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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
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Abstract |
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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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| Dr Shernan discloses that he has a financial relationship with Alexion Pharmaceuticals, Inc, and Procter and Gamble. Drs Chen, Malloy, Todaro, and Filloon disclose that they have a financial relationship with Procter and Gamble. Drs Mojcik and Rollins disclose that they have a financial relationship with Alexion Pharmaceuticals, Inc.
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The cause of perioperative organ dysfunction after cardiac surgery is multifactorial and can involve preexisting comorbidity, intraoperative emboli, hemodynamic instability, and nonphysiologic perfusion during cardiopulmonary bypass (CPB). In addition, several pro-inflammatory pathways including the complement, coagulation, and cytokine cascades are activated by reperfusion of ischemic organs and exposure of blood to bio-incompatible surfaces of the extracorporeal circuit. The products of these pathways can promote recruitment and activation of leukocytes, resulting in the generation of additional inflammatory mediators [1, 2], thereby exacerbating tissue injury and organ functional impairment [3, 4].
Complement activation plays an important role in systemic inflammation [3, 4]. C5a and C5b-9, the products of C5 cleavage, are potent inflammatory mediators with pleiotropic properties including alteration of vascular permeability and tone, leukocyte adhesion and activation, endothelial cell activation, and coagulation [5]. The generation of these byproducts during CPB has been shown to correlate directly with clinical morbidity [3, 4, 6]. In addition, complement activation after reperfusion of ischemic tissues has been associated with multiorgan dysfunction [7]. Thus, inhibition of complement activation in cardiac surgical patients undergoing CPB who are susceptible to ischemia-reperfusion (IR) injury may afford organ protection and reduce morbidity.
We have previously shown that pexelizumab (Alexion Pharmaceuticals, Inc, Cheshire, CT), a novel 25-kDa recombinant, humanized, single-chain monoclonal antibody, binds to human C5 with picomolar affinity and blocks C5 cleavage in the classic, alternative, and lectin complement pathways [8]. In pre-clinical studies, antibody-mediated C5 inhibition markedly reduced inflammation in a closed loop model of CPB [6] and attenuated myocardial damage in an animal model of IR injury [9]. Furthermore, in a phase I trial involving 35 patients undergoing coronary artery bypass grafting (CABG) requiring CPB, administration of pexelizumab reduced total complement activity, soluble C5b-9 formation, and leukocyte activation [3]. Compared with placebo-treated patients, those receiving pexelizumab (2 mg/kg) demonstrated a significant reduction in myocardial injury, cognitive deficits, and blood loss. This current investigation reports the results of a larger phase II study that evaluated the safety and impact of pexelizumab on total mortality and adverse cardiovascular outcomes in cardiac surgical patients requiring CPB.
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Primary and secondary endpoints
The primary endpoint was a composite of death (from any cause), MI (defined as new Q-wave by ECG criteria or non-Q-wave by CK-MB > 60 ng/mL), left ventricular dysfunction (use of four or more inotropic drugs, left ventricular assist device, or intraaortic balloon pump), or new CNS deficit (an increase of 1 point on the National Institutes of Health Stroke Scale) on POD 4. Secondary endpoints included the primary endpoint composite on POD 30 and its individual components on PODs 4 and 30.
Pexelizumab
Pexelizumab (Alexion Pharmaceuticals, Inc) was supplied as a sterile, nonpyrogenic solution (2 mg/mL) for intravenous injection. Immediately before CPB, pexelizumab (bolus and bolus plus infusion groups) or placebo bolus was infused more than 10 minutes, which was immediately followed by infusion of the study drug (bolus plus infusion) or placebo (placebo and bolus groups).
Biological assays
Pexelizumab pharmacokinetics were determined using a double-sandwich enzyme-linked immunoadsorbent assay (NUNC, Naperville, IL) as previously described [3]. Blood samples were collected at baseline at 1, 4, 12, 24, 48, and 168 hours after bolus administration. Pharmacodynamic results were based on the analysis of plasma C5b-9 concentrations and serum hemolytic activity as previously described [6]. Serum hemolytic activity is an in vitro measure of the capacity of human serum C5 to lyse chicken erythrocytes. Samples for both PD assays were collected at baseline at 1, 4, and 8 hours (reported for C5b-9 only) and 12, 24, 48, and 168 hours after bolus administration.
Creatine kinase assay
Myocardial-specific isoform of creatine kinase (CK-MB) was measured at a centralized core laboratory facility (Q-LABS, Atlanta, GA) using standard techniques. Blood samples were acquired preoperatively (baseline) and postoperatively at 4, 8, 16, 20, 24, 30, and 36 hours on PODs 2, 4, 7, and 30. All bio-analytical and core laboratory assays (ie, CK-MB) were validated according to International Conference on Harmonization Good Clinical Practice Guidelines.
Adverse events
Adverse events were defined as any unfavorable or unintended symptoms, signs, diagnoses, or laboratory results that occurred during the study and were not present at baseline or that were already present but appeared to worsen. Serious adverse events were defined as life-threatening, resulting in death, requiring or prolonging hospitalization, or resulting in a persistent or significant disability. Adverse events were determined by the investigator at each site and were tabulated for each treatment group by severity and investigator-assessed relationship to the study drug. An independent data and safety monitoring board oversaw both safety and ethical issues.
Statistical analysis
The population was prospectively stratified into isolated CABG and CABG with valve procedures to ensure a balanced distribution of patients among the three treatment groups. A sample size of 300 patients per treatment group was needed to obtain greater than or equal to 80% power for finding a 30% to 35% treatment effect on the primary endpoint using one-sided 0.05 significance testing. Analysis of binary endpoints (eg, composite endpoint) was carried out as pairwise treatment comparisons using stratified 
2 testing. Pairwise treatment comparisons were made using Fischer's exact test procedure when testing within the isolated CABG subgroup. Analysis of continuous endpoints was carried out by a pairwise treatment comparison using Wilcoxon rank sum testing. All p values were two-sided in nature and unadjusted for multiple comparisons.
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Results |
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There were no significant differences among the three treatment groups with respect to hematological, coagulation, or chemistry laboratory values. At least one nonserious adverse event was experienced in 288 placebo patients (94%), 287 bolus patients (93%), and 288 bolus plus infusion patients (96%) (Table 1). The types of reported infections were typical for this patient population (Table 1). Serious adverse events were experienced in 79 placebo patients (26%), 90 bolus patients (29%), and 91 bolus plus infusion patients (30%) (Table 2). Numerical differences among treatment groups in the incidence of serious infections including sepsis (1 placebo, 3 boluses, 5 boluses plus infusions), sternal wound infections (3 placebos, 7 bolus, 3 boluses plus infusions), and mediastinitis (3 placebos, 2 boluses, 3 boluses plus infusions) were not statistically significant. There were 14 deaths (7 placebos, 4 boluses, 3 boluses plus infusions) within the 30-day observation period. Three additional deaths (2 boluses and 1 bolus plus infusion) occurred beyond the pre-specified 30-day observation period. The study agent was discontinued because of an adverse event in 4 placebo-treated patients (1%), 3 bolus-treated patients (1%), and 4 bolus plus infusion-treated patients (1%). There were no significant differences in the number of patients within each treatment group who completed the trial through POD 30 (96% placebo; 95% bolus; 96% bolus plus infusion).
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100 ng/mL) were associated with a 7.4% mortality, which represented a sevenfold increase compared with lower concentrations. Given that CK-MB concentrations correlated with 30-day mortality and that fewer patients in the bolus plus infusion group experienced larger amounts of CK-MB release, a post hoc exploratory endpoint of death or MI (CK-MB 100 ng/mL) was constructed for the isolated CABG population. A statistically significant reduction in this post hoc composite endpoint was evident in the bolus plus infusion group compared with the placebo group on POD 4 (3% vs 8%; p = 0.007) and on POD 30 (3% vs 9%; p = 0.004) (Fig 5).
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100 ng/mL) on POD 30 in the isolated CABG population. During cardiac surgery, systemic production of pro-inflammatory complement byproducts is facilitated by direct surgical trauma, exposure of circulating blood to the bio-incompatible surfaces of the extracorporeal circuit [11] and endotoxin [12]. Substantial evidence also supports an important role for systemic and local complement activation in IR injury of multiorgan systems [7, 13, 14], which is initiated following blood flow restoration after CPB termination. Thus, different initiating stimuli may promote inflammation during CPB (contact activation) and IR injury (hypoxia and reoxygenation); however, the detrimental role of activated complement-mediated tissue injury is common to both mechanisms.
The late complement components (C5a and C5b-9) are important modifiers of inflammation-mediated tissue injury during cardiac surgery [3]. C5a is a potent anaphylatoxin, vasoconstrictor, leukocyte activator and chemotactic factor, and a promoter of cytokine production [14]. C5b-9 also promotes leukocyte activation, chemotaxis, leukocyte-endothelial cell interactions and cell lysis [7]. Anti-C5 monoclonal antibodies have been shown to reduce C5a and C5b-9 generation as well as leukocyte CD11b upregulation in a closed loop model of extracorporeal circulation [6]. In addition, administering an anti-C5 monoclonal antibody in a rodent model of myocardial IR injury dramatically reduced neutrophil infiltration, loss of high-energy phosphate stores, and infarct size [9]. Furthermore, C5 complement inhibition has been previously demonstrated to reduce soluble C5b-9 formation and leukocyte activation, and significantly attenuate myocardial injury in a placebo-controlled phase I trial involving patients undergoing CABG surgery [3]. Thus, preliminary pre-clinical and clinical investigations support a critical role for C5a and C5b-9 in inflammation-mediated tissue injury and provide a rationale for therapeutic complement inhibition in cardiac surgical patients.
In the present study, there were no statistically significant differences in the primary endpoint between the placebo-treated and pexelizumab-treated patients. Although the absence of a treatment effect should be considered, several issues pertaining to our definitions of primary endpoint components need to be addressed. Our definition of perioperative MI (new Q-wave or CK-MB > 60 ng/mL), the initial CK-MB concentration cutoff, may have been too low to reflect clinically significant morbidity. Greater CK-MB release has been shown to correlate with increased morbidity and mortality [15–18]. For example, in a study of approximately 3,000 patients undergoing CABG (GUARDIAN trial), the peak perioperative CK-MB and upper limits of normal ratio (< 5, 5 to < 10, 10 to < 20, and 20) were shown to be a significant predictor of 6-month mortality (3.4%, 5.8%, 7.8%, and 20.2%, respectively) [15]. Similarly in our study, a sevenfold increase in 30-day mortality was associated with any CK-MB concentration greater than or equal to 20 x the upper limits of normal ( 100 ng/mL) compared with lower concentrations. Because the postoperative CK-MB release can also reflect skeletal muscle trauma and myocardial manipulation, even moderate CK-MB increases delineated in the primary analysis and in those patients undergoing CABG plus valve procedures in our study do not necessarily indicate clinically significant myocardial injury [15]. The inclusion of new postoperative Q-waves independent of CK-MB concentration in our definition of MI also may have limited the demonstration of a pexelizumab-treatment effect on the primary composite endpoint. According to postmortem studies, 80% to 92% of post-CABG MIs occur without clinical evidence of transmural infarction [19, 20] suggesting that not all perioperative MIs are detected by new Q-waves on an ECG. Other investigators have demonstrated that the 3-year mortality rate after CABG is independent of new Q-waves (5% without vs 6.3% with new Q-waves) on a perioperative ECG [21], in the absence of concurrent cardiac enzyme release. Discrepancies in the incidence of postoperative Q-waves and its value as an independent predictor of adverse outcome may reflect difficulties in ECG assessment in view of rhythm and conduction disturbances, pericardial inflammation, variable lead positioning, and unmasking of previous electrocardiographic MIs [22]. Consistent with general consensus views regarding the definition of acute infarction [23], most likely future clinical trials will combine new perioperative Q-waves with a specific perioperative threshold of cardiac enzyme release when evaluating its clinical predictive value in CABG patients [24].
The reported incidence of MI after CABG surgery varies widely from 1% to 15% [25–27], reflecting the difficulty in establishing a uniform and clinically significant definition for irreversible perioperative MI. Our decision to perform an exploratory analysis was based on an appreciation for the evolving definition of perioperative MI and a recent recognition of the strong relationship between higher concentrations of perioperative CK-MB release and mortality in patients undergoing isolated CABG surgery [15–18]. We also considered that complete inhibition of complement activation in the bolus population in our study was not associated with any significant differences in assessed outcomes compared with the placebo group, suggesting that post-CPB IR injury may play a more important role compared with CPB-induced complement activation alone in mediating organ dysfunction. Consequently, a post hoc analysis was performed and demonstrated a significant reduction in the composite endpoint of mortality or Q-wave-independent MI (CK-MB > 100 ng/mL) in the isolated CABG pexelizumab bolus plus infusion subpopulation. This finding suggests the need for further investigation to confirm the potential benefit of complement inhibition in reducing inflammation-mediated myocardial injury and mortality in patients undergoing CABG surgery.
Pexelizumab administration had no effect on the incidence of left ventricular dysfunction or on new postoperative CNS deficits as defined in our primary endpoint. Theoretically, attenuation of IR injury should reduce the incidence of both adverse outcomes in CABG patients. However, our strict criteria for left ventricular dysfunction (ie, the use of at least four inotropic agents), and the liberal definition of new postoperative CNS deficits (ie, the increase of only 1 point on the National Institutes of Health Stroke Scale) may have accounted for our inability to demonstrate efficacy.
Pexelizumab effectively inhibited C5 and subsequent production of terminal complement components. Although numerical differences among treatment groups in the incidence of serious infections were not statistically significant, phase II studies are generally underpowered to adequately assess safety. However, complement inhibition at C5 preserves the generation of early products, such as C3b, the critical mediator of bacterial opsonization, as well as immune complex solubilization and clearance. Nonetheless, the risk of compromised immunity in complement-inhibited cardiac surgical patients and the incidence of serious infections (ie, sepsis, sternal wound infections, mediastinitis) must be closely evaluated in future clinical trials.
In summary, this study demonstrated that pexelizumab was an effective inhibitor of pathologic complement activation in CABG patients undergoing CPB. Although a reduction in the primary endpoint was not observed after pexelizumab administration, the significant reduction in mortality and the number of patients with an MI (CK-MB release 100 ng/mL) in the post hoc analysis suggests that further investigation is warranted. The results of this trial have been used to establish composite clinical endpoints pertaining to cardiovascular and neurologic dysfunction on a larger scale, phase III trial that is currently investigating the role of complement activation in CPB-induced systemic inflammation and IR injury.
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Appendix |
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Robert Albus, Inova Fairfax Hospital
Keith Allen, St. Vincent's Medical Center
Gabriel S. Aldea, Richard Anderson, University of Washington, School of Medicine
John Armitage, Mary Washington Hospital
Clinton Baisden, Scott and White Memorial Hospital
Daniel Beckman, Richard Kovacs, Methodist Research Institute
Elliott Bennett-Guerrero, Columbia University College of Physicians & Surgeons
Stuart Boe, North Ridge Medical Center
Michael Borkon, Mid-America Heart Institute (St. Luke's)
Steven Boyce, Washington Hospital
John H. Braxton, Maine Medical Center
Clay Burnett, Memorial Medical Center, Inc.
Paul Burns, Sinai Hospital
John C. Chen, Hawaii Kaiser Permanente
Richard P. Cochran, Robert Love, University of Wisconsin Hospitals and Clinics and William S. Middleton V.A. Hospital
Thomas Deal, Morton Plant Hospital
Pierre de Villiers, Cleveland Clinic Foundation
Luis Dibos, Union Memorial Hospital
Joseph Diliberto, Diagnostic Clinical Research
Francis X. Downey, St. Luke's Medical Center
Mercedes Dullum, Washington Adventist
Michael P. Eaton, University of Rochester Medical Center
Fred Edwards, University of FL- Health Science Center/ Jacksonville
Jack Julian Farahi, BreakThru Clinical Trials
John E. Fetter, St. Mary's-Duluth Clinic
Jane Fitch, Baylor College of Medicine
Stanley A. Gall, St. John's Hospital
Deepak Gangahar, Giles S. Hedderic, Nebraska Heart Institute
Michael Goldberg, Cooper Hospital UMC
Steven Goldman, Janice Christensen, Bruce Toporoff, Veteran Affairs Medical Center
L. Michael Graver, Long Island Jewish Medical Center
Michael Griffin, Yale University
Charles Hantler, University of Texas Health Sciences Center at San Antonio
Charles Hogue, Thoralf Sundt, Washington University School of Medicine
Ronald P. Karlsburg, Brotman Medical Center
Irving Kron, University of Virginia Health Science Center
Irvin Krukenkamp, Stony Brook Hospital
John H. Lemmer, Legacy Good Samaritan Hospital
Jerrold Levy, VA - Atlanta
Ted Lillehei, United Hospital
Stephen Lincoln, St. Joseph's Medical Center
Stephen Longo, Pennsylvania State College of Medicine - M.S. Hershey Medical Center
John Luber, Gilbert Johnston, St. Joseph Medical
Jose Marquez, Allegheny General Hospital
Joseph P. Matthew, Andrew Hilton, Duke University Medical Center
Imran Niazi, St. Francis Hospital
Nancy Nussmeier, Prashant Lotlikar, Texas Heart Institute
Dennis Pupello, Robert Goldstein, Florida West Coast Clinical Research Group
James G. Ramsay, Emory University Hospital
Jay Requarth, Camcare Health Education and Research Institute
Jeffrey B. Rich, Sentara Norfolk General Hospital
Michael Rosenbloom, Memorial Regional–Hollywood, FL
Mark Sand, Definitive Health Services
Stanton K. Shernan, Brigham and Womens Hospital
Christopher Stone, Kenosha Hospital and Medical Center
John Streitz, St. Luke's Hospital
Victor Tedesco, Touro Infirmary Center
James Todd, Peninsular Regional Medical Center
Melvin J. Tonkon, Anaheim Memorial
Clifford van Meter, Ochsner Foundation
Russell Vester, Lindner Center for Cardiovascular Research
Arthur Wallace, San Francisco VA Medical Center
Gary Yurow, Dale Senior, Jewish Hospital–KY
Robert Zeff, Iowa Heart Center
Kenton Zehr, Mayo Clinic
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