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Terminal Complement Blockade With Pexelizumab During Coronary Artery Bypass Graft Surgery Requiring Cardiopulmonary Bypass
A Randomized Trial
Edward D. Verrier, MD;
Stanton K. Shernan, MD;
Kenneth M. Taylor, MD;
Frans Van de Werf, MD;
Mark F. Newman, MD;
John C. Chen, MD;
Michel Carrier, MD;
Axel Haverich, MD;
Kevin J. Malloy, PhD;
Peter X. Adams, MD;
Thomas G. Todaro, MD, JD;
Christopher F. Mojcik, MD, PhD;
Scott A. Rollins, PhD;
Jerrold H. Levy, MD; for the PRIMO-CABG Investigators
JAMA. 2004;291:2319-2327.
ABSTRACT
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Context Inflammation and ischemia-reperfusion injury during coronary artery bypass graft (CABG) surgery requiring cardiopulmonary bypass are associated with postoperative myocardial infarction (MI) and mortality.
Objective To determine the efficacy and safety of pexelizumab, a C5 complement inhibitor, in reducing perioperative MI and mortality in CABG surgery.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled trial, including 3099 patients ( 18 years) undergoing CABG surgery with or without valve surgery at 205 hospitals in North America and Western Europe from January 2002 to February 2003.
Interventions Patients were randomly assigned to receive intravenous pexelizumab (2.0 mg/kg bolus plus 0.05 mg/kg per hour for 24 hours; n = 1553) or placebo (n = 1546) 10 minutes before undergoing the procedure.
Main Outcome Measures The primary composite end point was the incidence of death or MI within 30 days of randomization in those undergoing CABG surgery only (n = 2746). Secondary analyses included the intent-to-treat analyses of death or MI composite at days 4 and 30 in all 3099 study patients.
Results After 30 days, 134 (9.8%) of 1373 of patients receiving pexelizumab vs 161 (11.8%) of 1359 of patients receiving placebo (relative risk, 0.82; 95% confidence interval, 0.66-1.02; P = .07) died or experienced MI in the CABG surgery only population. In the intent-to-treat analyses, 178 (11.5%) of 1547 patients receiving pexelizumab vs 215 (14.0%) of 1535 receiving placebo died or experienced MI (relative risk, 0.82; 95% confidence interval, 0.68-0.99; P = .03). The trial was not powered to detect a reduction in mortality alone.
Conclusions Compared with placebo, pexelizumab was not associated with a significant reduction in the risk of the composite end point of death or MI in 2746 patients who had undergone CABG surgery only but was associated with a statistically significant risk reduction 30 days after the procedure among all 3099 patients undergoing CABG with or without valve surgery.
INTRODUCTION
Approximately 400 000 coronary artery bypass graft (CABG) surgical procedures are performed annually in the United States. Approximately 12 000 (3%) patients die within 30 days of surgery.1 The presence of an increased frequency of co-morbid risk factors has led to a 30% increase in predicted operative risk in the past decade.1 Despite recent advances in myocardial preservation, pharmacological intervention, and modification of cardiopulmonary bypass (CPB) circuits, perioperative myocardial infarction (MI) continues to contribute significantly to postoperative morbidity and mortality.2-6
Inflammation associated with ischemia and reperfusion injury is thought to contribute to myocardial damage via activation of the complement, coagulation and cytokine cascades. These proinflammatory pathways facilitate activation of leukocytes, platelets, and endothelial cells resulting in thrombosis, myocardial injury, and subsequent MI.7-13 Complement activation during CABG surgery requiring CPB may play a particularly important role in the development of perioperative tissue injury due to the proinflammatory effects of the terminal complement products of C5 cleavage, C5a, and C5b-9. C5a is an extremely potent anaphylatoxin,14 whereas C5b-9, otherwise known as the membrane attack complex, can directly lyse cells, including cardiomyocytes.15-16 Both C5a and C5b-9 exhibit pleiotropic activities that include direct cellular damage, alteration of vascular permeability and tone, leukocyte chemotaxis, initiation of cardiomyocyte apoptosis, initiation of thrombosis and promotion of both cellular activation and adhesion.15, 17 The generation of C5a and C5b-9 during CABG surgery requiring CPB has been well documented and correlates with clinical morbidity.18-20 In preclinical models of CPB-induced inflammation and MI, inhibition of C5 cleavage markedly reduced inflammation, myocardial necrosis, and apoptosis.15, 21
The terminal complement inhibitor, pexelizumab, is a recombinant, humanized single-chain antibody fragment that targets and binds to the human C5 complement component with high affinity (100 pmol/L), thereby blocking the cleavage of C5-by-C5 convertase enzymes generated from the classical, alternative and lectin pathways.22 Pexelizumab blocks the generation of C5a and C5b-9 but permits the generation of C3b, the critical mediator of bacterial opsonization and immune complex solubilization.15 Inhibition of C5 activation and cleavage therefore represents a potentially effective therapeutic strategy for reducing C5a and C5b-9 mediated MI associated with CABG surgery requiring CPB.
Initial evaluation of pexelizumab in 2 previous clinical trials indicated that pexelizumab reduced the composite end point of death or MI in patients undergoing CABG surgery without concomitant valve surgery, but a significant impact of pexelizumab on myocardial damage in patients undergoing CABG with concomitant valve surgery was not detected.5, 23 Based on these data, the Pexelizumab for Reduction in Infarction and Mortality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial was designed to test the following hypotheses: whether the C5 complement inhibitor pexelizumab would reduce perioperative MI in patients who had undergone CABG surgery and whether the reduction in MI with pexelizumab would be associated with sustained morbidity and mortality benefit.
METHODS
Patient Population
The PRIMO-CABG trial was conducted at 205 sites in 7 North American and Western European countries. Eligible patients included those scheduled for CABG surgery with or without concurrent valve surgery. Although the primary efficacy analysis was performed for patients undergoing CABG surgery without concomitant valve surgery (the CABG-only subpopulation), patients undergoing concomitant valve surgery were also enrolled (as requested by the US Food and Drug Administration) for the purpose of collecting additional safety and efficacy data for pexelizumab in the broader CABG population. The patients undergoing CABG surgery alone or with valve surgery represents the intent-to-treat cohort.
To be included, patients had to be at least 18 years and had to have met at least 1 of the following baseline risk factors: require urgent intervention defined according to the American College of Cardiology–American Heart Association (ACC/AHA) guidelines as being patients who are required to stay in the hospital due to medical factors but may be scheduled and operated on within a normal scheduling routine; have been diagnosed as having diabetes mellitus; be a woman; have undergone prior CABG procedure; have a history of a neurological event (cerebrovascular accident, transient ischemic attack, or carotid endarterectomy), congestive heart failure (New York Heart Association class III or IV), at least 2 MIs (excluding patients who have had an MI within 48 hours of undergoing CABG surgery) or experiencing an MI in not less than 48 hours but no more than 4 weeks before CABG surgery. Patients were excluded if they were scheduled to undergo planned aortic dissection repair and/or aortic root reconstruction; required salvage intervention; had current cardiogenic shock; had acute left ventricular, septal, or acute papillary muscle rupture; had uncontrolled diabetes (plasma blood glucose value >400 mg/dL [>22.2 mmol/L] within 3 days before surgery); had a history of renal failure and a serum creatinine value greater than 3.0 mg/dL (265.2 µmol/L), of chronic hepatic failure and/or hepatic cirrhosis, and of malignancy, excepting basal cell carcinoma and malignancies in remission (2 years); had known or suspected hereditary complement deficiency, any active infection that was clinically significant in the opinion of the investigator, participated in another investigational drug study, or was exposed to another investigational agent within 30 days; and had a known or suspected pregnancy, was breastfeeding, or intended to become pregnant during the study.
The institutional review boards or equivalent at each site approved the protocol, and all patients provided written informed consent. A 5-member independent data and safety monitoring board, consisting of physicians, statisticians, and other scientists, monitored and assessed unblinded patient safety outcomes throughout the study.
Study Protocol
Patients were randomly assigned in a double-blind fashion by a central telephone-based interactive voice randomization system to receive either intravenous pexelizumab (2.0 mg/kg bolus followed by 0.05 mg/kg per hour infusion of pexelizumab for 24 hours) or placebo (placebo bolus followed by 24-hour placebo infusion). Stratification occurred within each site and was based on whether valve surgery was planned, the type of valve surgery (whether mitral or other valve), and whether they had previously undergone CABG surgery.
Pexelizumab or placebo bolus was administered as soon as possible after the general anesthesia induction but not later than 10 minutes before CPB. Patients were followed up for in-hospital adverse events and clinical end points. In addition, patients were seen 14, 30, 90, and 180 days after CABG surgery for adverse events, electrocardiograms, and clinical outcomes and were contacted by telephone at 6 months to determine survival status if visits were missed.
Study End Points
The prespecified primary end point was defined as the incidence of a composite of death or MI within 30 days of randomization in patients undergoing CABG surgery without concomitant valve surgery, representing 2746 patients. Secondary analyses included the death or MI composite within 4 or 30 days of randomization in all 3099 patients, considered the intent-to-treat population, and the death or MI composite through day 4 in the CABG-only group. Myocardial infarction was also assessed through day 4 and day 30.
Death, defined as all-cause mortality, was determined through days 4, 30, 90, and 180. Myocardial infarction was defined as follows: a peak creatine kinase-MB (CK-MB) of at least 100 ng/mL by day 4 (defined as non-Q wave if no new evidence of Q wave existed); Q-wave evidence of MI, along with CK-MB of at least 70 ng/mL by day 4; new Q-wave evidence of MI by day 30 that was not present by day 4; or MI (Q wave or non-Q wave) as identified by the investigator and confirmed by the clinical events committee by day 30. All MIs were adjudicated by the clinical events committee, which consisted of 3 expert cardiologists who were blinded to patient treatment assignment. Additionally, at any time during the trial, the primary investigator was able to identify the occurrence of an MI for adjudication by the clinical events committee. Creatine kinase-MB measurements were collected at 4, 8, 12, 16, 24, 72, and 96 hours postoperatively and were analyzed at a central core laboratory. Electrocardiograms were recorded at patient enrollment as well as at 48 and 96 hours and 14, 30, 90, and 180 days postoperatively. All electrocardiograms for the primary end point and prespecified secondary analyses were read at a central core laboratory. The pharmacodynamic effect of pexelizumab (inhibition of serum complement activity) was determined using a standard total serum complement assay as previously described.5
Statistical Analyses
This trial's objective was to determine whether pexelizumab and placebo would have different composite end point rates of death or MI 30 days after randomization. To have 90% power for detecting a treatment difference between an expected 12% placebo group event rate and an 8% active group event rate using 2-sided, .05 significance testing ( 2 test), a sample size of 1250 CABG-only patients per treatment group was needed. To account for intent-to-treat analysis of the data and the additional patients undergoing CABG and valve surgery expected to be entered into the study, an estimated 1500 patients per treatment group were to be randomly assigned.
Primary efficacy analysis was performed on the binary composite end point, death or MI through day 30, using patients in the CABG-only strata. Comparison of incidence rates between the treatment groups was performed via stratified (Mantel-Haenszel) 2 testing, where stratification was defined by type of CABG procedure. Comparison of the incidence rates was made via relative risks and their associated 95% confidence intervals. Patients whose mortality status was unknown at day 30 and who reportedly did not experience an MI by day 30 were considered missing for the primary analysis. We considered them missing because their mortality status was unknown.
Secondary end points included analyzing the individual components of the primary composite end point at the end of days 4 and 30, analyzing the composite at day 4, and the primary end point and its components for the intent-to-treat population at days 4 and 30. Analysis of binary secondary end points was also carried out via stratified 2 testing. Logistic regression was performed to further evaluate treatment differences on the primary end point after adjustment for the following baseline covariates: age, race, valve surgery type, diabetes, female sex, repeat CABG procedure, urgent intervention, history of MI, history of congestive heart failure, and history of neurological event. Additionally, survival analysis was performed on the mortality data and included Kaplan-Meier curve estimation as well as Cox proportional hazard modeling using the above mentioned covariates. SAS version 8.2, S-Plus Version 2000 software (SAS Inc, Cary, NC) was used for all statistical analyses and primary statistical analyses were confirmed by an independent academic statistician.
RESULTS
Randomization, Demographics, Safety, and Pharmacodynamics
A total of 3099 patients undergoing CABG surgery with or without valve surgery were enrolled between January 2002 and February 2003. The primary analysis was performed on the locked 90-day database. An additional database lock was performed to assess 6-month mortality. The flow diagram of patient disposition through day 90 is shown in Figure 1. Baseline characteristics were generally balanced between the 2 treatment groups for both the CABG-only and intent-to treat populations for each baseline risk inclusion criteria and demographic parameter except that there were more women randomized to pexelizumab treatment than to placebo (Table 1).
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Figure 1. Coronary Artery Bypass Graft (CABG) Surgery Patient Flow Diagram
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Table 1. Baseline and Procedural Characteristics*
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Adverse events and infection log reporting are shown in Table 2. The proportions of adverse events were similar between treatment groups. Serious adverse events were also reported for a similar proportion between groups, except that there were numerical increases in pleural effusions and a numerical decrease in respiratory failure with pexelizumab. These differences were not statistically significant. There was a significant increase in pneumonia not otherwise specified in the pexelizumab group (P = .01). Further analysis of the pneumonia-related adverse events showed that when pneumonia–related Medical Dictionary for Regulatory Activities preferred terms were analyzed as a group, the difference between treatment groups was decreased and other lower respiratory tract infections and bronchitis were similar between treatment groups. The microorganisms seen in the treatment groups were also similarly distributed. Additionally, septicemia was significantly reduced in the pexelizumab group (P = .03).
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Table 2. Adverse Events and Infection Log Through 90 Days
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Compared with placebo, administration of pexelizumab bolus plus infusion resulted in rapid and complete inhibition of total serum complement hemolytic activity that was maintained for 24 hours after the procedure (Figure 2). In this group, total serum complement levels returned to baseline within 72 hours.
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Figure 2. Pexelizumab Effect on Serum Complement Activity
Serum complement levels were determined using a standard complement hemolysis assay as previously described.5
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Outcomes
The effect of pexelizumab on the death or MI composite end point through days 4 and 30 for the intent-to-treat population and for those who underwent CABG surgery alone is shown in Figure 3. The day 30 death or MI composite in the CABG-only subpopulation (n = 2746) was reduced by 18% with pexelizumab treatment (P = .07). However, at day 4, pexelizumab reduced death or MI by 24% (P = .008) in the CABG-only group and by 26% (P = .014) in the intent-to-treat population. At day 30, pexelizumab reduced death or MI by 18% (P = .03) in the intent-to-treat population. Although the study was underpowered to detect a reduction in mortality with pexelizumab, the nonsignificant reduction in death was consistent with the reduction in the death or MI composite and MI alone in the CABG-only and intent-to-treat populations.
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Figure 3. Death and Myocardial Infarction (MI) Rates Among Patients Who Underwent Coronary Artery Bypass Graft (CABG) Surgery
*Primary end point.
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The treatment-independent relationship between adjudicated MI through day 4 and mortality was determined (Figure 4). The population of patients who did not have an MI through day 4 experienced day 30, 90, and 180 mortality of 2.1%, 3.0%, and 4.0%, respectively. Among patients who had a clinically adjudicated MI through day 4, the day 30, 90, and 180 mortality was 10.9%, 14.6%, and 16.3%, respectively. Mortality incidence in the 2 populations was significantly different across the entire 6 months (P<.001, log-rank test). The mortality associated with non–Q wave MI and Q-wave MI through day 4 did not differ from each other (180-day mortality with non–Q wave MI, 16.7%; with Q-wave MI, 14.8%; P = .39, log-rank test).
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Figure 4. Treatment-Independent Relationship Between Myocardial Infarction and Death
Panel depicts treatment-independent effect of adjudicated postoperative day 4 myocardial infarction or mortality. CABG indicates coronary artery bypass.
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The impact of pexelizumab on clinically adjudicated MI was determined through days 4 and 30 in the CABG-only subpopulation and in the intent-to-treat population. Through day 4, pexelizumab reduced MI by 24% (P = .01) in the intent-to-treat population and by 27% (P = .01) in the CABG-only subpopulation (Figure 5). Through day 30, pexelizumab significantly reduced MI by 18% (P = .04) in the intent-to-treat population and by 22% (P = .04) in the CABG-only subpopulation (Figure 3). There were consistent relative reductions in non–Q wave MI and Q-wave MI in both populations at all time points.
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Figure 5. Pexelizumab Effect on Perioperative Myocardial Infarction
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Pexelizumab's effect on long-term morbidity and mortality was further explored in a post hoc analysis of event-free (death or MI) survival through day 180 in the intent-to-treat population (Figure 6). Pexelizumab was associated with a statistically significant reduction in death or MI throughout the entire 6-month period (P = .03), with a 17% relative reduction and a 2.6% absolute reduction in patients experiencing death or MI at 6 months. A Kaplan Meier survival analysis was determined for the intent-to-treat study population through 6 months (Figure 6). Patients treated with pexelizumab showed an improvement in survival that widened from day 4 to day 30 to day 90 and was maintained at day 180, with an absolute 1.0% improvement in 6-month survival in the intent-to-treat population.
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Figure 6. Event-Free and 6-Month Survival
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COMMENT
The PRIMO-CABG trial represents, to the best of our knowledge, the first large prospective study designed to investigate the safety and efficacy of a novel anti-inflammatory agent, the terminal complement inhibitor pexelizumab, for its effect on reducing death or MI in patients undergoing CABG surgery requiring CPB. The primary end point of the study, the incidence of death or MI in the CABG-only subpopulation through day 30 (n = 2746), was nonstatistically significantly reduced by 18%. In the larger intent-to-treat population (n = 3099), which included a broad spectrum of patients with diverse baseline risk factors undergoing CABG surgery with or without valve surgery, pexelizumab statistically significantly reduced the 30-day incidence of death or MI by 18%.
The consistent and statistically significant reductions in MI and in the death or MI composite through day 4 among the CABG-only and intent-to-treat study populations support the reductions in MI and the death or MI composite observed through day 30. The PRIMO-CABG trial prespecified primary analysis excluded 353 patients who needed valve surgery because pexelizumab had not statistically significantly reduced perioperative MI in about 30 to 35 patients in each treatment group who had undergone CABG surgery as part of a phase 2 trial.5 When the data from these 353 patients were included for the intent-to-treat analysis, the day 30 death or MI end point was reduced by 18%. Taken together, these observations suggest that the trial may have been underpowered to detect the observed drug effect in the CABG-only subpopulation. Nevertheless, the consistent reductions in the death or MI composite in the intent-to-treat population at days 4 and 30 and the reduction in death or MI in the CABG-only population at day 4 support a positive treatment effect of pexelizumab in CABG patients.
We found that perioperative myocardial damage correlated with 6-month mortality and supports similar findings from previous CABG surgery trials.5, 24 Through the use of a prespecified adjudication process in this trial, PRIMO-CABG further solidifies the correlation between perioperative MI (both non-Q wave and Q wave) through day 4, with longer-term mortality through 6 months. Patients who experienced an MI through day 4 manifested a 4-fold increase in 6-month mortality. Hence, 1 out of every 6 patients who experienced an MI through day 4 died by 6 months. The trend in mortality incidence through days 30, 90, and 180 among the patients who experienced an MI by day 4 was somewhat greater than mortality in patients with elevated CK-MB levels following elective percutaneous coronary intervention (2.8%, in-hospital cardiac mortality; 6.6%, cardiac mortality at 1 year).25 Thus, compared with postpercutaneous coronary intervention MI, post-CABG surgery MI as defined in this study appears to be a stronger predictor of earlier adverse clinical outcomes.
The results, which demonstrated pexelizumab's impact on early improvements through day 4, are further supported by the mortality data that showed a widening of the absolute reduction in death between pexelizumab and placebo from days 4 to 90, with a 1% absolute reduction measured at day 180. Furthermore, in a post hoc analysis, event-free (death or MI) survival remained significantly improved through day 180. The data suggest that a reduction in early perioperative MI with pexelizumab affords a sustained reduction in clinical morbidity and mortality through day 180.
The reduction in death or MI among patients treated with pexelizumab may be mediated through an amelioration of ischemia-reperfusion-injury-induced inflammation via terminal complement inhibition. However, in 2 other phase 2 trials on acute MI that used angioplasty26 and thrombolysis,27 it is of interest to note that although pexelizumab treatment did not significantly reduce CK-MB levels, it did significantly reduce mortality in patients who had undergone angioplasty in the Complement Inhibition in Myocardial Infarction Treated with Angioplasty (COMMA) trial but not in patients who had undergone thrombolysis in the Complement Inhibition in Myocardial Infarction Treated with Throbolytics (COMPLY) trial.26 One possible explanation for this apparent discrepancy is that pexelizumab treatment in patients undergoing CABG surgery is initiated prior to ischemia or reperfusion while pexelizumab is administered well after the onset of ischemia for patients experiencing acute MI and therefore may not significantly affect the assessment of acute myocardial damage as measured by CK-MB release. Nevertheless, the anti-inflammatory effect of pexelizumab was correlated with the mortality benefit in the COMMA trial because the severity of post–acute MI inflammation predicted mortality and pexelizumab administration significantly reduced IL-6 and C-reactive protein levels compared with placebo.28 Additionally, pexelizumab has shown a consistent and significant reduction in 30-day mortality in a pooled analysis of 4986 patients across multiple acute cardiovascular disease trials for patients undergoing both CABG surgery and who experience acute MI, suggesting that terminal complement activation plays an important role in cardiac ischemic outcomes in multiple settings.29
In summary, the PRIMO-CABG trial, a prospective, randomized controlled cardiac surgery trial, demonstrated a reduction in perioperative MI with a novel anti-inflammatory drug that has a favorable safety profile. Our primary analysis demonstrated a nonstatistically significant reduction in the composite of death or MI, and our intent-to-treat analysis, which included all patients undergoing CABG, demonstrated a statistically significant reduction in the composite. In addition, both analyses showed a durable effect through day 180. Pexelizumab represents a novel therapeutic approach for CABG surgery with potential for sustained beneficial effects on morbidity and mortality.
AUTHOR INFORMATION
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Corresponding Author: Edward D. Verrier, MD, Division of Cardiothoracic Surgery, University of Washington School of Medicine, 1959 NE Pacific, Seattle, WA 98195-6310 (edver{at}u.wash.edu).
Author Contributions: Dr Verrier had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Verrier, Taylor, Newman, Chen, Carrier, Haverich, Malloy, Adams, Todaro, Mojcik, Rollins, Levy.
Acquisition of data: Verrier, Shernan, Taylor, Adams, Mojcik.
Analysis and interpretation of data: Verrier, Shernan, Taylor, Van de Werf, Newman, Chen, Malloy, Adams, Todaro, Mojcik, Rollins, Levy.
Drafting of the manuscript: Verrier, Shernan, Adams, Todaro, Rollins, Levy.
Critical revision of the manuscript for important intellectual content: Verrier, Shernan, Taylor, Van de Werf, Newman, Chen, Carrier, Haverich, Malloy, Adams, Todaro, Mojcik, Rollins, Levy.
Statistical expertise: Verrier.
Obtained funding: Verrier, Malloy.
Administrative, technical, or material support: Verrier, Taylor, Newman, Malloy, Adams, Todaro, Mojcik, Rollins.
Study supervision: Verrier, Shernan, Taylor, Van de Werf, Newman, Chen, Carrier, Haverich, Adams, Rollins, Levy.
Funding/Support: The PRIMO-CABG study was funded by Procter & Gamble Pharmaceuticals, Cincinnati, Ohio, and Alexion Pharmaceuticals, Cheshire, Conn.
Role of the Sponsor: The PRIMO-CABG Steering Committee, Alexion Pharmaceuticals, and Procter & Gamble Pharmaceuticals designed the study, developed the protocol, and determined a statistical analysis plan by consensus. Procter & Gamble Pharmaceuticals and Alexion Pharmaceuticals also provided the study drug and placebo and hired a contract research organization to collect the data from the study sites. Data were collected on electronic case report forms managed by Quintiles and Procter & Gamble, which housed the blinded trial database. The data analyses were conducted at Procter & Gamble, and the data analyses were then given to Dr Verrier and the PRIMO-CABG Steering Committee. Final decision on the content of the manuscript rested with the corresponding author in consultation with the other authors. There was no formal approval of the manuscript from Procter & Gamble and Alexion; however, Alexion and Procter & Gamble authors contributed to writing the manuscript.
Steering Committee: Edward D. Verrier, MD, chairman; Michel Carrier, MD, John C. Chen, MD, Robert W. Colman, MD, Dr Med, Axel Haverich, Jerrold H. Levy, MD, Christopher F. Mojcik, MD, PhD, Mark F. Newman, MD, Stanton K. Shernan, MD, Thomas G. Todaro, MD, JD, Kenneth M. Taylor, MD, Frans Van de Werf MD.
Data and Safety Monitoring Board: Joseph J. McPhillips, PhD, chairman; Arshed Ali Quyyumi, MD, Philip D. Pulaski, MD, Francis E. Rosato, MD, N. Phillip Ross, PhD, William E. Wilkinson, PhD.
Clinical Events Committee: Robert Harrington, MD, Kenneth Mahaffey, MD, Bernard Chaitman, MD.
Electrocardiogram Readings: Saint Louis University Core ECG laboratory, Bernard Chaitman, MD, Director.
Alexion Pharmaceuticals: Scott A. Rollins, PhD, Christopher F. Mojcik, MD PhD, Peter X. Adams, MD, Melinda Karwon.
Procter & Gamble Pharmaceuticals: Kevin J. Malloy, PhD, Thomas G. Todaro, MD, JD, Laurie Gunderson, PhD, Donna McAfee, RN, MBA, Bettina Wick, PhD, and Michael van der Laan, MD.
PRIMO-CABG Investigators and Study Sites: Listed are site principal investigators.
United States (2139 Patients): Brotman Medical Center, Beverly Hills, Calif: R. Karlsberg; South Denver Cardiology Associates, Littleton, Colo: I. Dauber; Western Cardiology Associates, Denver, Colo: N. Vijay; Apex Cardiology, Inglewood, Calif: J. Farahi; South Texas Cardiovascular Consultants Clinical Research Center, San Antonio: A. Jain; IMC-Diagnostic and Medical Clinic, Mobile, Ala: M. Lester; University of Arizona, Tucson: S. Butman; Oklahoma Foundation for Cardiovascular Research, Oklahoma City: R. Kipperman; Sparks Regional Medical Center, Fort Smith, Ariz: J. Schwarz; Cardiovascular Associates of the Delaware Valley, Haddon Heights, NJ: J. Kramer; Garden State Cardiology, Paramus, NJ: M. Kesselbrenner; Brevard Cardiology Group, Pa, Merritt Island, Fla: K. Sheikh; University of Louisville, Louisville, Ky: M. Leesar; Cardiac Centers of Louisiana, LLC, Shreveport: J. Ghali; the Chattanooga Heart Institute Cardiovascular Group, PC, Chattanooga, Tenn: B. Negus; MIMA Century Research Associates, Melbourne, Fla: R. Vicari; Brigham and Women's Hospital, Boston, Mass: S. Shernan; Legacy Good Samaritan Hospital, Portland, Ore: J. Lemmer; the Linder Clinical Trial Center, Cincinnati, Ohio: R. Vester; Orlando Heart Center, Orlando, Fla: M. Sand; Washington Hospital Center—Washington Heart, Washington, DC: S. Boyce; Union Memorial Hospital C/O: RX Trials, Inc, Baltimore, Md: L. Dibos; Southern Arizona Veteran Affairs Medical Center, Tucson: S. Goldman; Wisconsin Center for Clinical Research, Milwaukee: F. Downey; Mary Washington Hospital, Fredericksburg, Va: J. Armitage; University of Washington School of Medicine, Seattle: G. Aldea; Camcare Health Education & Research Institute, Charleston, WVa: J. Khan; Sentara Norfolk General Hospital—Cardiac Research, Norfolk, Va: J. Rich; Inova Fairfax Hospital, Falls Church, Va: R. Albus; Washington University School of Medicine, St Louis, Mo: C. Hantler; Scott and White Memorial Hospital, Temple, Tex: C. Baisden; Alton Ochsner Medical Foundation—Brent House, New Orleans, La: C. Van Meter; St Vincent's Medical Center, Indianapolis, Ind: K. Allen; Bethea, Mouskoukas and Weaver, LLC, New Orleans, La: V. Tedesco; FHS Research Center, Tacoma, Wash: J. Luber; St Luke's Hospital Mid-America Heart Institute, Kansas City, Mo: M. Borkon; St Mary's Duluth Health System, Duluth, Minn: J. Fetter; Iowa Heart Center–Laurel, Des Moines, Iowa: R. Zeff; Midatlantic Cardiovascular Associates–Towson, Towson, Md: J. Laschinger; St Luke's Hospital–Duluth, Duluth, Minn: J. Streitz, Jr; University of Hawaii, Honolulu: J. Chen; University of Louisville, Louisville, Ky: M. Chandra; Florida Cardiovascular Research, LC, Atlantis: J. Kieval; St Vincent's Medical Center, Cardiology Division, Bridgeport, Conn: E. Kosinski; Parkway Cardiology Associates, PC, Oak Ridge, Tenn: M. Sharma; St Jude Medical Center, Fullerton, Calif: A. Choe; Cornell University Medical College, New York, NY: M. Fontes; Pepin Heart and Vascular Institute, Tampa, Fla: M. Bloom; University of Louisville, Louisville, Ky: R. Bolli; Texas Heart Institute, Houston, Tex: C. D. Collard; the Greater Fort Lauderdale Heart Group Research, Fort Lauderdale, Fla: L. Herskowitz; St Joseph's Hospital, Towson, Md: P. Horneffer; Duke University Medical Center, Durham, NC: J, Lowe; San Diego Cardiac Center, San Diego, Calif: D. Marsh; North Memorial Pain Institute, Philadelphia, Pa: N. Schwann; Mt Carmel West, Columbus, Ohio: M. Shah; Good Samaritan Hospital—Seton Center, Cincinnati, Ohio: M. Smith; Appleton Medical Center, Appleton, Wis: L. Suarez; Guthrie Clinical Research, Sayre, Pa: N. Zama; Baptist Medical Center Cardiology, PC, Birmingham, Ala: A. Bouchard; Sarasota Memorial Hospital, Sarasota, Fla: R. Carlson; Sinai Hospital of Baltimore, Baltimore, Md: P. Cho; Jacksonville Center for Clinical Research, Jacksonville, Fla: C. Cousar; Tri Health Bethesda North Hospital, Cincinnati, Ohio: L. Hiratzka; VA Medical Center–Seattle, Seattle, Wash: K. Lehmann; Baylor College of Medicine, Houston, Tex: Z. Wojciechowski; VA Medical Center–Houston, Houston, Tex: S. Shenaq; Florida Heart Institute at Florida Hospital, Orlando: C. Stowe; Akron General Medical Center, Akron, Ohio: J. Hodsden; University Hospitals of Cleveland, Cleveland, Ohio: R. Nair; Integris Baptist Medical Center, Oklahoma City: J. Anderson; Tacoma General Hospital, Tacoma, Wash: L. Annest; Wisconsin Center for Clinical Research, Milwaukee: T. Barragry; Tri-City Medical Center, Oceanside, Calif: K. Carr; Emory University Hospital, Atlanta, Ga: J. Levy; VA Medical Center–Atlanta, Decatur, Ga: J. Levy; Gunderson-Lutheran Hospital, LaCrosse, Wis: V. Paramesh; Northside Hospital and Heart Institute, St Petersburg, Fla: J. Pruitt; United Health Services Hospitals for Healthy Aging, Johnson City, NY: M. Yousuf; Wake Forest School of Medicine, Winston-Salem, NC: M. Wall; Cardiology Associates, PC, Washington, DC: S. Bennett; University Hospital, Augusta, Ga: B. Chandler; Georgetown University Hospital, Washington, DC: P. Corso; Jackson Heart Clinic, Jackson, Miss: J. Fletcher; Carilion Roanoke Memorial Hospital, Roanoke, VA: P. Frantz; VA Medical Center—Washington DC, Washington, DC: D. Lu; Bend Memorial Clinic, Bend, Ore: B. McLellan; Morton Plant Mease Health Care, Clearwater, Fla: R. Murbach; Gulf Bay Cardiovascular and Thoracic Associates, Hudson, Fla: R. Sharma; VA Medical Center–Dublin, Macon, Ga: J. Van De Water; Cardiology Diagnostics, Ltd, Des Peres, Mo: G. Williams; Bridgeport Hospital–Cardiology, Bridgeport, Conn: S. Zarich; Westchester County Medical Center, Valhalla, NY: E. Zias; University of Rochester, Rochester, NY: J. Delehanty; North Ohio Heart Center, Sandusky: H. Ibrahim; Allegheny General Hospital–Cardiology, Pittsburgh, Pa: J. Magovern; Christiana Care Health Services, Newark, Del: K. McNicholas; Washington Adventist Hospital, Takoma Park, Md: T. Militano; University of Texas Southwestern Medical Center, Dallas: M. Wait; Mercy General Hospital, Sacramento, Calif: M. Chang; Chester County Cardiovascular Center, West Chester, Pa: V. DiSesa; Cardiovascular and Thoracic Surgery Associates, PC, Arlington, Va: J. Garrett; Convenant Medical Center, Saginaw, Mich: C. Genco; Northwest Surgical Associates, Portland, Ore: J. Hill; Rochester General Hospital, Rochester, NY: R. Kirshner; VA Medical Center West Los Angeles, Los Angeles, Calif: F. Mody; West Shore Cardiology, Muskegon, Mich: M. Meengs; Heart and Vascular Clinic of Northern Colorado, Fort Collins: W. Miller; Tallahassee Memorial Regional Medical Center, Tallahassee, Fla: T. Bixler; University of Texas Health Science Center at San Antonio, San Antonio: J. Calhoon; Thoracic and Cardiovascular Institute, Lansing, Mich: A. Holden; Baystate Medical Center, Springfield, Mass: R. Engelman; Asheville Cardiothoracic Surgeons, Asheville, NC: A. Johnson; University of Pittsburgh Medical Center, Pittsburgh, Pa: E. Sullivan; University of Iowa, Iowa City: J. Everett; Crozer-Chester Medical Center, Upland, Pa: K. Grunewald; Texas Tech University Health Sciences Center–Lubbock: A. Halldorsson; Cardiovascular Associates of the Delaware Valley, PA-ARC, Haddon Heights, NJ: G. Fortino; Cardiovascular Research and Education Foundation, Inc, Wausau, Wis: R. Miles; St Vincents Hospital, Los Angeles, Calif: A Gheissari; University of Alabama at Birmingham, Birmingham: W. Lell; Kaiser Foundation Hospital, San Francisco, Calif: G. Roach; Good Samaritan Regional Medical Center, Phoenix, Ariz: P. Tibi; Cardiovascular Associates of the Peninsula, Burlingame, Calif: S. Pope; Desert Samaritan—Lutheran Heart, Mesa, Ariz: V. Dreicer; Dayton Heart Center, Dayton, Ohio: A. Goyal; St Joseph's Hospital of Atlanta, Atlanta, Ga: D. Murphy; University of Arkansas, Little Rock: C. Napolitano; Fletcher Allen Health Care, Burlington, Vt: M. Tischler; Maimonides Medical Center, Brooklyn, NY: J. Cunningham; Indiana Heart Surgeons, Indianapolis: D. Evans; Seton Medical Center, Daly City, Calif: A. Yap; the Heart Center, Doylestown, Pa: R. Metcalf; University of California, Los Angeles: J. Jahr; Wesley Medical Center, Wichita, Kan: C. McCoy; Massachusetts General Hospital, Boston: V. Mehta; University of San Francisco Moffitt-Long Hosp, San Francisco, Calif: I. Russell; Methodist Hospital, New Orleans, La: M. Weaver; Baptist Memorial Hospital, Memphis, Tenn: H. E. Garrett; Thoracic and Cardiovascular Surgery, St Louis, Mo: N. Munfakh; McLaren Regional Medical Center, Flint, Mich: F. Armenti; University of Southern California, Los Angeles: P. Lumb; Baptist Health System, Inc, Birmingham, Ala: D. Randleman; Indiana Ohio Heart, Fort Wayne, Ind: J. Ladowski; Nebraska Heart Institute, Lincoln: J. Wudel; Sterling Research Group, Ltd, Cincinnati, Ohio: Eric Roth.
Canada (271 Patients): Health Sciences Centre, Winnipeg, Manitoba: M. Raabe; Notre Dame Hospital (CHUM), Montreal, Quebec: B. Coutu; McMaster University, Hamilton, Ontario: A. Lamy; University of British Columbia, Vancouver: G. Fradet; Dalhousie University, Halifax, Nova Scotia: I. Ali; Montreal Heart Institute, Montreal, Quebec: M. Carrier; St Paul's Hospital, Vancouver, British Columbia: W. Jamieson; Hopital Laval, Quebec City: F. Dagenais; Royal Victoria Hospital, Montreal, Quebec: B. de Varennes, Benoit; Victoria Heart Institute Foundation, Victoria, British Columbia: P. Klinke; Mackenzie Health Science Center, Edmonton, Alberta: B. Finegan; Cathy Metcalfe Research Consultants, Richmond, British Columbia: R. Merchant; General Hospital Health Science Center, St John's, Newfoundland: B. Rose; University of Manitoba Health Sciences Center, Winnipeg: E. Pascoe; Regina General Hospital, Regina, Saskatchewan: J. Tsang; Sunnybrook & Women's College Health Science Centre, Toronto, Ontario: S. Fremes; New Brunswick Heart Center, Saint John, British Columbia: C. Brown; Toronto General Hospital, Toronto, Ontario: V. Rao.
United Kingdom (195 Patients): NHLI Imperial College School of Medicine, London: P. Punjabi; Bristol Heart Institute, Bristol: G. Angelini; John Radcliffe Hospital, Oxford: C. Ratnatunga; Papworth Hospital, Cambridge: A. Vuylsteke; Glenfield Hospital, Leicester: M. Galinanes; Southampton General Hospital, Southampton: S. Ohri; Morriston Hospital, Swansea: A. Youhana; Guys & St Thomas' Hospitals, London: G. Venn; Cardiothoracic Centre, Liverpool: M. Fox.
Germany (337 Patients): Medizinische Hochschule Hannover, Hannover: A. Haverich; Deutsches Herzzentrum, Muenchen: R. Bauernschmitt; Kerckhoff Klinik GmbH, Bad Nauheim: M. Roth; Deutsches Herzzentrum Lahr, Lahr/Schwarzwald: J. Ennker; Medizinische Universitaetsklinik Luebeck, Luebeck: H. H. Sievers; Universitaetsklinikum Giessen, Giessen: P. Vogt; Johann Wolfgang Goethe Universitaet Frankfurt, Frankfurt: P. Kleine; Herzzentrum Leipzig GmbH, Leipzig: F. Mohr; St Johannes Hospital, Dortmund: G. Walterbusch; Schuechtermann Klinik, Bad Rothenfelde: H. Warnecke; Herzzentrum Wuppertal, Wuppertal: H. Vetter; Herz-Zentrum Bad Krozingen, Bad Krozingen: E. Jaehnchen.
Netherlands (69 Patients): Academisch Ziekenhuis Maastricht, Maastricht: J. Maessen; Onze Lieve Vrouwe Gasthuis, Amsterdam: R. G. H. Speekenbrink; Academisch Ziekenhuis Groningen, Groningen: P. W. Boonstra; Leids Universitair Medisch Centrum, Leiden: R. A. E. Dion; Catharina Ziekenhuis, Eindhoven EJ: J. P. A. M. Schönberger; Isala Klinieken, Zwolle: A. P. Nierich; Amphia Ziekenhuis, Breda: P. M. J. Rosseel.
France (55 Patients): CHRU de Lille-Hopital Cardiologique, Lille: A. Prat; Hopital du Bocage, Dijon: M. David; Hopital Civil de Strasbourg, Strasbourg Cedex: B. Eisenmann; Hopital Europeen Georges Pompidou, Paris: A. Deloche; CHRU de Tours, Tours Cedex: M. Marchand; Institut du Coeur-Groupe Hospitalier Pitie-Salpetriere, Paris: A. Pavie; Hopital Rangueil, Toulouse Cedex: D. Duterque.
Italy (33 Patients): Ospedale San Raffaele, Milano: O. Alfieri; Ospedale Niguarda Cà Granda, Milano: E. Vitali; Istituto Policlinico San Donato, San Donato Milanese: M. Ranucci; Centro Cardiologico Monzino, Milano: P. Biglioli; Policlinico S. Orsola–Malpighi, Bologna: R. Di Bartolomeo; Azienda Ospedaliera Lancisi, Ancona: G. Di Eusanio.
Financial Disclosures: Drs Malloy and Todaro are employees of Procter & Gamble Pharmaceuticals. Drs Rollins, Mojcik, and Adams are employees of and hold stock in Alexion Pharmaceuticals, Inc.
Author Affiliations: University of Washington School of Medicine, Seattle (Dr Verrier); Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Dr Shernan); Hammersmith Hospital, NHLI Imperial College School of Medicine, London, England (Dr Taylor); University Hospital Gasthuisberg, Leuven, Belgium (Dr Van de Werf); Duke Clinical Research Institute, Duke University, Durham, NC (Dr Newman); Kaiser Permanente Medical Center, University of Hawaii, Honolulu (Dr Chen); Montreal Heart Institute, Montreal, Canada (Dr Carrier); Medizinische Hochschule Hannover, Hannover, Germany (Dr Haverich); Procter & Gamble Pharmaceuticals, Cincinnati, Ohio (Drs Malloy and Todaro); Alexion Pharmaceuticals, Cheshire, Conn (Drs Adams, Mojcik, and Rollins); Emory University Hospital, Emory University, Atlanta, Ga (Dr Levy).
REFERENCES
1. Ferguson TB Jr, Hammill BG, Peterson ED, DeLong ER, Grover FL. A decade of change-risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999. Ann Thorac Surg. 2002;73:480-489.
FREE FULL TEXT
2. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol. 1998;31:241-251.
FREE FULL TEXT
3. Rao V, Christakis GT, Weisel RD, et al. The insulin cardioplegia trial: myocardial protection for urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2002;123:928-935.
FREE FULL TEXT
4. Theroux P, Chaitman BR, Danchin N, et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Circulation. 2000;102:3032-3038.
FREE FULL TEXT
5. Shernan SK, Fitch JCK, Nussmeier NA, et al. Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass. Ann Thorac Surg. 2004;77:942-950.
FREE FULL TEXT
6. McCarthy PM, Yared JP, Foster RC, et al. A prospective randomized trial of Duraflo II heparin-coated circuits in cardiac reoperations. Ann Thorac Surg. 1999;67:1268-1273.
FREE FULL TEXT
7. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 2003;75(suppl):S715-S720.
FREE FULL TEXT
8. Royston D. Systemic inflammatory responses to surgery with cardiopulmonary bypass. Perfusion. 1996;11:177-189.
FREE FULL TEXT
9. Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest. 1997;112:676-692.
FREE FULL TEXT
10. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass. Anesth Analg. 1997;85:766-782.
FULL TEXT
|
ISI
| PUBMED
11. Wachtfogel YT, Kucich U, Greenplate J, et al. Human neutrophil degranulation during extracorporeal circulation. Blood. 1987;69:324-330.
FREE FULL TEXT
12. Gillinov AM, Bator JM, Zehr KJ, et al. Neutrophil adhesion molecule expression during cardiopulmonary bypass with bubble and membrane oxygenators. Ann Thorac Surg. 1993;56:847-853.
ABSTRACT
13. Rinder CS, Bonan JL, Rinder HM, et al. Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood. 1992;79:1201-1205.
FREE FULL TEXT
14. Muller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem. 1988;57:321-347.
FULL TEXT
|
ISI
| PUBMED
15. Vakeva AP, Agah A, Rollins SA, et al. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Circulation. 1998;97:2259-2267.
FREE FULL TEXT
16. Homeister JW, Satoh P, Lucchesi BR. Effects of complement activation in the isolated heart. Circ Res. 1992;71:303-319.
FREE FULL TEXT
17. Matis LA, Rollins SA. Complement-specific antibodies: designing novel anti-inflammatories. Nature Med. 1995;1:839-842.
FULL TEXT
|
ISI
| PUBMED
18. Chenoweth DE, Cooper SW, Hugli TE, et al. Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med. 1981;304:497-503.
ABSTRACT
19. Kirklin JK, Westaby S, Blackstone EH, et al. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1983;86:845-857.
ABSTRACT
20. Seghaye MC, Duchateau J, Grabitz RG, et al. Complement activation during cardiopulmonary bypass in infants and children: relation to postoperative multiple system organ failure. J Thorac Cardiovasc Surg. 1993;106:978-987.
ABSTRACT
21. Rinder CS, Rinder HM, Smith BR, et al. Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest. 1995;96:1564-1572.
ISI
| PUBMED
22. Thomas TC, Rollins SA, Rother RP, et al. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol. 1996;33:1389-1401.
FULL TEXT
|
ISI
| PUBMED
23. Fitch JC, Rollins S, Matis L, et al. Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation. 1999;100:2499-2506.
FREE FULL TEXT
24. Gavard JA, Chaitman BR, Sakai S, et al. Prognostic significance of elevated creatine kinase MB after coronary bypass surgery and after an acute coronary syndrome. J Thorac Cardiovasc Surg. 2003;126:807-813.
FREE FULL TEXT
25. Kong TQ, Davidson CJ, Meyers SN, et al. Prognostic implications of creatine kinase elevations following elective coronary artery interventions. JAMA. 1997;277:461-466.
FREE FULL TEXT
26. Mahaffey KW, Granger CB, Nicolau JC, et al, for the COMPLY Investigators. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction. Circulation. 2003;108:1176-1183.
FREE FULL TEXT
27. Granger CB, Mahaffey KW, Weaver WD, et al, for the COMMA Investigators. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction. Circulation. 2003;108:1184-1190.
FREE FULL TEXT
28. Theroux P, Armstrong PW, Mahaffey KW, et al. Markers of inflammation predict mortality and are reduced by pexelizumab in patients with acute myocardial infarction. J Am Coll Cardiol. 2004;43:287A.
29. Van de Werf FJ, Armstrong PW, Levy J, et al. Pexelizumab, a C5 complement inhibitor, reduces 30-day mortality in patients undergoing coronary artery bypass surgery or receiving reperfusion therapy for acute myocardial infarction. J Am Coll Cardiol. 2004;43:474A.
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