Ann Thorac Surg 2006;82:492-493
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Invited commentary
Henry Rinder, MD
Department of Hematology, Yale School of Medicine, 333 Cedar St, PO Box 208035, New Haven, CT 06520-8035
(Email: henry.rinder{at}yale.edu).
Complement activation is one pathway of the inflammatory response to cardiac surgery requiring cardiopulmonary bypass (CPB). In vitro extracorporeal circulation models have demonstrated that terminal (C5 and beyond) complement blockade inhibits activation of circulating neutrophils and platelets, indicating a potential for ameliorating complement-dependent ischemia-reperfusion injury. Early clinical studies of pexelizumab showed promise in preventing death or myocardial infarction (MI), or both, and bleeding, and neurocognitive dysfunction after CPB, but the phase III Pexelizumab for Reduction in Myocardial Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial did not significantly reduce the primary endpoint of death or MI, or both, in CABG-only patients. (Full disclosure: this commentator was an author on the in vitro model and the earliest of the in vivo clinical studies.)
Haverich and colleagues [1] have now clarified that it is the subset of patients with multiple risk factors for post-CPB complications who benefited from pexelizumab in PRIMO-CABG, as reflected in a significantly lower incidence of death or MI, or both, at 30 days postoperatively. Unlike the primary endpoint, this significant benefit occurred independent of whether patients received valve replacement in addition to CABG. It is not known how these risk factor subsets may interact with the pathophysiology of CPB-induced complement activation, but interestingly, despite this treatment effect on myocardial tissue injury, the incidence of postoperative atrial fibrillation (approximately 20%) did not differ between treated and placebo groups. Recent data from in vivo cardiac surgery suggest that activated monocytes (but not neutrophils) are associated with an increased risk of post-CPB atrial fibrillation; unlike neutrophils and platelets, monocytes seem to be activated during CPB by complement components proximal to C5.
A November 2005 press release from Alexion Pharmaceuticals (Cheshire, CT), the study co-sponsor, indicated that a second phase III trial of pexelizumab (PRIMO-CABG2) in moderate-high risk patients undergoing cardiac surgery with CPB apparently did not reach statistical significance for the same composite endpoint (death or MI, or both) used in PRIMO-CABG. It will be critical not only to identify relevant patient subsets for outcomes within this second trial, but perhaps to analyze the total experience of both trials to further define what specific preoperative risk factors are most amenable to complement intervention on CPB, and hence to determine which, if any, patient groups may benefit from such an intervention.
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References
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- Haverich A, Shernan SK, Levy JH, et al. Pexelizumab reduces death and myocardial infarction in higher risk cardiac surgical patients Ann Thorac Surg 2006;82:486-493.[Abstract/Free Full Text]
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