mend-cabg ii acc08 lbct jha, 1 john h. alexander, md, ms, facc on behalf of the mend-cabg ii...
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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 theMEND-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 theMEND-CABG II Trial
MEND-CABG II ACC08 LBCT JHA, 2
Disclosures
The MEND-CABG II Trial was supported by Medicure International Inc.
Disclosures
John Alexander: Research Support MedicureSignificant
Honoraria Medicure Modest
This presentation discusses the unapproved use of MC-1 in patients undergoing CABG surgery
MEND-CABG II ACC08 LBCT JHA, 3
II IIaIIa IIbIIb IIIIII
—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
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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 2005;14:1435-1442.
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MEND-CABG Phase II Study 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.
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MEND-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 Post-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 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 2008;0:1-9 (in press).
MEND-CABG II ACC08 LBCT JHA, 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
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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
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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
(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 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
Placebo rate = 14%
80% power, 25% RRR, alpha 0.05
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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 (<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%
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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 >10 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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9.3%9.0%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Day 3
0 C
ard
iovascu
lar
Death
or
MI
Primary Outcome
P = 0.76
MC-1 Placebo
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Primary Outcome
0.8
0.9
1.0
0 5 10 15 20 25 30
Su
rviv
al R
ate
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 OutcomeSubgroups
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
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Other Outcomes
MC-1 Placebo(n = 1508) (n = 1506)
Mortality Day 4* 1.0% 0.3%
Day 301.9% 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
9.3%9.0%
8.1%7.3%
12.7%11.8%
19.7%
17.3%
0%
5%
10%
15%
20%
Da
y 3
0 C
ard
iov
as
cu
lar
De
ath
or
MI
Primary Result CV Death / MI(CKMB>100)
CV Death / MI(CKMB>70)
CV Death / MI(CKMB>50)
MC-1
Placebo
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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/