reduction (n=117) Baseline ESVI > 90 mL/m 2 with Large Reduction (n=118) CABG+SVR Better CABG Only Better

18. Kaplan-Meier Estimates: Cumulative Risk of Death Patients with Pre & Post Surgery Studies Baseline ESVI > 90 mL/m 2 and Small/or No Reduction in Post_Op ESVI (n=117) HR=1.54 (95% CI: 0.80 – 2.98; rank test: p=0.1950) Total events (36): 17 in CABG+SVR and 19 in CABG Only mL/m 2 Small/or no reduction = change from baseline ESVI -23.7 mL/m 2

19. Kaplan-Meier Estimates: Cumulative Risk of Death Patients with Pre & Post Surgery Studies Baseline ESVI > 90 mL/m 2 and Large Reduction in Post_Op ESVI (n=118) HR=1.20 (95% CI: 0.51 – 2.80; rank test: p=0.6777) Total events (23): 16 in CABG+SVR and 8 in CABG Only mL/m 2 Large reduction = change from baseline ESVI > -23.7 mL/m 2

20. Limitations of Study Baseline LV volume and regional function data were not available in every STICH patient. Baseline LV volume and regional function data were not available in every STICH patient. Secondary structural and hemodynamic variables related to LV function, such as sphericity index or mitral regurgitation, were not considered in this analysis. Secondary structural and hemodynamic variables related to LV function, such as sphericity index or mitral regurgitation, were not considered in this analysis. Bias of investigators towards not sending suboptimal postoperative studies cannot be excluded. Bias of investigators towards not sending suboptimal postoperative studies cannot be excluded.

21. Conclusions 1.A broad range of baseline ESVI is represented among STICH patients. 2.The postoperative ESVI decrease is significantly larger for CABG+SVR patients. 3.In patients with larger volumes, ESVI > 90 ml/m 2, CABG alone resulted in a substantial reduction in ESVI. 4.Patients with preoperative ESVI values 90 ml/m 2 trended toward benefit from CABG + SVR, whereas patients with preoperative ESVI values > 90 ml/m 2 trended toward benefit from CABG alone. 5.No threshold of ESVI at baseline, ESVI at 4 months postoperative or ESVI volume change identified a patient group that benefited from adding SVR to CABG. 6.The post-op ESVI is the most important prognostic mortality measure. Its prognostic importance is significant even after accounting for the baseline ESVI or the pre-to-post change in ESVI.

22. Discussion Slides

23. Postoperative Preoperative Group 1: LVESVI < 60 mL/m 2 (N = 129) CABG N = 70 CABG + SVR N = 59 Change in Regional Cardiac Function in 504 SVR Hypothesis Pts Dyskinesia Normal

24. Group 2: LVESVI 60–90 mL/m 2 (N = 170) CABG N = 96 CABG + SVR N = 74 Change in Regional Cardiac Function in 504 SVR Hypothesis Pts Postoperative Preoperative Dyskinesia Normal

25. Group 3: LVESVI > 90 mL/m 2 (N = 205) CABG N = 105 CABG + SVR N = 100 Change in Regional Cardiac Function in 504 SVR Hypothesis Pts Postoperative Preoperative Dyskinesia Normal

26. Hazard Ratios and 95% Confidence Intervals All-Cause Mortality Patients with Pre & Post Surgery Studies (n=595) Post-Op ESVI > 90 mL/m 2 (n=150) Post-Op ESVI 60- 90 mL/m 2 (n=198) Post-Op ESVI < 60 mL/m 2 (n=247) CABG+SVR BetterCABG Only Better