MEND-CABG II: No Benefit of MC-1 in Reducing Death/MI Post-CABG

Shelley Wood

April 04, 2008

April 4, 2008 (Chicago, IL) - Full results of the phase 3 MC-1 to Eliminate Necrosis and Damage in CABG (MEND-CABG) II trial, showing no benefit of the drug in reducing death or MI following CABG, were published online April 1, 2008 in the Journal of the American Medical Association [1]. Lead investigator Dr John H Alexander (Duke Clinical Research Institute, Durham, NC) also presented the findings during a late-breaking abstracts session at the American College of Cardiology 57th Annual Scientific Session.

As previously reported by heartwire , the sponsor of the trial, Medicure, announced back in February that the trial had failed to reach its primary end point. The trial was investigating the use of MC-1 (pyridoxal 5'-phosphate), a purinergic P2-receptor antagonist that blocks intracellular calcium influx, potentially reducing cell damage and cell death in patients undergoing CABG. As reported previously by heartwire , the MEND-CABG I trial produced promising results in roughly 900 patients, apparently reducing perioperative MI, defined as peak CK-MB >100 ng/mL, with no safety concerns associated with the drug.

As Alexander showed during the meeting, however, the 1519 patients who received a 250-mg/day dose of MC-1 in MEND-CABG 2 fared no better than patients who were given placebo. All patients were intermediate- to high-risk patients undergoing CABG at one of 130 sites in Canada, the US, and Germany. After 30 days, the primary efficacy outcome of death or nonfatal MI was roughly 9% in both groups. After four days, all-cause deaths were actually higher in MC-1–treated patients than in placebo-treated patients: 1% vs 0.3% (p=0.03). This finding, while "concerning," is "most likely due to chance," given the lack of differences in 30-day mortality, the authors note. In subgroup analyses, no group appeared to derive benefit from MC-1.

"Among intermediate- to high-risk patients undergoing CABG surgery, MC-1 given immediately before and for 30 days following surgery does not reduce cardiovascular death or nonfatal MI," Alexander concluded.

Seeking explanations

In an interview with heartwire , Alexander said that there were at least two possible explanations for why investigators didn't see a treatment effect in MEND-CABG 2: one is that the effect in MEND-CABG 1 was due to chance; the second is that there may have been differences in the design of the two trials, despite efforts to make them as similar as possible.

"We are teasing through the data looking for differences: there are none that are so apparent that I would really hang my hat on them, although there's some indication that there may have been more baseline pyridoxal 5'-phosphate deficiency in the first trial than in the second." Pyridoxal 5'-phosphate monohydrate is also a naturally occurring metabolite of vitamin B6 (pyridoxine).

There is also some intriguing preliminary data that MC-1 may have beneficial metabolic effects in terms of lowering blood pressure and lipids in diabetic patients with high blood pressure. "It's not inconceivable that MC-1 might be beneficial in those chronic conditions," Alexander suggested to heartwire . "There's more work to do here: we often throw away drugs after a negative trial, and maybe we shouldn't. The problem is really the investment that's needed to move it forward."

For this particular indication in a broad, higher-risk CABG population, however, the jig is likely up, he hinted. "I think that the likelihood of finding something that explains the difference between the first and second MEND-CABG trials to the degree that it would be worth going forward with the development of MC-1 as a cardioprotective drug in bypass surgery is very low."

Effective therapies needed

In the paper, Alexander et al note that MC-1 is just one of several agents that have been investigated as possible avenues for preventing complications of ischemia-reperfusion injury during and following CABG, many of which have failed, including pexelizumab and cariporide. More promising is the adenosine-regulating drug acadesine, licensed by Schering-Plough from PeriCor Therapeutics, which at least in a phase 2 study was associated with significantly reduced dopamine use and better left ventricular function postoperatively; a phase 3 trial is in the works.

That said, the phase 2 MEND-CABG study also raised hopes that were subsequently dashed by the trial results presented earlier this week, a point emphasized by Alexander. "Ischemia-reperfusion injury is clearly a problem, and we haven't yet found something that addresses it. We saw again in MEND-CABG 2 the extent of myocardial injury that does occur," he said.

Alexander disclosed receiving "significant" research support and "modest" honoraria from Medicure.

  1. MEND-CABG II investigators. Efficacy and safety of pyridoxal 5'-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery. JAMA 2008; 299: doi:10.1001/jama.299.15.joc80027. Available at: http://jama.ama-assn.org . Abstract

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