Faculty/Presenter Disclosure

Faculty/Presenter Disclosure Faculty: Andre Lamy Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: None Consulting Fees: None Other: None

CORONARY: The Coronary Artery Bypass Grafting Surgery Off or On Pump Revascularization Study André Lamy Population Health Research Institute Hamilton Health Sciences McMaster University Hamilton, CANADA on behalf of the CORONARY Investigators

Disclosure No conflict of interest for all co-authors Presented on behalf of the CORONARY Investigators 3

Background Benefits and risks of performing CABG surgery on beating heart (off pump) not clearly established. Majority of prior trials had few events and short follow-up or inexperienced surgeons. 4

CORONARY Trial Organization 79 centers in 19 countries 4,752 patients recruited between (November 2006 October 2011) Designed, coordinated, managed and data analysed and reported by the Population Health Research Institute, Hamilton Health Sciences and McMaster University in Hamilton, Canada The data was monitored by independent DSMB Funded by Canadian Institutes of Health Research 5

Study Hypotheses - Off pump CABG compared to on-pump CABG would reduce major clinical events in shortterm (30 Days) - Benefits maintained in long-term (5 yrs) 6

Inclusion/Exclusion Criteria Inclusion Criteria Isolated CABG with median sternotomy One of the following: 1. Peripheral vascular disease 2. Cerebrovascular disease 3. Renal Insufficiency 4. Age 70 years 5. Age 60-69 with at least one risk factor (diabetes, urgent revascularization, smoker, LVEF 35) 6. Age 55-59 with at least two of the above risk factors Exclusions Additional cardiac procedure planned Contraindications to off-pump or on-pump CABG Emergency or re-do CABG 7

Qualifications of Surgeons Surgical expertise-based randomization > 2 years of experience as staff cardiac surgeon and > 100 cases of one or both techniques Trainees were not allowed to be primary operators 8

Primary Outcomes 1 st Co-Primary Outcome Composite of total mortality, stroke, non fatal myocardial infarction, new renal failure at 30 days post randomization NEJM NEJM 30 days: presented ACC.12 and 1 Year: presented ACC.13 and 2 nd Co-Primary Outcome Composite of above outcomes plus repeat coronary revascularization over 5 yrs of follow-up (expected 9

Baseline Characteristics OFF-PUMP (n = 2375) ON-PUMP (n = 2377) Mean Age (years) 67.6 67.5 Males () 80.0 81.7 Prior MI 33.8 35.2 Previous Stroke 6.7 7.8 Peripheral Arterial Disease 8.0 8.2 Congestive Heart Failure 5.9 6.6 Urgent Surgery 39.5 38.1 Euroscore 0 2 3 5 > 5 28.6 51.7 18.1 27.8 54.2 16.8 10

Baseline Disease Pre-op Angiogram OFF-PUMP (n = 2375) ON-PUMP (n = 2377) Left Main 22.1 20.9 Triple Vessel 56.1 60.4 Double Vessel 18.7 16.4 Single Vessel 3.0 2.1 11

Operation Details 4752 Randomized (ITT Analyses) CABG 30 days Off Pump 2148 (90.4) On Pump 2183(91.8 ) Cross-overs 184 (7.8) 150 (6.4) Incomplete revascularization Operating room (median hrs) Initial ventilation (median hrs) Off Pump On Pump 11.8 10.0 1.18 RR 95 CI p value 1.00-1.3 9 0.05 4.0 4.2 <0.001 9.6 11.2 <0.001 12

Conduits OFF-PUMP (n = 2375) ON-PUMP (n = 2377) p-value n n CABG Completed 2349 98.9 2356 99.1 Total grafts performed CONDUIT 3.0 3.2 <0.001 LIMA or RIMA 2199 93.6 2201 93.4 0.788 Saphenous Vein 2028 86.3 2117 89.9 <0.001 13

Peri-operative Transfusions and Bleeding OFF-PUMP (n = 2375) ON-PUMP (n = 2377) p value Any Blood Transfusion 50.7 63.3 <0.001 Antifibrinolytics 26.1 37.0 <0.001 Re-operation for bleeding 1.4 2.4 0.02 14

1 st Co-Primary Outcome (30 Days) Primary Outcome Death, Stroke, MI, Renal Failure Off Pump On Pump Hazard Ratio 95 CI p value 9.8 10.3 0.95 0.79-1.14 0.59 15

1 st Co-Primary Outcome (30 Days) Primary Outcome Death, Stroke, MI, Renal Failure Components Off Pump On Pump Hazard Ratio 95 CI p value 9.8 10.3 0.95 0.79-1.14 0.59 Death 2.5 2.5 1.02 0.71-1.46 Stroke 1.0 1.1 0.89 0.51-1.54 Non Fatal MI 6.7 7.2 0.93 0.75-1.15 New Renal Failure 1.2 1.1 1.04 0.61-1.76 16

Death/MI/Stroke/New Renal Failure at 30 Days Cumulative Event Rate # at Risk OFF ON 0.0 0.02 0.04 0.06 0.08 0.10 0.12 HR 0.95 95 CI 0.79-1.14 p value 0.59 Off Pump On Pump 0 10 Days of Follow-up 20 30 2375 2176 2151 2142 2377 2178 2146 2133 17

Other Outcomes at 30 days Off Pump On Pump Hazard Ratio 95 CI p value Angina 0.1 0.1 1.50 0.25-8.99 0.66 PCI 0.5 0.1 3.67 1.02-13.2 0.05 Re-do CABG 0.2 0.04 6.00 0.72-49.8 0.01 PCI/Re-do CABG 0.7 0.2 4.01 1.34-12.0 0.01 All re-operations (re-do CABG) All re-operations/re-do CABG/PCI 3.3 3.9 0.85 0.63-1.14 0.27 3.7 4.0 0.94 0.70-1.25 0.65 18

Other Outcomes at 30 days Off Pump On Pump Relative Risk 95 CI p value Respiratory Infection or failure 5.9 7.5 0.79 0.63-0.9 8 0.03 Acute Kidney Injury AKIN Stage 1 28.0 32.1 0.87 0.80-0.96 0.01 RIFLE risk 17.0 19.6 0.87 0.76-0.98 0.02 New Renal Failure requiring Dialysis 1.2 1.1 1.04 0.61-1.76 0.77 Acute Kidney Injury Network (AKIN): absolute increase in serum creatinine value 27 µmol/l OR an increase of 150 from the baseline serum creatinine value Risk, Injury, Failure, Loss and End-stage Renal Disease (RIFLE): increase of 150 from the baseline serum creatinine value 19

Primary Outcome at Hospital Discharge Tertiary Outcome Death/MI/Stroke/Renal Failure Off Pump On Pump Hazar d Ratio 95 CI p value 9.6 10.4 0.94 0.78-1.13 0.50 Components Death 2.6 2.8 0.97 0.68-1.37 Stroke 0.9 1.0 0.94 0.52-1.69 Non Fatal MI 6.7 7.2 0.93 0.75-1.15 New Renal Failure 1.2 1.1 1.11 0.65-1.87 20

Subgroups (1) 21

Subgroups (2) 22

Conclusions At 30 days there was no difference in the primary outcome between Off pump CABG and On pump CABG. Off-pump was associated with: Less transfusions and re-operation for bleeding Less acute kidney injury Less respiratory infections/failure More early revascularizations 23

Subgroups (2) 24

Results by Region EuroSCO RE OFF-PUMP ON-PUMP Hazard Ratio p value 0.058 South America 4.21 10.6 15.3 0.68 0.05 North America + Europe + Australia 4.27 10.8 12.2 0.89 0.39 China 3.44 7.4 6.7 1.12 0.69 India 3.21 9.3 6.7 1.41 0.09 25

Primary outcome per EuroSCORE 15 HR 1.35 HR 0.87 HR 0.85 12 Primary Outcome () 9 6 3 0 Off-pump On-pump Off-pump On-pump Off-pump On-pump 0-2 3 to 5 >5 P=0.047 EuroSCORE

Primary Outcome per EuroSCORE 15 Primary Outcome () 12 9 6 3 ON-PUMP 0 0-2 3 4 to 5 6 + EuroSCORE 27

Primary Outcome per EuroSCORE 15 Primary Outcome () 12 9 6 3 OFF-PUMP 0 0-2 3 4 to 5 6 + EuroSCORE 28

Primary Outcome per EuroSCORE 15 Primary Outcome () 12 9 6 3 0 OFF-PUMP ON-PUMP 0-2 3 4 to 5 6 + EuroSCORE

Hazard Ratio 1.5 Hazard Ratio Off-pump/On-pump 1.0 0.5 0 0-2 3 4 to 5 6 + EuroSCORE 30

Hazard Ratio 1.5 Hazard Ratio Off-pump/On-pump 1.0 ROOBY CORONARY GOPCAB E 0.5 0 0-2 3 4 to 5 6 + EuroSCORE 31

Results by Region adjusted by EuroSCORE Eurosco re OFF-PUMP ON- PUMP HR 95 CI p value South America 0-2 13.3 15.2 0.89 0.40-1.96 0.77 3+ 10.0 15.5 0.63 0.40-1.00 0.05 North America + Europe + Australia 0-2 8.3 7.0 1.20 0.57-2.54 0.63 3+ 11.4 13.5 0.84 0.63-1.13 0.26 India 0-2 8.5 6.0 1.43 0.74-2.77 0.29 3+ 9.9 7.2 1.40 0.86-2.27 0.17 China 0-2 8.6 3.5 2.50 0.88-7.12 0.09 3+ 6.8 8.5 0.79 0.42-1.50 0.47 32

Conclusions No variations of results per regions after adjustment by EuroSCORE Moderate and high risk patients tend to benefit from Off-pump technique compared to Onpump Reverse is seen in low-risk patients 33

1 st Co-Primary Outcome (1 Year) Primary Outcome Death, Stroke, MI, Renal Failure Components Off Pump On Pump Hazard Ratio 95 CI p value 12.1 13.3 0.91 0.77-1.07 0.24 Death 5.1 5.0 1.03 0.8-1.32 Stroke 1.5 1.7 0.90 0.57-1.41 Non Fatal MI 6.8 7.5 0.90 0.73-1.12 New Renal Failure 1.3 1.3 0.97 0.59-1.60 34

Other Outcomes at 1 Year Off Pump On Pump Hazard Ratio 95 CI p value Angina 1.0 0.9 1.05 0.58-1.88 0.87 PCI 1.1 0.8 1.43 0.79-2.57 0.23 Re-do CABG 0.3 0.01 7.00 0.86-57.0 0.07 PCI/Re-do CABG 1.4 0.8 1.66 0.95-2.89 0.07 Primary outcome per protocol 11.5 13.2 0.86 0.73-1.02 0.08 35

Death/MI/Stroke/New Renal Failure at 1 Year Primary Outcome () P=0.25 Months

Conclusions At 1 year there was no difference between Off-pump CABG and On-pump CABG: In the primary outcome Repeat revascularization Quality of life Neuro-cognitive function 37

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1 st Co-Primary Outcome (30 Days) (830 patients) Primary Outcome Death, Stroke, MI, Renal Failure Components Off Pump On Pump Hazard Ratio 95 CI p value 9.2 13.7 0.66 0.44-1.00 0.049 Death 1.4 1.4 1.01 0.33-3.13 0.98 Stroke 1.2 1.7 0.72 0.23-2.27 0.57 Non Fatal MI 7.5 10.6 0.70 0.44-1.11 0.13 New Renal Failure 0.2 1.0 0.25 0.03-2.25 0.22 * Not a pre-specified sub-group 40

1 st Co-Primary Outcome (Discharge) (830 patients) Primary Outcome Death, Stroke, MI, Renal Failure Components Off Pump On Pump Hazard Ratio 95 CI p value 9.0 13.9 0.65 0.43-0.98 0.040 Death 1.4 2.6 0.64 0.23-1.78 0.40 Stroke 1.0 1.4 0.72 0.20-2.57 0.62 Non Fatal MI 7.5 10.6 0.72 0.45-1.14 0.16 New Renal Failure 0.2 1.0 0.26 0.03-2.34 0.23 41

Other Outcomes at 30 days Off Pump On Pump Hazard Ratio 95 CI Blood transfusions 31.2 45.0 0.70 0.57-0.84 AKI (stage 1) 16.5 26.9 0.61 0.45-0.83 p value <0.00 1 <0.00 1 Re-hospitalization 8.2 11.8 0.70 0.46-1.06 0.09 PCI 0.5 0.2 2.02 0.18-22.3 0.56 Re-do CABG 0 0 1.00 - - Re-operations 1.9 3.6 0.54 0.23-1.25 0.15 All re-operations/re-do CABG/PCI 2.2 3.6 0.61 0.27-1.36 0.23 42

1 st Co-Primary Outcome (30 days to 1 Year) (830 Off Pump # pts patients) On Pump #pts Hazard Ratio 95 CI p value Primary Outcome Death, Stroke, MI, Renal Failure 6 9 0.64 Components Death 4 6 0.64 Stroke 1 1 0.96 Non Fatal MI 2 2 0.95 New Renal Failure 0 1 0.28 PCI 6 2 2.88 Re-do CABG 0 0 1.00 43

1 st Co-Primary Outcome (1 Year) (830 patients) Primary Outcome Death, Stroke, MI, Renal Failure Components Off Pump On Pump Hazard Ratio 95 CI p value 10.5 16.3 0.63 0.43-0.93 0.019 Death 3.4 4.1 0.83 0.41-1.68 0.60 Stroke 1.5 2.0 0.76 0.26-2.18 0.61 Non Fatal MI 7.8 11.2 0.69 0.44-1.09 0.11 New Renal Failure 0.2 1.2 0.20 0.02-1.72 0.14 PCI 1.7 1.0 1.78 0.52-6.08 0.36 Re-do CABG 0 0 1.00.. 44

Costs per patient at 1 year Off-pump $ On-pump $ Difference $ Initial Hospitalization 8588 9522-935 Discharge to 6 months 907 572 335 6 to 12 months 286 533-247 Total 9780 10627-847 The costs do not include the off-pump retractor or the CPB disposals The final cost will vary per center and their local contracts 45

Conclusions Significant benefits with Off-pump CABG at 30 days and 1 year in Canadian centres Same variation of risks/benefits by EuroSCORE is seen Reduction of $847 average cost per patient Off-pump CABG should be mastered by all Canadian cardiac surgeons 46

Recruitment CHUM: 309 Hamilton General: 210 London Univ. Hosp.: 106 Vancouver St Paul s: 61 Foothills Medical Centre: 51 Montreal Heart Institute: 35 Sunnybrook HSC: 30 Toronto General: 14 CHUS: 14 47