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,

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


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


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


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


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 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.


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 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).


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


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


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


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


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%


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%


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%


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%


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%


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


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)


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


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


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


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.


MEND-CABG II Manuscript

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

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,

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