The German Off-Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) Study Prof. Dr. med. Anno Diegeler Bad Neustadt Heart Center For the GOPCABE study group

Payment exclusively for web-based data German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Disclosures Sponsor of the study is the German Society of Thoracic and Cardiovascular Surgery (DGTHG) Unrestricted grant (≅250.000 Euro) from Maquet™ Inc. Rastatt Germany Payment exclusively for web-based data management of the IKKF™ (Institut für klinisch- kardiovaskuläre Forschung), Munich

Several randomized trials* with different patient German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Background There are some rationales, that avoiding the heart-lung machine in coronary bypass surgery reduces invasiveness and by this has a clinical benefit on major adverse events (MACCE) However… Several randomized trials* with different patient characteristics could not confirm a significant difference * ROOBY1; CORONARY2; BEST SURGICAL REVASCULARIZATION3 1 3 N Engl J Med 2009; 361: 1827 – 37 Circulation 2010; 121: 498 - 504 2 N Engl J Med 2012; 366: 1489 – 97

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

• 12 German Centers with high experience level German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale The GOPCABE –Trial Features • Patients ≥ 75 years • All comers screened • 12 German Centers with high experience level for both techniques • Nominated Surgeons for both techniques • Screening log for excluded patients Enrollement between 6/2008 and 9/2011

• Additional cardiac disease necessitating • Previous pericardiotomy German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Patient exclusion criteria • Additional cardiac disease necessitating additional surgery • Previous pericardiotomy • Immediate surgery i.e. within 24 hours after admission • Inability or unwillingness to provide consent Anatomy , morphology of the coronary artery or left ventricular function was not an exclusion criteria

Primary endpoint: at 30 days after surgery German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Outcome Features Hypothesis: Off pump is not able to reduce a combined endpoint MACCRE to 30%; OR 0.63 with a power of 90% MACCRE: death, myocardial infartion, additional revascularization, stroke, new onset renal replacement therapy Primary endpoint: at 30 days after surgery Secondary endpoints: 12 months MACCRE; Ventilation time, stay on ICU, hospital stay, resources utilization

German Off-Pump CABG in Elderly Trial (GOPCABE) patients > 75 years with isolated first-time CABG n = 4355 potentially eligible patients n = 3683 Randomization n = 2539 (69%) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale exclusion criteria: - urgent operation (n = 526) - inability to provide consent (n = 122) - participation in another study (n = 24) - unwillingness to provide consent (n = 537) - logistic reasons (n= 607) off-pump CABG (n = 1271) isolated CABG performed by assigned surgeon (n = 1191) available for analysis at 30 days (n = 1187) at 12 months (n = 1179) On-pump CABG (n = 1268) isolated CABG performed by assigned surgeon (n = 1212) available for analysis at 30 days (n = 1207) at 12 months (n = 1191) exclusion after randomization (n = 80) - additional cardiovascular procedure (n = 20) - urgent operation (n = 9) - no surgery performed (n = 16) - withdrawn consent (n = 19) - miscellaneous (n = 16) - lost to follow-up (n = 3) - withdrawn consent (n = 1) - lost to follow-up (n = 8) exclusion after randomization (n = 56) - additional cardiovascular procedure (n = 21) - urgent operation (n = 6) - no surgery performed (n = 11) - withdrawn consent (n = 11) - missing consent form (n = 1) - death before surgery (n = 1) - miscellaneous (n = 5) - lost to follow-up (n = 4) - withdrawn consent (n = 1) - lost to follow-up (n = 15)

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale baseline characteristics [No (%)] on-pump off-pump baseline characteristics [No (%)] on-pump off-pump n = 1207 n = 1187 left ventricular fraction ejection < 30% 39 (3.2) 25 (2.1) 30-50% 341 (28.3) 365 (30.7) female gender 389 (32.2) 366 (30.8) > 50% 827 (68.5) 797 (67.1) age [years] body mass index [kg / m2] 78.4 ± 2.87 27.8 ± 4.1 78.6 ± 2.98 27.8 ± 4.1 CCS scale angina grading I II 230 (19.0) 425 (35.2) 224 (18.9) 396 (33.4) insulin-dependent diabetes mellitus chronic obstructive pulmonary disease previous stroke peripheral vascular disease pulmonary arterial hypertension previous myocardial infarction previous percutaneous coronary intervention history of atrial fibrillation implanted pacemaker 166 (13.8) 118 (9.8) 95 (7.9) 392 (32.5) 26 (2.2) 456 (37.8) 263 (21.8) 190 (15.7) 33 (2.7) 179 (15.1) 127 (10.7) 121 (10.2) 388 (32.7) 39 (3.3) 427 (36.0) 268 (22.6) 177 (14.9) 31 (2.6) III IV extent of coronary artery disease 1 vessel 2 vessel 3 vessel left main disease + 1 – 3 vessel renal replacement therapy critical condition 496 (41.1) 56 (4.6) 14 (1.2) 106 (8.8) 730 (60.5) 357 (29.6) 11 (0.9) 36 (3.0) 523 (44.1) 44 (3.7) 23 (1.9) 119 (10.0) 712 (60.0) 333 (28.1) 11 (0.9) 22 (1.9) creatinine level < 2.3 mg/dl 1169 (96.9) 1150 (96.9) logistic EuroSCORE 8.23 ± 6.61 8.31 ± 7.17 > 2.3 mg/dl 27 (2.2) 26 (2.2)

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale off-Pump (n = 1187) on-Pump (n = 1207) No. (%) mean number of anticipated grafts * anticipated number of grafts 1 2 3 4 >4 mean number of performed grafts *** number of performed grafts *** anticipated vs. performed grafts per patient *** no. anticipated = No. performed no. anticipated < No. performed no. anticipated > No. performed 2.95 28 (2.4%) 242 (20.4%) 700 (59%) 197 (16.6%) 20 (1.7%) 2.66 74 (6.2 %) 414 (34.9 %) 557 (46.9 %) 123 (10.4 %) 19 (1.6 %) 663 (56%) 121 (10 %) 403 (34 %) 3 12 (1%) 260 (21.5%) 683 (56.6%) 222 (18.4%) 30 (2.5%) 2.84 44 (3.6 %) 382 (31.6 %) 551 (45.7 %) 187 (15.5 %) 43 (3.5 %) 651 (54 %) 202 (17 %) 354 (29 %)

Cross-over by conversion German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Cross-over by conversion off-pump n = 116 (9.7%) on-pump n = 62 (5.1%) before skin incision 61(5.1%) - hemodynamic instability / unstabe angina (n = 6) - logistic reasons (n = 52) - unknown (n = 3) - calcified ascending aorta (n = 13) - logistic reaosons (n = 21) - unknown (n = 2) 36(2.9%) before first anastomosis - hemodynamic instability 34(2.8%) / myocardial ischemia (n = 17) - diffuse calcified small vessel (n = 6) - intramyocardial vessel (n = 3) - pericardial adhesion / inadequate vessel exposure (n = 3) - bleeding / myocardial injury (n = 2) - unknown (n = 3) - calcified ascending aorta (n = 24) - miscellaneous (n = 2) 61(2.1%) after first anastomosis 21(1.8%) - hemodynamic instability / myocardial ischemia (n = 16) - diffuse calcified small vessel (n = 1) - intramyocardial vessel (n = 1) - pericardial adhesion / inadequate vessel exposure (n = 1) - revision of coronary anastomosis (n = 2)

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale German Off-Pump CABG in Elderly Trial (GOPCABE) Primary endpoint 30 days after surgery modified intention to treat analysis primaryendpoint[no(%)] off-pump on-pump oddsratio [95%CI] pvalue 30daysaftersurgery n=1187 n=1207 composite 93(7.8%) 99(8.2%) 0.95[0.71–1.28] 0.74 deathwithin30daysaftersurgery 31(2.6%) 34(2.8%) 0.92[0.57–1.51] 0.75 myocardialinfarction 18(1.5%) 20(1.7%) 0.92[0.51–1.66] 0.79 stroke 26(2.2%) 32(2.7%) 0.83[0.50–1.38] 0.47 repeatrevascularization 15(1.3%) 5(0.4%) 2.42[1.03–5.72] 0.04 newrenalreplacementtherapy 29(2.4%) 37(3.1%) 0.80[0.49–1.29] 0.36

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale German Off-Pump CABG in Elderly Trial (GOPCABE) Composite endpoint (death, myocardial infarction, stroke, repeat revascularisation, new renal replacement therapy) within 30 days after surgery according to center

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale German Off-Pump CABG in Elderly Trial (GOPCABE) Primary endpoint 30 days after surgery Per protocol analysis primaryendpoint[no(%)] off-pump on-pump oddsratio pvalue 30daysaftersurgery n=1071 n=1145 [95%CI] composite 75(7.0%) 92(8.0%) 0.87[0.63–1.20] 0.40 deathwithin30daysafter surgery 22(2.1%) 31(2.7%) 0.76[0.44–1.31] 0.32 myocardialinfarction 13(1.2%) 19(1.7%) 0.77[0.40–1.47] 0.42 stroke 20(1.9%) 32(2.8%) 0.68[0.39–1.18] 0.17 repeatrevascularization 14(1.3%) 4(0.3%) 2.65[1.10–6.40] 0.03 newrenalreplacementtherapy 24(2.2%) 33(2.9%) 0.80[0.48–1.34]

German Off-Pump CABG in Elderly Trial (GOPCABE) Secondary endpoints use of resources: Off-pump Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale On-pump patients with allogenic blood transfusion *** units of transfused packed red blood cells† *** operative time [min]† duration of mechanical ventilation [hours]† postoperative length of stay ICU [days]† postoperative length of stay hospital [days]† 668 (56.3%) 2 (1) 175 (170) 25.1 (12) 3.7 (2) 11.5 (9) 757 (62.7%) 2.4 (2) 174 (168) 30.7 (12) 4.3 (2) 11.6 (9)

German Off-Pump CABG in Elderly Trial (GOPCABE) 12 months follow-up Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale primaryendpoint[no(%)] off-pump on-pump hazardratio [95%CI] pvalue 12monthsaftersurgery n=1179 n=1191 composite 154(13.1) 167(14.0) 0.93[0.76–1.16] 0,483 deathwithinoneyearaftersurgery 83(7.0) 95(8.0) 0.88[0.65.1.18] 0.383 myocardialinfarction 25(2.1) 28(2.4) 0.90[0.53–1.54] 0.701 stroke 41(3.5) 52(4.4) 0.79[0.53–1.19] 0.260 repeatrevascularization 36(3.1) 24(2.0) 1.52[0.90–2.54] 0.112 newrenalreplacementtherapy 34(2.9) 42(3.5) 0.82[0.52–1.28] 0.375

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale

• Modified intention to treat analysis German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Limitation • Modified intention to treat analysis • Nomitation of a surgeon creates a time interval before surgery and more cross overs • Only local data confirmation performed • Minor events such as neurocognitive impairments or graft patency not evaluated

In a randomized trial comparing off- pump and on- German Off-Pump CABG in Elderly Trial (GOPCABE) Prof. Dr. Anno Diegeler Herz- und Gefäß-Klinik Bad Neustadt a. d. Saale Conclusion In a randomized trial comparing off- pump and on- pump coronary bypass surgery we did not find a significant difference in clinical outcome at 30 days and at 12 months