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MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery II — Presented at SCAI-ACC i2 Summit/ACC 2008 - MEND-CABG II
Description:
The goal of this trial was to evaluate treatment with pyridoxal 5’-phosphate (MC-1) compared with placebo in intermediate- to high-risk patients undergoing coronary artery bypass grafting (CABG).
Hypothesis:
MC-1 will be more effective in reducing death or myocardial infarction (MI) after CABG.
Study Design
- Placebo Controlled
- Randomized
- Blinded
Patients Screened: 7,230
Patients Enrolled: 3,023
Mean Follow Up: 90 days
Mean Patient Age: 66 years
Female: 24
Mean Ejection Fraction: LVEF ≥50%, 64%; LVEF 40-49%, 20%; LVEF 25-39%, 13%
Patient Populations:
• Intermediate- to high-risk patients undergoing CABG
At least two of the following features required:
• Age greater than 65 years
• Current smoking
• Diabetes mellitus
• Left ventricular (LV) dysfunction (ejection fraction [EF] ≤45%) or congestive heart failure
• History of stroke, transient ischemic attack, or carotid endarterectomy
• Need for urgent CABG
• Recent MI (48 hours to 6 weeks prior to enrollment)
• Prior peripheral artery revascularization
• Moderate renal insufficiency (creatinine clearance 30-60 ml/min)
• Asymptomatic carotid artery stenosis of at least 50%
Exclusions:
• Pregnancy
• Planned concomitant valve or other surgery
• Inability to have a screening visit 4 hours before surgery
• Mini-Mental State Examination score <24
• Cardiogenic shock
• Interventricular or papillary muscle rupture
• Uncontrolled diabetes
• Creatinine clearance <30 ml/min
• Malignancy in the last 5 years
• Current alcohol or drug abuse
• Any medical or psychiatric condition that would limit the patient’s ability to be an optimal study participant
• Participation in another investigation study in the last 30 days
Primary Endpoints:
• Cardiovascular death or nonfatal MI at 4 days
• MI was defined as creatine kinase-myocardial band (CK-MB) ≥100 ng/ml
Secondary Endpoints:
• Cardiovascular death or nonfatal MI at 30 days
• All-cause and cardiovascular death at 4, 30, and 90 days
• Stroke at 4, 30, and 90 days
• New atrial fibrillation at 4, 30, and 90 days
• Intensive care unit and hospitalization length of stay
• CK-MB fraction under the curve at 24 hours
Drug/Procedures Used:
Intermediate- to high-risk patients undergoing CABG were randomized to MC-1 (n = 1,519) or placebo (n = 1,504). MC-1 or placebo was given immediately before and 30 days after CABG. Medications were given intravenously if the patient was unable to swallow.
Concomitant Medications:
Aprotinin and tranexamic acid were given to 16% and 22% of patients, respectively. At discharge, aspirin was given to 86% of patients, angiotensin-converting enzyme inhibitors to 45%, beta-blockers to 86%, and statins to 84%.
Principal Findings:
Among the participants, there were 27% current smokers, 13% with renal dysfunction, 29% with MI in the past 6 weeks, 8.4% with prior stroke, 13% with peripheral vascular disease, and 24% with congestive heart failure.
Cardiopulmonary bypass support was used in 98% of study participants with a median duration of aortic cross-clamp time of 1.0 hours. An internal mammary artery graft was used in 90%.
The primary outcome, cardiovascular death or nonfatal MI at 30 days, occurred in 9.3% of the MC-1 group and 9.0% of the control group (p = 0.76). There was no difference in the primary outcome in any subgroup tested: age, diabetes, hypertension, renal dysfunction, region of enrollment, or need for intravenous study medication.
All-cause mortality was 1.0% versus 0.3% at 4 days (p = 0.03) and 1.9% versus 1.5% at 30 days (p = 0.44), respectively, for MC-1 versus placebo. Cardiovascular mortality was 1.0% versus 0.3% at 4 days (p = 0.03) and 1.7% versus 1.2% at 30 days (p = 0.32), respectively. There was no difference in nonfatal MI, nonfatal stroke, or atrial fibrillation at 30 days.
Interpretation:
This study failed to demonstrate a benefit of MC-1 among intermediate- to high-risk patients undergoing CABG. This agent did not reduce the composite outcome of cardiovascular death or nonfatal MI at 30 days. It was concerning that MC-1 increased cardiovascular and all-cause mortality at 4 days, although by 30 days, there was no longer a difference in either of these outcomes between MC-1 and placebo. No benefit was observed among the subgroups tested, although it is unknown if certain patients with very high risk for ischemic reperfusion injury (for example, cardiogenic shock or prolonged ischemic time) would benefit from MC-1.
MC-1 is a purinergic receptor antagonist that contains a naturally occurring metabolite of pyridoxine (vitamin B6). Preclinical studies had suggested that MC-1 could prevent cellular calcium overload and ischemia-reperfusion injury. This study is similar to previous trials that failed to demonstrate a benefit with pexelizumab and cariporide.
References:
Alexander JH, Emery RW, Carrier M, et al., on behalf of the MEND-CABG II Investigators. Efficacy and safety of pyridoxal 5’-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: The MEND-CABG II randomized clinical trial. JAMA 2008;299:1777-1787.
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 (CABG) Surgery: Primary Results of the MEND-CABG II Trial. Presented by Dr. John Alexander at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.
Keywords: Antibodies, Monoclonal, Humanized, Ischemic Attack, Transient, Creatinine, Calcium, Shock, Cardiogenic, Vitamin B 6, Cardiopulmonary Bypass, Carotid Stenosis, Hypertension, Single-Chain Antibodies, Phosphates, Stroke, Endarterectomy, Carotid, Guanidines, Purinergic Antagonists, Pyridoxine, Sulfones, Smoking, Peripheral Vascular Diseases, Renal Insufficiency, Reperfusion Injury, Heart Failure, Mammary Arteries, Coronary Artery Bypass, Pyridoxal, Diabetes Mellitus
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