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

MEND-CABG II ACC08 LBCT JHA, 1

John H. Alexander, MD, MS, FACCJohn H. Alexander, MD, MS, FACC

Robert W. Emery, MD, FACCRobert W. Emery, MD, FACC

On behalf of the MEND-CABG II InvestigatorsOn 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

Primary Results of the Primary Results of the MEND-CABG II TrialMEND-CABG II Trial


DisclosuresDisclosures

The MEND-CABG II Trial was sponsored by The MEND-CABG II Trial was sponsored by Medicure International Inc.Medicure International Inc.

DisclosuresDisclosures

John Alexander: John Alexander: Research SupportResearch Support MedicureMedicure SignificantSignificant

HonorariaHonoraria MedicureMedicure ModestModest

Robert Emery:Robert Emery: HonorariaHonoraria MedicureMedicure ModestModest

This presentation discusses the unapproved use This presentation discusses the unapproved use of MC-1 in patients undergoing CABG surgeryof MC-1 in patients undergoing CABG surgery


IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

—http://www.acc.org/clinical/guidelines/cabg/cabg.pdf

Indications for CABG Indications for CABG ACC/AHA Practice Guidelines 2004ACC/AHA Practice Guidelines 2004

CABG for left main diseaseCABG for left main disease

CABG for LM equivalent disease (prox CABG for LM equivalent disease (prox LAD + LCX)LAD + LCX)

CABG for angina w/ 3v disease (benefit CABG for angina w/ 3v disease (benefit greater w/ greater w/ ▼ ▼ LVEF)LVEF)

CABG for 2v disease w/ prox LAD and CABG for 2v disease w/ prox LAD and either LVEF < 50% or ischemiaeither LVEF < 50% or ischemia

CABG for 1 or 2v disease w/o prox LAD CABG for 1 or 2v disease w/o prox LAD if significant viability and high-riskif significant viability and high-risk


Complications of CABGComplications of CABG

Complications of CABG surgeryComplications 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 injuryIschemia reperfusion injury


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.


MEND-CABG Phase II Trial of MC-1 in High-risk Patients Undergoing Coronary Artery Bypass Graft Surgery

N=901Undergoing

CABG42 sites April 1, 2004 -

July 12, 2005

RANDOMIZE

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/day30 days

(n = 301)

-Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.-Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.


MEND-CABG ResultsMEND-CABG Results

25.1%

21.6%

25.6%

20.1%

13.6%

15.6%16.4%

10.3%11.3%

0%

5%

10%

15%

20%

25%

30%

30-d

ay C

V D

eath

, MI,

Str

oke

Primary Endpoint CKMB>70ng/mL CKMB>100ng/mL

Placebo

250mg MC-1

750mg MC-1

P=0.89

P=0.31 P=0.15

P=0.03 P=0.07

P=0.03

Readjudicated, Blinded Readjudicated, Blinded Post-Hoc AnalysesPost-Hoc Analyses

-Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.-Tardif JC. J Thorac Cardiovasc Surg 2007;133:1604-1611.

CKMB>50ng/mL


MEND-CABG II ObjectivesMEND-CABG II Objectives

To assess the effect of MC-1 (250mg / day) To assess the effect of MC-1 (250mg / day) on the incidence of 30-day cardiovascular on the incidence of 30-day cardiovascular death or non-fatal MI in high-risk patients death or non-fatal MI in high-risk patients undergoing CABG surgery. undergoing CABG surgery.

To assess the safety of MC-1 administered in To assess the safety of MC-1 administered in patients undergoing CABG surgery. patients undergoing CABG surgery.

-Mehta RH. Am Heart J 2008;0:1-9 (in press).


Inclusion CriteriaInclusion Criteria Planned CABG surgery with CPBPlanned CABG surgery with CPB Age Age ≥≥18 years18 years Two or more high-risk featuresTwo 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 consentInformed consent


Exclusion CriteriaExclusion Criteria

Planned concomitant valve or other major surgeryPlanned concomitant valve or other major surgery Acute MI (<48 hours), cardiogenic shock, or acute Acute MI (<48 hours), cardiogenic shock, or acute

interventricular or papillary muscle ruptureinterventricular 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 Severe renal dysfunction (eCrCl <30mg/dL) or

nephrotic syndromenephrotic syndrome Mini-Mental State Examination (MMSE) score <24Mini-Mental State Examination (MMSE) score <24 History of malignancy in the past 5 yearsHistory of malignancy in the past 5 years Alcohol or drug abuseAlcohol or drug abuse PregnancyPregnancy Participation in an investigational drug or device trial Participation in an investigational drug or device trial

within 30 dayswithin 30 days


Study DrugStudy Drug

MC-1 or matching placeboMC-1 or matching placebo

First oral dose 3-10 hours before surgeryFirst oral dose 3-10 hours before surgery

First postoperative dose 24 (First postoperative dose 24 (8) hours after 8) hours after preoperative dose and then daily for 30 dayspreoperative dose and then daily for 30 days

IV study drug (MC-1 5mg) or placebo given IV study drug (MC-1 5mg) or placebo given for up to 4 days postoperatively for patients for up to 4 days postoperatively for patients unable to take oral medicationunable to take oral medication


Study OutcomesStudy Outcomes

Primary - CV death or MI through 30-daysPrimary - CV death or MI through 30-daysTo Day 4: To Day 4: CKMB >100ng/mLCKMB >100ng/mL

CKMB >70ng/mL with new Q wavesCKMB >70ng/mL with new Q wavesDay 4-30: Day 4-30: CKMB >25ng/mL or new Q wavesCKMB >25ng/mL or new Q waves

Statistical AnalysisIntent-to-treat, chi-square testPlacebo rate = 14%, 80% power, 25% RRR, alpha 0.05


Study FlowStudy 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)

90-day Follow-up

MC-1(n=1510, 99.4%)

Placebo(n=1476, 98.8%)

Ongoing Ongoing

Did not receiveassigned study drug

Did not undergo surgery N=28

N=33

N=22

N=20

130 Sites

Canada, USA, Germany

Oct 2006 - Sept 2007

30-day cardiovascular death or MI


Study OrganizationStudy Organization Steering Committee: 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:Data Safety Monitoring Board: Bruce Ferguson (chair), Bruce Ferguson (chair), Chris Buller, Lemuel Moye, Uwe ZeymerChris Buller, Lemuel Moye, Uwe Zeymer

Clinical Events Committee: Clinical Events Committee: Philippe L’Allier (chair), Karen Philippe L’Allier (chair), Karen Modesto, Jean Gregoire, Reda Ibrahim, Celine Chayer, Modesto, Jean Gregoire, Reda Ibrahim, Celine Chayer, Sylvain LanthierSylvain Lanthier

Collaborators:Collaborators: Almac (randomization, pharmacy), Cirion Almac (randomization, pharmacy), Cirion (core labs), Duke Clinical Research Institute (stats), i3 (core labs), Duke Clinical Research Institute (stats), i3 Research (data management), Medicure (sponsor)Research (data management), Medicure (sponsor)


John H. Alexander, MD, MS, FACCJohn H. Alexander, MD, MS, FACC

Robert W. Emery, MD, FACCRobert W. Emery, MD, FACC

On behalf of the MEND-CABG II InvestigatorsOn behalf of the MEND-CABG II Investigators


Baseline CharacteristicsBaseline Characteristics

MC-1MC-1 PlaceboPlacebo(n = 1519)(n = 1519) (n = 1504)(n = 1504)

Age (yr)Age (yr) 66 (58-73)66 (58-73) 67 (58-73)67 (58-73)

FemaleFemale 24%24% 24%24%

White White 90%90% 92%92%

Weight (kg)Weight (kg) 86 (76-100)86 (76-100) 86 (76-98)86 (76-98)

HypertensionHypertension 83%83% 83%83%

Smoking (current) Smoking (current) 28%28% 27%27%

Diabetes Diabetes 48%48% 45%45%

Renal dysfunctionRenal dysfunction 13%13% 14% 14%


Past Medical HistoryPast Medical History


Recent MI (<6 weeks) Recent MI (<6 weeks) 29%29% 29%29%

Prior PCI Prior PCI 32%32% 29%29%

Prior CABGPrior CABG 4.7%4.7% 4.4%4.4%

Stroke Stroke 8.0%8.0% 8.8%8.8%

PVDPVD 12%12% 14%14%

Atrial fibrillationAtrial fibrillation 5.4%5.4% 5.2%5.2%

Heart failureHeart failure 24%24% 25%25%

NYHA HF class III / IV NYHA HF class III / IV 8.8%8.8% 9.4%9.4%

COPDCOPD 15%15% 15%15%


Surgical DetailsSurgical Details


Cardiopulmonary bypassCardiopulmonary bypass 99%99% 97%97%

Cross Clamp duration, (hrs)Cross Clamp duration, (hrs) 1.0 (0.7-1.3) 1.0 (0.7-1.3) 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, (Nadir body temp, (OOC)C) 3333 3333

Internal thoracic artery graft Internal thoracic artery graft 90%90% 90%90%

Vein graftVein graft 93%93% 92%92%

Other arterial graftOther arterial graft 8.4%8.4% 9.3%9.3%


Study DrugStudy Drug


Study drug before surgeryStudy drug before surgery 99%99% 99%99%

Time from study drug Time from study drug 5.0 (3.9-7.5)5.0 (3.9-7.5) 5.2 (4.0-7.7)5.2 (4.0-7.7)

to surgery, (hrs)to surgery, (hrs)

Received postoperative Received postoperative 20%20% 19%19%

IV study drugIV study drug

Missed >10 doses of study drugMissed >10 doses of study drug 9.3%9.3% 6.7%6.7%


Primary OutcomePrimary Outcome

0.8

0.9

1.0

0 5 10 15 20 25 30

Fre

edo

m f

rom

CV

Dea

th o

r M

I

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)


Primary OutcomePrimary OutcomeSubgroupsSubgroups

1010.1

MC-1 Better Placebo Better

NoYes

GermanyCanadaU.S.

NoYes

NoYes

NoYes

<70≥70

IV Study Medication

Region

Renal Dysfunction

Hypertension

Diabetes

Age (yrs)

Overall


Other OutcomesOther Outcomes


MortalityMortality Day 4*Day 4* 1.0%1.0% 0.3%0.3%

Day 30Day 30 1.9%1.9% 1.5%1.5%

Non-fatal MI Day 30Non-fatal MI Day 30 8.0%8.0% 8.2%8.2%

StrokeStroke 1.6%1.6% 1.7%1.7%

Atrial fibrillationAtrial fibrillation 31%31% 33%33%

CardioversionCardioversion 3.2%3.2% 3.1%3.1%

Blood transfusionBlood transfusion 52%52% 52%52%

Renal failureRenal failure 3.1%3.1% 2.2%2.2%

ICU LOS, daysICU LOS, days 2 (1-3)2 (1-3) 1 (1-3)1 (1-3)

Hospital LOS, daysHospital LOS, days 6 (5-8)6 (5-8) 6 (5-8)6 (5-8)

*P = 0.03


ConclusionsConclusions

Among intermediate- to high-risk patients undergoing Among intermediate- to high-risk patients undergoing CABG surgery, MC-1 (250 mg/day) given immediately CABG surgery, MC-1 (250 mg/day) given immediately before and for 30-days following surgery does not before and for 30-days following surgery does not reduce cardiovascular death or non-fatal MI. reduce cardiovascular death or non-fatal MI.

Significant myocardial injury remains common following Significant myocardial injury remains common following CABG surgery. CABG surgery.

The discrepant results between MEND-CABG and MEND-The discrepant results between MEND-CABG and MEND-CABG II deserve further investigation, including CABG II deserve further investigation, including additional investigation of higher-risk groups. additional investigation of higher-risk groups.

Effective therapies to reduce perioperative morbidity and Effective therapies to reduce perioperative morbidity and mortality are needed but remain elusive. mortality are needed but remain elusive.


MEND-CABG II ManuscriptMEND-CABG II Manuscript

http://jama.ama-assn.org/http://jama.ama-assn.org/

Documents

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