John H. Alexander, MD, MS, FACC

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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

• John H. Alexander, MD, MS, FACC
• On behalf of the MEND-CABG II Investigators

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Disclosures

• The MEND-CABG II Trial was supported by Medicure
  International Inc.
• Disclosures
• John Alexander Research Support Medicure Signifi
  cant
• Honoraria Medicure Modest
• This presentation discusses the unapproved use of
  MC-1 in patients undergoing CABG surgery

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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 lt
  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
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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

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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
2005141435-1442.
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MEND-CABG Phase II Study of MC-1 in High-risk
Patients Undergoing Coronary Artery Bypass Graft
Surgery

• N901
• Undergoing CABG
• 42 sites
• April 1, 2004 - July 12, 2005

-Tardif JC. J Thorac Cardiovasc Surg
20071331604-1611.
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MEND-CABG Results
Readjudicated, Blinded Post-Hoc Analyses
CKMBgt50ng/mL
-Tardif JC. J Thorac Cardiovasc Surg
20071331604-1611.
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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 safety of MC-1 administered in
  patients undergoing CABG surgery.

-Mehta RH. Am Heart J 200801-9 (in press).
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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 (gt48 hours but lt6 weeks)
• Prior PVD revascularization procedure
• Moderate renal dysfunction (eCrCl 30-60 ml/min)
• Informed consent

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Exclusion Criteria

• Planned concomitant valve or other major surgery
• Acute MI (lt48 hours), cardiogenic shock, or acute
  interventricular or papillary muscle rupture
• Uncontrolled diabetes (serum glucose gt432 mg/dL)
• Severe renal dysfunction (eCrCl lt30mg/dL) or
  nephrotic syndrome
• Mini-Mental State Examination (MMSE) score lt24
• History of malignancy in the past 5 years
• Alcohol or drug abuse
• Pregnancy
• Participation in an investigational drug or
  device trial within 30 days

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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

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Study Flow
CABG Surgery Assessed for Eligibility (n7230)
130 Sites Canada, USA, Germany Oct 2006 - Sept
2007

• Excluded
• Did not meet criteria (n3119)
• Refused (n605)
• Other (n483)

Randomized (n3023)
Assigned to MC-1 (n1519)
Assigned to Placebo (n1504)
Did not receiveassigned study drug
N33
N20
Did not undergo surgery
N28
N22
MC-1 (n1510, 99.4)
Placebo (n1476, 98.8)
Primary Outcome 30-day CV Death or MI
Placebo rate 14 80 power, 25 RRR, alpha 0.05
Ongoing
Ongoing
90-day Follow-up
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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

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Past Medical History

• MC-1 Placebo (n 1519) (n 1504)
• Recent MI (lt6 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

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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

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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 gt10 doses of study drug 9.3 6.7

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Concomitant Medications Hospital Discharge

• MC-1 Placebo (n 1508) (n 1506)
• Aspirin 86 86
• ACE inhibitor 45 44
• ARB 7 7
• Beta blocker 86 86
• Statin 84 85
• Antiarrhythmic 24 24

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Primary Outcome
P 0.76
MC-1 Placebo
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Primary Outcome
1.0
Placebo (9.0)
Survival Rate
0.9
MC-1 (9.3)
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
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Primary OutcomeSubgroups
Overall
70
Age (yrs)
lt70
Yes
Diabetes
No
Yes
Hypertension
No
Yes
Renal
No
Dysfunction
U.S.
Region
Canada
Germany
Yes
IV Study
No
Medication
10
1
0.1
MC-1 Better
Placebo Better
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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
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Primary Outcome Post-hoc w/ Different Thresholds
for MI
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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 high-risk
  groups.
• Effective therapies to reduce perioperative
  morbidity and mortality are needed but remain
  elusive.

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