John H. Alexander, MD, MS, FACC Robert W. Emery, MD, FACC

1. A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Cardioprotective Effects of MC-1 in Patients Undergoing High-Risk Coronary Artery Bypass Graft Surgery Primary Results of the MEND-CABG II Trial John H. Alexander, MD, MS, FACC Robert W. Emery, MD, FACC On behalf of the MEND-CABG II Investigators

2. Disclosures The MEND-CABG II Trial was sponsored by Medicure International Inc. Disclosures John Alexander: Research Support Medicure Significant Honoraria Medicure Modest Robert Emery: Honoraria Medicure Modest This presentation discusses the unapproved use of MC-1 in patients undergoing CABG surgery

3. I IIa IIb III Indications for CABG ACC/AHA Practice Guidelines 2004 CABG for left main disease CABG for LM equivalent disease (prox LAD + LCX) CABG for angina w/ 3v disease (benefit greater w/ ▼ LVEF) CABG for 2v disease w/ prox LAD and either LVEF < 50% or ischemia CABG for 1 or 2v disease w/o prox LAD if significant viability and high-risk —http://www.acc.org/clinical/guidelines/cabg/cabg.pdf

4. Complications of CABG • Complications of CABG surgery • Death (1-3%) • Myocardial infarction (2-15%) • Stroke (2-5%) • Acute renal injury (5-8%) • Ischemia reperfusion injury

5. MC-1 (Pyridoxal 5’-Phosphate) • Naturally occurring metabolite of pyridoxine (vitamin B6) • Blocks ATP-induced calcium influx via purinergic receptor inhibition • Reduces infarct size in animal models of myocardial and cerebral ischemia-reperfusion injury • Reduces infarct size (AUC CK-MB) in high-risk patients undergoing PCI • Excellent safety profile -Kandzari DE. Expert Opin Investig Drugs 2005;14:1435-1442.

6. Placebo 30 days (n = 298) RANDOMIZE • End points • Composite of death, non-fatal MI, and non-fatal stroke POD 30 • Follow up to POD 90 • Study objectives • Demonstrate efficacy of MC-1 in CABG population • Identify appropriate end points and dose of MC-1 for phase III trial(s) MC-1 250 mg/day 30 days (n = 301) • MC-1 750 mg/day • 30 days (n = 301) MEND-CABG Phase II Trial of MC-1in High-risk Patients Undergoing Coronary Artery Bypass Graft Surgery • N=901 • Undergoing CABG • 42 sites • April 1, 2004 - July 12, 2005 -Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.

7. P=0.89 P=0.31 P=0.15 P=0.07 P=0.03 P=0.03 MEND-CABG Results Readjudicated, Blinded Post-Hoc Analyses CKMB>50ng/mL -Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.

8. MEND-CABG II Objectives • To assess the effect of MC-1 (250mg / day) on the incidence of 30-day cardiovascular death or non-fatal MI in high-risk patients undergoing CABG surgery. • To assess the safety of MC-1 administered in patients undergoing CABG surgery. -Mehta RH. Am Heart J 2008;0:1-9 (in press).

9. Inclusion Criteria • Planned CABG surgery with CPB • Age ≥18 years • Two or more high-risk features • Age ≥65 years • Current or recent smoker • Diabetes mellitus • LVEF 45% or clinical heart failure • History of stroke, TIA, CEA, or ≥50% carotid stenosis • Requirement for urgent surgery • Recent MI (>48 hours but <6 weeks) • Prior PVD revascularization procedure • Moderate renal dysfunction (eCrCl 30-60 ml/min) • Informed consent

10. Exclusion Criteria • Planned concomitant valve or other major surgery • Acute MI (<48 hours), cardiogenic shock, or acute interventricular or papillary muscle rupture • Uncontrolled diabetes (serum glucose >432 mg/dL) • Severe renal dysfunction (eCrCl <30mg/dL) or nephrotic syndrome • Mini-Mental State Examination (MMSE) score <24 • History of malignancy in the past 5 years • Alcohol or drug abuse • Pregnancy • Participation in an investigational drug or device trial within 30 days

11. Study Drug • MC-1 or matching placebo • First oral dose 3-10 hours before surgery • First postoperative dose 24 (8) hours after preoperative dose and then daily for 30 days • IV study drug (MC-1 5mg) or placebo given for up to 4 days postoperatively for patients unable to take oral medication

12. Study Outcomes • Primary - CV death or MI through 30-days • To Day 4: CKMB >100ng/mL CKMB >70ng/mL with new Q waves • Day 4-30: CKMB >25ng/mL or new Q waves • Statistical Analysis • Intent-to-treat, chi-square test • Placebo rate = 14%, 80% power, 25% RRR, alpha 0.05

13. CABG Surgery Assessed for Eligibility (n=7230) Study Flow 130 Sites Canada, USA, Germany Oct 2006 - Sept 2007 • Excluded • Did not meet criteria (n=3119) • Refused (n=605) • Other (n=483) Randomized (n=3023) Assigned to MC-1 (n=1519) Assigned to Placebo (n=1504) Did not receiveassigned study drug N=20 N=33 N=22 Did not undergo surgery N=28 MC-1 (n=1510, 99.4%) Placebo (n=1476, 98.8%) 30-day cardiovascular death or MI Ongoing Ongoing 90-day Follow-up

14. Study Organization • Steering Committee: Jean-Claude Tardif (co-chair), Robert Emery (co-chair),Robert Harrington, Michel Carrier, John Alexander, Michael Mack, Phillipe Ménasché, Robert Coté, Elliott Bennett-Guerrero, Gerhard Schuler, Jan-Ake Westin • Data Safety Monitoring Board: Bruce Ferguson (chair), Chris Buller, Lemuel Moye, Uwe Zeymer • Clinical Events Committee: Philippe L’Allier (chair), Karen Modesto, Jean Gregoire, Reda Ibrahim, Celine Chayer, Sylvain Lanthier • Collaborators: Almac (randomization, pharmacy), Cirion (core labs), Duke Clinical Research Institute (stats), i3 Research (data management), Medicure (sponsor)

15. John H. Alexander, MD, MS, FACC Robert W. Emery, MD, FACC On behalf of the MEND-CABG II Investigators

16. Baseline Characteristics MC-1 Placebo (n = 1519) (n = 1504) Age (yr) 66 (58-73) 67 (58-73) Female 24% 24% White 90% 92% Weight (kg) 86 (76-100) 86 (76-98) Hypertension 83% 83% Smoking (current) 28% 27% Diabetes 48% 45% Renal dysfunction 13% 14%

17. Past Medical History MC-1 Placebo (n = 1519) (n = 1504) Recent MI (<6 weeks) 29% 29% Prior PCI 32% 29% Prior CABG 4.7% 4.4% Stroke 8.0% 8.8% PVD 12% 14% Atrial fibrillation 5.4% 5.2% Heart failure 24% 25% NYHA HF class III / IV 8.8% 9.4% COPD 15% 15%

18. Surgical Details MC-1 Placebo (n = 1508) (n = 1506) Cardiopulmonary bypass 99% 97% Cross Clamp duration, (hrs) 1.0 (0.7-1.3) 1.0 (0.7-1.3) Surgery duration, (hrs) 4.2 (3.4-5.1) 4.2 (3.5-5.1) Nadir body temp, (OC) 33 33 Internal thoracic artery graft 90% 90% Vein graft 93% 92% Other arterial graft 8.4% 9.3%

19. Study Drug MC-1 Placebo (n = 1508) (n = 1506) Study drug before surgery 99% 99% Time from study drug 5.0 (3.9-7.5) 5.2 (4.0-7.7) to surgery, (hrs) Received postoperative 20% 19% IV study drug Missed >10 doses of study drug 9.3% 6.7%

20. Primary Outcome 1.0 Placebo (9.0%) 0.9 MC-1 (9.3%) Freedom from CV Death or MI Relative Risk 1.04 (95% CI 0.83-1.30, p = 0.76) 0.8 0 5 10 15 20 25 30 Days Since Surgery or Randomization

21. Primary OutcomeSubgroups Overall Age (yrs) ≥70 <70 Diabetes Yes No Hypertension Yes No Renal Yes No Dysfunction Region U.S. Canada Germany IV Study Yes No Medication 0.1 1 10 MC-1 Better Placebo Better

22. Other Outcomes MC-1 Placebo (n = 1508) (n = 1506) Mortality Day 4* 1.0% 0.3% Day 30 1.9% 1.5% Non-fatal MI Day 30 8.0% 8.2% Stroke 1.6% 1.7% Atrial fibrillation 31% 33% Cardioversion 3.2% 3.1% Blood transfusion 52% 52% Renal failure 3.1% 2.2% ICU LOS, days 2 (1-3) 1 (1-3) Hospital LOS, days 6 (5-8) 6 (5-8) *P = 0.03

23. Conclusions • Among intermediate- to high-risk patients undergoing CABG surgery, MC-1 (250 mg/day) given immediately before and for 30-days following surgery does not reduce cardiovascular death or non-fatal MI. • Significant myocardial injury remains common following CABG surgery. • The discrepant results between MEND-CABG and MEND-CABG II deserve further investigation, including additional investigation of higher-risk groups. • Effective therapies to reduce perioperative morbidity and mortality are needed but remain elusive.

24. MEND-CABG II Manuscript http://jama.ama-assn.org/