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Ann Thorac Surg 2004;77:942-949
© 2004 The Society of Thoracic Surgeons
a Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
b Department of Anesthesiology, University of Oklahoma, Oklahoma City, Oklahoma, USA
c Department of Cardiovascular Anesthesiology, Texas Heart Institute, Houston, Texas, USA
d Division of Cardiothoracic Surgery, University of Hawaii School of Medicine, Honolulu, Hawaii, USA
e Alexion Pharmaceuticals, Inc, Cheshire, Connecticut, USA
f Division of Cardiac Surgery, Procter and Gamble Pharmaceuticals, Mason, Ohio, USA
g Washington Hospital Center, Washington, DC, USA
h Department of Thoracic and Cardiovascular Surgery, Nebraska Heart Institute, Lincoln, Nebraska, USA
i Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, New Jersey, USA
j Department of Anesthesia, Stanford University, Stanford, California, USA
k Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation, San Francisco, California, USA
Accepted for publication August 19, 2003.
* Address reprint requests to Dr Shernan, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
e-mail: shernan{at}zeus.bwh.harvard.edu
BACKGROUND: During cardiac surgery requiring cardiopulmonary bypass, pro-inflammatory complement pathways are activated by exposure of blood to bio-incompatible surfaces of the extracorporeal circuit and reperfusion of ischemic organs. Complement activation promotes the generation of additional inflammatory mediators thereby exacerbating tissue injury. We examined the safety and efficacy of a C5 complement inhibitor for attenuating inflammation-mediated cardiovascular dysfunction in cardiac surgical patients undergoing cardiopulmonary bypass.
METHODS: Pexelizumab (Alexion Pharmaceuticals, Inc, Cheshire, CT), a recombinant, single-chain, anti-C5 monoclonal antibody, was evaluated in a randomized, double-blinded, placebo-controlled, multicenter trial that involved 914 patients undergoing coronary artery bypass grafting with or without valve surgery requiring cardiopulmonary bypass.
RESULTS: Pexelizumab was administered intravenously as a bolus (2.0 mg/kg) or bolus plus infusion (2.0 mg/kg plus 0.05 mg/kg/h for 24 hours), and inhibited complement activation. There were no statistically significant differences between placebo-treated and pexelizumab-treated patients in the primary endpoint (composite of death, or new Q-wave, or non-Q-wave [myocardial-specific isoform of creatine kinase > 60 ng/mL] myocardial infarction, or left ventricular dysfunction, or new central nervous system deficit). However, post hoc analysis revealed a reduction in the composite of death or myocardial infarction (myocardial-specific isoform of creatine kinase 
100 ng/mL) for the isolated coronary artery bypass grafting, bolus plus infusion subgroup on POD 4 (p = 0.007) and on POD 30 (p = 0.004).
CONCLUSIONS: Pexelizumab had no statistically significant effect on the primary endpoint. However, the reduction in death or myocardial infarction (myocardial-specific isoform of creatine kinase 100 ng/mL) as revealed in the post hoc analysis in the isolated coronary artery bypass grafting bolus plus infusion subpopulation, suggests that further investigation of anti-C5 therapy for ameliorating complement-mediated inflammation and myocardial injury is warranted.
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