1. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Randomized Comparison of Percutaneous Coronary Intervention with Sirolimus-Eluting Stents versus Coronary Artery Bypass Grafting in Unprotected Left Main Stem Stenosis E. Boudriot*, H.Thiele*, T.Walther, C.Liebetrau, P.Boeckstegers, T.Pohl, B.Reichart, H.Mudra, F.Beier, B. Gansera, F.J.Neumann, M.Gick, T. Zietak, S. Desch, G.Schuler, F.W.Mohr Disclosures: supported in part by Deutsche Stiftung für Herzforschung * Both authors contributed equally

2. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Study Primary combined endpoint within 12 months - Mortality - Myocardial infarction - Target vessel revascularization (TVR)  Secondary endpoints - Individual clinical endpoints - Periinterventional complications - CCS-classification Prospective randomized trial CABG (arterial grafts) versus PCI + Sirolimus-Eluting Stent in left main stem stenosis 1)low output syndrome (intravenous catecholamines and/or IABP) 2)Congestive heart failure requiring hospital admission 3)cerebrovascular events (stroke, coma, TIA, PRIND) 4)pericardial tamponade 5)arrhythmia (ventricular fibrillation, VT, A. fibrillation) 6)major bleeding requiring blood transfusion 7)re-thoracotomy for bleeding 8)renal failure requiring dialysis 9)major infections compromising post-procedural rehabilitation 10)vascular access site complications requiring surgery 11)Sternum instability requiring additional treatment

3. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Study Centers Universität München - Großhadern Klinikum Neuperlach München Herzzentrum Bad Krozingen Herzzentrum Leipzig

4. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Statistics – Sample Size Zone of non-inferiority Limit of equivalence (10.0%) 90% CI Stenting better CABG better -15.0 -10.0 -5.0 05.0 10.015.0 Difference in MACE rates Inferior Assumed event rates: CABG: 15%, DES: 12.5% Difference in MACE rates of 2.5%  2 x 100 patients to show non-inferiority

5. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Study Flow Chart 201 Eligible 100 Assigned to PCI101 Assigned to CABG 100 Included in Primary Analysis 100 Included in Secondary Analysis 0 Lost to Follow-up 430 Patients with Unprotected Left Main Disease 229 Non-Eligible 22 Infarction < 48 Hours 11 Cardiogenic Shock 8 Chronic Total Occlusion 65 Lesion Length > 30 mm 6 Non-CABG Suitable 14 Prior Cardiac Surgery 36 Age > 80 Years 21 Malignancy 27 Combined Cardiac Surgery 19 Dominant Left Circumflex 1 Lost to Follow-up 100 Included in Primary Analysis 100 Included in Secondary Analysis 40 PCI 179 CABG 10 Conservative 5 No Angiographic Follow-up 20 No Angiographic Follow-up 3 Converted to CABG

6. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Patient Characteristics Variable PCI * (n=100) CABG (n=101) P Value Age (y), median (IQR) 66 (62;73)69 (63;73) 0.24 Men, No. (%) 72 (72)78 (77) 0.49 Body-mass-index (kg/m 2 ), median (IQR) 27.2 (24.6;31.5)27.0 (24.9;30.1) 0.31 Cardiovascular risk factors, No. (%) Current smoking, No. (%) Hypertension, No. (%) Hypercholesterolemia, No. (%) Diabetes mellitus, No. (%) 35 (35) 82 (82) 68 (68) 40 (40) 28 (28) 83 (82) 65 (64) 33 (33) 0.34 0.88 0.89 0.35 Previous myocardial infarction, No. (%) Q wave infarction, No. (%) Non-Q wave infarction, No. (%) 19 (19) 17 (17) 2 (2) 14 (14) 10 (10) 4 (4) 0.43 Previous stroke, No. (%) 3 (3)6 (6) 0.51 Baseline creatinine, median (IQR),  mol/l 86.0 (76.5;100.0)86.0 (75.0;97.0) 0.52 Left ventricular ejection fraction (%), median (IQR) 65.0 (55.0;70.0)65.0 (55.0;68.0) 0.88 Logistic EuroSCORE, median (IQR) 2.4 (1.5;3.7)2.6 (1.7;4.9) 0.08 Discharge medication, No. (%) Aspirin, No. (%) Clopidogrel, No. (%) Beta-blocker, No. (%) ACE-inhibitor‡/AT-1-ant.§, No. (%) Statins, No. (%) 100 (100) 99 (99) 98 (98) 97 (97) 101 (100) 32 (32) 96 (95) 93 (92) 95 (94) 0.99 <0.001 0.22 0.11 0.51

7. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Angiographic Characteristics VariablePCI (n=100) CABG (n=101) P Value Lesion type, No. (%) Ostial, No. (%) Trunk, No. (%) Distal, No. (%) 20 (20) 6 (6) 74 (74) 23 (23) 8 (8) 70 (69) 0.72 Isolated left main, No. (%) Left main + 1-vessel disease, No. (%) Left main + 2-vessel disease, No. (%) Left main + 3-vessel disease, No. (%) 28 (28) 35 (35) 26 (26) 11 (11) 29 (29) 27 (27) 28 (28) 17 (17) 0.49 PCI technique for distal left main T-Stenting, No. (%) Provisional T-stenting, No. (%) Crush-Stenting, No. (%) V-Stenting, No. (%) 40 (40) 30 (30) 3 (3) 1 (1) -------- CABG, conduits per patient Left internal mammary artery, No. (%) Right internal mammary artery, No. (%) Radial artery, No. (%) Venous graft, No. (%) -------- 100 (99) 55 (54) 37 (37) 35 (35) SYNTAX score, median (IQR) 24.0 (19.0;29.0)23.0 (14.8;28.0)0.09

8. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Ostium Body Distal PCI 20% 6% 74% CABG 23% 8% 70% Type of Left Main Stenosis p = 0.72

9. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Stenting CABGp (n=100) (n=101) Major bleeding-2 (2%) CV accident-2 (2%) A. fibrillation3 (3%)19 (19%) Access site complication - -- Re-thoracotomy-2 (2%) Major infection-5 (5%) Renal failure + dialysis1 (1%)1 (1%) Critical illness PNP-1 (1%) CHF with readmission-- Pericardial tamponade-- Periinterventional Complications Any complication4 (4%)30 (30%)<0.001

10. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Change in CCS-Classification 0 0.5 1 1.5 2 2.5 3 Baseline PCI CABG CCS-Class p=0.19 p<0.001 3.0 (IQR 2.0;4.0) 2.0 (IQR 2.0;4.0) 12 Months p=0.67 0.0 (IQR 0.0;1.0)

11. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M PCICABG95% CI p-Value (n=100) (n=101) Non-inferiority Death2 (2.0%)5 (5.0%) -8.2 to 2.9 <0.001 AMI 3 (3.0%)3 (3.0%)-5.8 to 5.9 0.002 <30 days3 (3.0%)3 (3.0%)-5.8 to 5.9 0.002 day 30-12 m.-- Death + AMI5 (5.0%)8 (7.9%)-10.6 to 4.4 <0.001 Repeat revasc.14 (14.0%)6 (5.9%)-0.3 to 17.1 0.35 <30 days 1 (1.0%) 2 (2.0%)-6.1 to 3.7 <0.001 day 30-12 m.13 (13.0%) 4 (4.0%)-1.3 to 17.6 0.45 Any MACE19 (19.0%)14 (13.9%)-5.3 to 15.7 0.19 Primary Endpoint – MACE 12 Months

12. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M MACE 12 Month p < 0.001 p = 0.02 p = 0.35 p = 0.19 p value for non-inferiority

13. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Primary Endpoint – MACE 12 Months Limit of equivalence PCI better CABG better -15.0 -10.0 -5.0 0 5.0 10.015.0 5.9 0 -5.8 AMI 0.002 Repeat revascularization 17.1 8.1 -0.3 0.35 MACE 15.7 5.1 -5.3 0.19 Intention to treat Death 2.7 -3.0 -9.4 <0.001

14. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Days after randomization 0 20 40 60 80 100 Cumulative major adverse cardiac event free survival (%) MACE Mid-term Follow-up 300 600 900 1200 1500 1800 Median follow-up 36.5 months CABG Log-rank: p = 0.13 PCI

15. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M Death and MI – Mid-term Follow-up Days after randomization 0 20 40 60 80 100 Cumulative death and MI event free survival (%) 300 600 900 1200 1500 1800 Median follow-up 36.5 months Log-rank: p = 0.97 PCI CABG

16. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M TVR - Mid-term Follow-up Days after randomization 0 20 40 60 80 100 Cumulative major adverse cardiac event free survival (%) 300 600 900 1200 1500 1800 Median follow-up 36.5 months CABG Log-rank: p = 0.03 PCI

17. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M In patients with unprotected left main stenosis PCI using DES failed to show non-inferiority to CABG. The inferiority for PCI is driven by the higher repeat revascularization rate. For death and MI the results in both groups are comparable. Both treatment strategies effectively reduce symptoms. Summary

18. UNIVERSITÄT LEIPZIG H E R Z Z E N T R U M In highly-experienced centers the decision making process on how to treat unprotected left main disease should therefore be based on an interdisciplinary approach taking into account the - individual success, - periprocedural risk - bypass graft occlusion risk - potential restenosis rate based on the morphology of the underlying lesion and patient comorbidities. Conclusions