Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass.
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.
Shernan
Stanton K
SK
Division of Cardiothoracic Surgery, University of Hawaii School of Medicine, Honolulu, Hawaii, USA. shernan@zeus.bwh.harvard.edu
Fitch
Jane C K
JC
Nussmeier
Nancy A
NA
Chen
John C
JC
Rollins
Scott A
SA
Mojcik
Christopher F
CF
Malloy
Kevin J
KJ
Todaro
Thomas G
TG
Filloon
Thomas
T
Boyce
Steven W
SW
Gangahar
Deepak M
DM
Goldberg
Michael
M
Saidman
Lawrence J
LJ
Mangano
Dennis T
DT
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000209:etiology*; D003167:Complement Activation / Q000187:drug effects*; D003182:Complement C5 / Q000276:immunology*; D001026:Coronary Artery Bypass / Q000009:adverse effects* / Q000401:mortality*; D003402:Creatine Kinase / Q000097:blood; D052279:Creatine Kinase, MB Form; D004311:Double-Blind Method; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000097:blood; D009203:Myocardial Infarction / Q000209:etiology; D011446:Prospective Studies; D057127:Single-Chain Antibodies; D018487:Ventricular Dysfunction, Left / Q000209:etiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; D007527:Isoenzymes; D057127:Single-Chain Antibodies; C402724:pexelizumab; D003402:Creatine Kinase; D052279:Creatine Kinase, MB Form