Diagnostic, Technical and Medical

Diagnostic, Technical and Medical Approaches to Reduce CABG Related Stroke Pieter Kappetein, Michael Mack, M.D. Dept Thoracic Surgery, Rotterdam, The Netherlands Baylor Healthcare System Dallas, TX

Background Risk of Stroke Neurological deficit > 72 hours In hospital/ 30 days CABG STS Database 2002-2006, n= 774,881 Stroke =1.4% PCI NCDR Database, 2004-2007, n=706,782 Stroke = 0.22 % SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 2

CVA (Stroke) to 12 Months CABG (N=897) TAXUS (N=903) (%) 20 P=0.003 * Cumu ulative Ev vent Rate 10 0 0 6 12 Months Since Allocation Event rate ± 1.5 SE. * Fisher exact test 2.2% 0.6% ITT population SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 3

In SYNTAX, with CABG one is trading a stroke for repeat revascularization. Who wouldn t want to risk repeat revascularization with PCI rather than a stroke with CABG Common interventional cardiologist s interpretation of Syntax results

CVA to 3 Years CABG (N=897) TAXUS (N=903) P=0.07 Cumula ative Even nt Rate (% %) 40 20 0 Before 1 year * 1-2 years * 2-3 years * 2.2% vs 0.6% 0.6% vs 0.7% 0.5% vs 0.6% P=0.003 P=0.82 P=1.00 3.4% 2.0% 0 12 24 36 Months Since Allocation Cumulative KM Event Rate ± 1.5 SE; log-rank P value;*binary rates EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 5 ITT population

Patients with Stroke in SYNTAX Randomized Cohort, Intent-to-Treat Enrolled N=1800 CABG TAXUS * n=897 n=903 1 Year Follow-up N=1740 (96.7%) CABG TAXUS * n=849 n=891 Stroke n=19 Stroke n=5 * TAXUS Express SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 6

Outcomes Following Stroke (Per Patient) CABG (n=19) PCI (n=5) Death 10.5% (n=2) Non-fatal stroke 89.5% (n=17) Non-fatal stroke 100% (n=5) SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 7

Stroke With CABG Causes Preoperative Intraoperative Postoperative SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 8

Timing of Stroke CABG PCI Total 30 (2.8%) 18 (1.4%) Pre-procedure 3(03%) (0.3%) 0 Procedural- 30 days 9 (1%) 2 (0.2%) 30 days- 1Y Year 7(08%) (0.8%) 3(03%) (0.3%) 1-2 Years 6 (0.6%) 7 (0.7%) 2-3 Years 5 (0.5%) 6 (0.6%) SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 9 Syntax September 3, 9

Timing of Stroke CABG PCI Total 30 (2.8%) 18 (1.4%) Pre-procedure 3(03%) (0.3%) 0 Procedural- 30 days 9 (1%) 2 (0.2%) 30 days- 1Y Year 7(08%) (0.8%) 3(03%) (0.3%) 1-2 Years 6 (0.6%) 7 (0.7%) 2-3 Years 5 (0.5%) 6 (0.6%) SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 10 10

Stroke With CABG Risk Factors Preoperative Intraoperative Postoperative SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 11

Early -35% Delayed- 65% Female Prior Stroke Female Prior Stroke Aortic Aortic Atherosclerosis Atherosclerosis Duration of CPB Diabetes Atrial Fibrillation SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 13

EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 14

Metabolic Syndrome Stroke Rate 4.7% vs 2.1% EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 15

EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 16

EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 17

Periprocedural Multivariate Predictors of Stroke at 12 Months Predictors by Treatment tarm 12 P CABG (n=897) Odds Ratio ± 95% CI OR 95% CI value Poor or moderate LVEF 10 6.3 2.1, 18.4 <0.001 Prior MI 0.1 0, 0.1 0.02 Age 8 1.1 1.0, 1.1 0.06 TAXUS (n=903) Hyperlipidemia Female 6 4 0.1 0.1, 0.6 0.01 5.5 0.9, 33.7 0.09 Time to treatment 10 1.0 10 1.0, 11 1.1 0.001001 2 0 1 2 3 4 5 6 7 Reduced Increased 0 *TAXUS Express SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 18

Stroke With CABG Risk Factors Preoperative Intraoperative Postoperative SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 19

Timing of Stroke CABG PCI Total 25 (2.8%) 12 (1.4%) Pre-procedure 3(03%) (0.3%) 0 Procedural- 30 days 9 (1%) 2 (0.2%) 30 days- 1Y Year 7(08%) (0.8%) 3(03%) (0.3%) 1-2 years 6 (0.6%) 7 (0.7%) SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 20 Syntax September 3, 20

CVA to 12 Months by SYNTAX Score Tercile CABG TAXUS 12 Mon nth Event Rate, % 20 15 10 5 0 P=0.10 P=0.21 P=0.07 1.9 2.4 2.3 0.3 1.0 0.4 Scores 0-22 Scores 23-32 Scores 33 KM Event Rate; chi-square test RCT ITT pts; site-reported data SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 21

Stroke With CABG Risk Factors Intraoperative Aortic Atherosclerosis Aortic Manipulation Cardiopulmonary Bypass Cerebral Perfusion On pump vs. Off pump SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 22

Procedural Characteristics Notable Differences CABG RCT + Registry Procedure-related CABG RCT * (n=897) CABG Reg (n=644) Off-pump surgery, % 15.0 18.6 Graft revascularization, % At least one arterial graft 97.3 96.7 Arterial graft to LAD 95.6 94.7 LIMA + venous 78.1 85.1 Double LIMA/RIMA 27.6 16.1 Complete arterial revascularization 18.9 11.2 Venous graft only 2.6 3.3 Grafts per patient, mean ±SD 2.8 ± 0.7 3.0 ± 0.9 Distal anastomoses, mean ±SD 3.2 ± 0.9 3.5 ± 1.0 * SYNTAX: Stroke TCT 2009 M.J. Mack For descriptive purposes only; no statistical comparisons done San Francisco, CA 22sep2009 Slide 23

Procedural Characteristics Potential Risk Factors for Stroke CABG N=897 TAXUS N=903 P value Urgent Procedure, % 3.8 4.1 0.72 Emergent Procedure, % 3.9 1.8 0.007 Time to procedure, d, mean ± SD 17.4 ± 28.0 6.9 ± 13.0 <0.001 Off-pump surgery % 15.0 -- -- Off Pump On Pump P value Stroke 1/134 (0.7%) 18/763 (2.3%) ns Site-reported data Allocation to procedure For PCI patients, includes time for staged procedure

EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 25

Risk Factors, and Outcomes Associated With Stroke After Coronary Artery Bypass Grafting.more than half of strokes occurred postoperatively rather than intraoperatively JAMA. 2011;305(4):381-390 SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 27

EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 28

SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 29

Ascending Aortic Atherosclerosis SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 30

Ascending Aortic Atherosclerosis SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 31

Stroke With CABG Risk Factors Preoperative Intraoperative Postoperative SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 32

Timing of Stroke CABG PCI Total 25 (2.8%) 12 (1.4%) Pre-procedure 3(03%) (0.3%) 0 Procedural- 30 days 9 (1%) 2 (0.2%) 30 days- 1Y Year 7(08%) (0.8%) 3(03%) (0.3%) 1-2 years 6 (0.6%) 7 (0.7%) Syntax September 3, 33

Medications Potential Risk Factors for Stroke Pre/periprocedural p Medication CABG N=897 TAXUS N=903 P value Aspirin, % 34.9 96.9 <0.001 Heparin (unfractionated), % 40.2 84.5 <0.001 Heparin (low molecular weight), % 10.8 9.5 0.36 Bivalirudin, % 0.1 7.1 <0.001 Thienopyridine, % 16 1.6 97.5 <0.001001 Aprotinin, % 36.7 -- -- Medication at Discharge Aspirin, % 88.5 96.3 <0.001 Thienopyridine, % 19.5 96.8 <0.001 Coumadin, % 71 7.1 26 2.6 <0.001 001 Statin, % 74.5 86.7 0.57 Site-reported data

Medications at 12 Months Potential Risk Factors for Stroke CABG N=897 TAXUS N=903 P value Aspirin, % 84.3 91.2 <0.001 Statin, % 81.6 85.5 0.03 Beta blockers, % 76.4 78.7 0.26 ACE inhibitors, % 51.0 51.0 0.97 Thienopyridines, % 15.0 71.1 <0.001 Diuretics, % 27.4 25.6 039 0.39 Calcium channel blockers, % 18.9 25.5 0.001 Angiotensin II receptor antagonists, % 13.5 19.0 0.002 Nitrates 7.5 17.4 <0.001 Oral antidiabetic, non insulinsensitizer, % 11.1 10.3 0.61 H2-receptor blockers, % 10.7 12.2 0.35 Medications taken by 10% of patients in either group. Site-reported data

Adverse Cardiac Events to 12 Months CABG (n=19) 6 patients experienced atrial fibrillation (1 patient had an additional ST elevation MI); in 2 of these patients, the arrhythmia possibly led to the stroke 13 -no adverse cardiac events PCI (n=5) 3 patients had cardiac events (cardiac failure, angina, ST+MI) 2 -no adverse cardiac events SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 36

30 day Mortality and stroke higher in the 24% of patients with AF (2.4 % vs 19%) 1.9%) SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 37

Antiplatelet Therapy Status at Time of Stroke (Per Patient) Neither 26.3% (n=5) Unknown 10.5% (n=2) CABG (n=19) Aspirin i 52.6% (n=10) PCI (n=5) Dual Antiplatelet Therapy 80.0% (n=4) Clopidogrel Dual Antiplatelet only Therapy 53%(n=1) 5.3% 53%( 5.3% (n=1) Unknown 20.0% (n=1) SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 38

SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 39

Statins Reduce: Stroke Atrial Fibrillationill Inflammatory Response from CPB SVG Disease Native CAD SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 40

EACTS 2010 Three-year Outcomes of the SYNTAX Trial Kappetein Slide 41

Conclusions How to Reduce Stroke With CABG Preoperative Screening Recognition of High Risk Patients Epiaortic Scanning on ALL Patients At Least Selective Use of Off Pump CABG No Touch Aortic Technique as Much As Possible Aggressive Treatment of AF Anticoagulation of Postoperative AF??? Aggressive Use of Statins Consider dual anti-platelet therapy (DAPT) especially with Off Pump SYNTAX: Stroke TCT 2009 M.J. Mack San Francisco, CA 22sep2009 Slide 42 42