Tardif and associates 1 from the Montreal Heart Institute report the results of the double-blind, placebo-controlled MC-1 (cardoxal) to Eliminate Necrosis Damage in Coronary Artery Bypass Grafting (MEND-CABG) trial conducted at 40 centers in the United States and Canada between April 2004 and July 2005. The MEND-CABG trial is a phase II study intended to evaluate the potential cardioprotective and neuroprotective effects of pyridoxal-5=-phosphate (cardoxal) in patients undergoing high-risk coronary artery bypass grafting (CABG). Pyridoxal-5=-phosphate monohydrate (P-5=-P, or MC-1) is a naturally occurring metabolite of pyridoxine that acts as a purinergic receptor antagonist that blocks intracellular influx of calcium, thereby theoretically reducing cell damage during episodes of ischemia and reperfusion.It is important to realize that in the study design the authors and their statistical colleagues decided on the primary and secondary end points on the basis of a careful account of predictable event rates that would balance enrollment (number and associated costs) with need to achieve believable statistical significance. The primary efficacy end point was the combined incidence of cardiovascular death, nonfatal myocardial infarction, and nonfatal cerebral infarction to day 30. Secondary efficacy end points included individual components of the combined end point, area under the curve of creatine kinase isoenzyme MB (CK-MB) within the first 24 hours after CABG, mortality from all causes, and composite and component end points to postoperative day 90. Myocardial infarction was defined in the independent central core electrocardiographic laboratory as follows: (1) peak CK-MB value greater than 50 ng/mL, or greater than 35 ng/mL with electrocardiographic evidence of Q waves through postoperative day 4; (2) peak CK-MB greater than 25 ng/mL or new Q waves occurring after postoperative day 4; and (3) Q-wave or non-Q wave myocardial infarction identified by investigator and confirmed by central core laboratory.P-5=-P did not significantly affect relative to placebo the prespecified composite or component end points of cardiovascular death, myocardial infarction, and nonfatal cerebral infarction at either low (250 mg/d for 30 days) or high (750 mg/d for 30 days) doses. In a post hoc analysis in which the peak CK-MB level was increased to 70 ng/mL or 100 ng/mL, there were significant reductions in the combined end points of death, nonfatal stroke, and nonfatal myocardial infarction with both dosing regimens (250 and 750 mg/d). On the basis of this post hoc analysis, the authors conclude, "Cardoxal may be particularly effective in preventing larger, more significant perioperative infarcts." They then suggest that a larger, better powered trial is needed to evaluate further the cardioprotective effects of cardoxal.There are a number of aspects of this trial that deserve comment. First, we currently live in a clinical world in which more and more emphasis is placed on evidence-based medicine. In the pyramid of importance of ...
