1. MEND-CABG II ACC08 LBCT JHA, 1 John H. Alexander, MD, MS, FACC On behalf of the MEND-CABG II Investigators 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 Main Results of the MEND-CABG II Trial 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 Main Results of the MEND-CABG II Trial

2. MEND-CABG II ACC08 LBCT JHA, 2 Disclosures The MEND-CABG II Trial was supported by Medicure International Inc. Disclosures John Alexander: Research SupportMedicureSignificant HonorariaMedicureModest This presentation discusses the unapproved use of MC-1 in patients undergoing CABG surgery

3. MEND-CABG II ACC08 LBCT JHA, 3IIIIaIIaIIbIIbIIIIII http://www.acc.org/clinical/guidelines/cabg/cabg.pdf 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

4. MEND-CABG II ACC08 LBCT JHA, 4 Complications of CABG Complications of CABG surgery Complications of CABG surgery Death (1-3%) Death (1-3%) Myocardial infarction (2-15%) Myocardial infarction (2-15%) Stroke (2-5%) Stroke (2-5%) Acute renal injury (5-8%) Acute renal injury (5-8%) Ischemia reperfusion injury Ischemia reperfusion injury

5. MEND-CABG II ACC08 LBCT JHA, 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. MEND-CABG II ACC08 LBCT JHA, 6 MEND-CABG Phase II Study of MC-1 in High-risk Patients Undergoing Coronary Artery Bypass Graft Surgery N= 901 Undergoing CABG 42 sites April 1, 2004 - July 12, 2005 RANDOMIZERANDOMIZE Placebo 30 days (n = 298) MC-1 250 mg/day 30 days (n = 301) 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-1 750 mg/day 30 days (n = 301) -Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.

7. MEND-CABG II ACC08 LBCT JHA, 7 MEND-CABG Results P=0.89 P=0.31 P=0.15 P=0.03 P=0.07 P=0.03 Readjudicated, Blinded Post-Hoc Analyses -Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611. CKMB>50ng/mL

8. MEND-CABG II ACC08 LBCT JHA, 8 MEND-CABG II Objectives To assess the cardioprotective 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 cardioprotective 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. 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. MEND-CABG II ACC08 LBCT JHA, 9 Inclusion Criteria Planned CABG surgery with CPB Planned CABG surgery with CPB Age 18 years Age 18 years Two or more high-risk features 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 Informed consent

10. MEND-CABG II ACC08 LBCT JHA, 10 Exclusion Criteria Planned concomitant valve or other major surgery Planned concomitant valve or other major surgery Acute MI (<48 hours), cardiogenic shock, or acute interventricular or papillary muscle rupture Acute MI (<48 hours), cardiogenic shock, or acute interventricular or papillary muscle rupture Uncontrolled diabetes (serum glucose >432 mg/dL) Uncontrolled diabetes (serum glucose >432 mg/dL) Severe renal dysfunction (eCrCl <30mg/dL) or nephrotic syndrome Severe renal dysfunction (eCrCl <30mg/dL) or nephrotic syndrome Mini-Mental State Examination (MMSE) score <24 Mini-Mental State Examination (MMSE) score <24 History of malignancy in the past 5 years History of malignancy in the past 5 years Alcohol or drug abuse Alcohol or drug abuse Pregnancy Pregnancy Participation in an investigational drug or device trial within 30 days Participation in an investigational drug or device trial within 30 days

11. MEND-CABG II ACC08 LBCT JHA, 11 Study Drug MC-1 or matching placebo MC-1 or matching placebo First oral dose 3-10 hours before surgery First oral dose 3-10 hours before surgery First postoperative dose 24 ( 8) hours after preoperative dose and then daily for 30 days 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 IV study drug (MC-1 5mg) or placebo given for up to 4 days postoperatively for patients unable to take oral medication

12. MEND-CABG II ACC08 LBCT JHA, 12 Study Flow CABG Surgery Assessed for Eligibility (n=7230) Randomized (n=3023) Excluded Did not meet criteria (n=3119) Refused (n=605) Other (n=483) Assigned to MC-1 (n=1519) Assigned to Placebo (n=1504) Primary Outcome 30-day CV Death or MI 90-day Follow-up MC-1 (n=1510, 99.4%) Placebo (n=1476, 98.8%) Ongoing Did not receive assigned study drug Did not undergo surgeryN=28 N=33 N=22 N=20 130 Sites Canada, USA, Germany Oct 2006 - Sept 2007 Placebo rate = 14% 80% power, 25% RRR, alpha 0.05

13. MEND-CABG II ACC08 LBCT JHA, 13 Baseline Characteristics MC-1Placebo (n = 1519)(n = 1504) Age (yr)66 (58-73)67 (58-73) Female24%24% White 90%92% Weight (kg)86 (76-100)86 (76-98) Hypertension83%83% Smoking (current) 28%27% Diabetes 48%45% Renal dysfunction13%14%

14. MEND-CABG II ACC08 LBCT JHA, 14 Past Medical History MC-1Placebo (n = 1519)(n = 1504) Recent MI (<6 weeks) 29%29% Prior PCI 32%29% Prior CABG4.7%4.4% Stroke 8.0%8.8% PVD12%14% Atrial fibrillation5.4%5.2% Heart failure24%25% NYHA HF class III / IV 8.8%9.4% COPD15%15%

15. MEND-CABG II ACC08 LBCT JHA, 15 Surgical Details MC-1Placebo (n = 1508)(n = 1506) Cardiopulmonary bypass99%97% Cross Clamp duration, (hrs)1.0 (0.7-1.3) 1.0 (0.7-1.3) Surgery duration, (hrs) Surgery duration, (hrs)4.2 (3.4-5.1)4.2 (3.5-5.1) Nadir body temp, ( O C)3333 Internal thoracic artery graft 90%90% Vein graft93%92% Other arterial graft8.4%9.3%

16. MEND-CABG II ACC08 LBCT JHA, 16 Study Drug MC-1Placebo (n = 1508)(n = 1506) Study drug before surgery99%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 drug9.3%6.7%

17. MEND-CABG II ACC08 LBCT JHA, 17 Concomitant Medications Hospital Discharge MC-1Placebo (n = 1508)(n = 1506) Aspirin86%86% ACE inhibitor45%44% ARB7%7% Beta blocker86%86% Statin84%85% Antiarrhythmic24%24%

18. MEND-CABG II ACC08 LBCT JHA, 18 Primary Outcome P = 0.76 MC-1Placebo

19. MEND-CABG II ACC08 LBCT JHA, 19 Primary Outcome 0.8 0.9 1.0 051015202530 Survival Rate Days Since Surgery or Randomization Placebo (9.0%) MC-1 (9.3%) Relative Risk 1.04 (95% CI 0.83-1.30, p = 0.76)

20. MEND-CABG II ACC08 LBCT JHA, 20 Primary Outcome Subgroups 1010.1 MC-1 BetterPlacebo Better No Yes Germany Canada U.S. No Yes No Yes No Yes <70 70 IV Study Medication Region Renal Dysfunction Hypertension Diabetes Age (yrs) Overall

21. MEND-CABG II ACC08 LBCT JHA, 21 Other Outcomes MC-1Placebo (n = 1508)(n = 1506) MortalityDay 4*1.0%0.3% Day 301.9%1.5% Non-fatal MI Day 308.0%8.2% Stroke1.6%1.7% Atrial fibrillation31%33% Cardioversion3.2%3.1% Blood transfusion52%52% Renal failure3.1%2.2% ICU LOS, days2 (1-3)1 (1-3) Hospital LOS, days6 (5-8)6 (5-8) *P = 0.03

22. MEND-CABG II ACC08 LBCT JHA, 22 Primary Outcome Post-hoc w/ Different Thresholds for MI

23. MEND-CABG II ACC08 LBCT JHA, 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. 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. 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 high-risk groups. The discrepant results between MEND-CABG and MEND- CABG II deserve further investigation, including additional investigation of high-risk groups. Effective therapies to reduce perioperative morbidity and mortality are needed but remain elusive. Effective therapies to reduce perioperative morbidity and mortality are needed but remain elusive.

24. MEND-CABG II ACC08 LBCT JHA, 24 MEND-CABG II Manuscript http://jama.ama-assn.org/