Effects of C5 Complement Inhibitor Pexelizumab on Outcome in High-Risk Coronary Artery Bypass Grafting: Combined Results From the PRIMO-CABG I and II Trials

Study Questions:

What is the safety and efficacy of terminal complement inhibition in reducing perioperative myocardial infarction (MI) and mortality in patients undergoing coronary artery bypass graft (CABG) surgery who have two or more predefined preoperative risk factors?

Methods:

PRIMO-CABG II, a randomized, double-blind, placebo-controlled trial, enrolled 4,254 patients undergoing CABG with or without valve surgery at 249 hospitals in North America and Western Europe from June 2004 to July 2005. The patients were randomly assigned to receive intravenous pexelizumab or placebo. The primary composite endpoint was the incidence of death or MI within 30 days of randomization. Survival analysis was performed on the mortality data and included Kaplan-Meier curve estimation and Cox proportional hazard modeling.

Results:

The PRIMO-CABG II trial did not meet its prespecified primary endpoint of death or MI at 30 days, the secondary endpoints of death at 30 days, or the development of new or worsening congestive heart failure (relative risk, 0.91, 0.82, and 1.01, respectively; p > 0.05). However, in a combined analysis of both pivotal trials, PRIMO-CABG I and II (n = 7,353), death at 30 days was significantly reduced for the greatest risk subset (n = 2,156, pexelizumab 5.7% vs. placebo 8.1%, p = 0.024). Furthermore, this mortality reduction persisted throughout the 180-day follow-up period (pexelizumab 11.1% vs. placebo 14.4%; p = 0.036).

Conclusions:

The authors concluded that pexelizumab was associated with a nonsignificant 6.7% reduction in the primary composite endpoint of death or MI at postoperative day 30 in CABG patients enrolled in the PRIMO-CABG II trial.

Perspective:

The primary finding of this study is that the previously reported relationship between the predefined patient risk factors and treatment effect with pexelizumab was not demonstrable in the PRIMO-CABG II trial. The absence of a significant favorable treatment effect of pexelizumab on reducing myocardial damage was consistent with the results of the APEX trial, which showed no benefit of pexelizumab in patients with acute MI treated with percutaneous coronary intervention. The mortality benefit for high-risk surgical patients with pexelizumab should only be considered hypothesis generating, but may merit further study.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Cardiac Surgery and Heart Failure, Novel Agents, Acute Heart Failure

Keywords: Antibodies, Monoclonal, Humanized, North America, Myocardial Infarction, Follow-Up Studies, Risk Factors, Complement C5, Europe, Percutaneous Coronary Intervention, Postoperative Period, Incidence, Heart Failure, Survival Analysis, Coronary Artery Bypass, Single-Chain Antibodies


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