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
MEND-CABG II ACC08 LBCT JHA, 2
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
MEND-CABG II ACC08 LBCT JHA, 3
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
MEND-CABG II ACC08 LBCT JHA, 4
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
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.
MEND-CABG II ACC08 LBCT JHA, 6
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 II ACC08 LBCT JHA, 7
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 ACC08 LBCT JHA, 8
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).
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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
MEND-CABG II ACC08 LBCT JHA, 10
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
MEND-CABG II ACC08 LBCT JHA, 11
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
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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
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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
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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)
MEND-CABG II ACC08 LBCT JHA, 15
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
MEND-CABG II ACC08 LBCT JHA, 16
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%
MEND-CABG II ACC08 LBCT JHA, 17
Past Medical HistoryPast Medical History
MC-1MC-1 PlaceboPlacebo(n = 1519)(n = 1519) (n = 1504)(n = 1504)
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%
MEND-CABG II ACC08 LBCT JHA, 18
Surgical DetailsSurgical Details
MC-1MC-1 PlaceboPlacebo(n = 1508)(n = 1508) (n = 1506)(n = 1506)
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%
MEND-CABG II ACC08 LBCT JHA, 19
Study DrugStudy Drug
MC-1MC-1 PlaceboPlacebo(n = 1508)(n = 1508) (n = 1506)(n = 1506)
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%
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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)
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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
MEND-CABG II ACC08 LBCT JHA, 22
Other OutcomesOther Outcomes
MC-1MC-1 PlaceboPlacebo(n = 1508)(n = 1508) (n = 1506)(n = 1506)
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
MEND-CABG II ACC08 LBCT JHA, 23
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.
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MEND-CABG II ManuscriptMEND-CABG II Manuscript
http://jama.ama-assn.org/http://jama.ama-assn.org/