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Ann Thorac Surg 2006;82:486-492
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Pexelizumab Reduces Death and Myocardial Infarction in Higher Risk Cardiac Surgical Patients

^a Hannover Medical School, Hannover, Germany
^b Brigham and Women's Hospital, Boston, Masschusetts
^c Emory University Hospital, Atlanta, Georgia
^d University of Hawaii, Honolulu, Hawaii
^e Montreal Heart Institute, Montreal, Quebec, Canada
^f Imperial College of Medicine, London, United Kingdom
^g University Hospital Gasthuisberg, Leuven, Belgium
^h Duke University Medical School, Durham, North Carolina
ⁱ Alexion Pharmaceuticals, Cheshire, Connecticut
^j Procter & Gamble Pharmaceuticals, Cincinnati, Ohio
^k Procter & Gamble Pharmaceuticals, Egham, United Kingdom
^l University of Washington, Seattle, Washington

Accepted for publication December 1, 2005.

^_* Address correspondence to Dr Haverich, Klinik fur Thorax Herz und Gefasschirurgie, Konstanty-Gutschow-Str 8, Hannover, 30623, Germany (Email: haverich{at}thg.mh-hannover.de).

Drs Haverich, Taylor, Newman, Todaro, van der Laan, and Verrier disclose that they have a financial relationship with Proctor & Gamble; Dr Adams with Alexion; and Drs Shernan, Levy, and Chen with Alexion and Proctor & Gamble.

 

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: Morbidity and mortality after coronary artery bypass graft surgery are directly related to specific preoperative risk factors. We assessed the influence of preoperative risk factors on the effect of pexelizumab, a C5 complement inhibitor, to reduce postoperative morbidity and mortality in this post hoc analysis of the Pexelizumab for Reduction in Myocardial Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial, a phase III double-blind, placebo-controlled study of 3,099 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

METHODS: The composite endpoint of death or myocardial infarction or both through postoperative day 30 was examined in subpopulations of patients with pre-specified risk factors, which included diabetes mellitus, prior coronary artery bypass graft, urgent intervention, female sex, history of neurologic event, history of congestive heart failure, and two or more previous myocardial infarctions or a recent myocardial infarction. Stratified post hoc analyses were also performed on patients presenting with two or more and three or more of those risk factors.

RESULTS: Pexelizumab significantly reduced the incidence of the composite endpoint of death or myocardial infarction through postoperative day 30 by 28% in patients with two or more risk factors (p = 0.004) and 44% in patients with three or more risk factors (p < 0.001).

CONCLUSIONS: The C5 complement inhibitor, pexelizumab, reduced morbidity and mortality among high-risk patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

Patients currently presenting for coronary artery bypass graft (CABG) surgery are more likely to have multivessel occlusive coronary artery disease (CAD) and represent an increasingly higher risk population [1]. Several previously defined risk stratification scores have consistently identified a number of risk factors associated with advanced CAD, including recent or multiple myocardial infarctions (MI), low ejection fraction, a requirement for urgent surgery, and repeat revascularization, as independent predictors of increased perioperative morbidity, mortality, and cost after CABG surgery [2–4]. The proportion of patients predisposed to an increased risk of adverse outcomes after CABG surgery owing to the presence of preoperative comorbidities has continued to increase over the last decade [1]. In addition, demographic changes throughout North America and Western Europe have demonstrated a gradual, yet consistent, increasing trend in the age of patients undergoing CABG [1, 5]. Consequently, a greater proportion of patients once considered poor candidates for surgery because of the presence of higher risk profiles are becoming the more typical population presenting for CABG procedures.

Despite significant improvements in surgical techniques and medical care, the incidence of postoperative morbidity and mortality associated with organ dysfunction after CABG surgery remains an important concern. The myocardium is especially vulnerable to injury associated with perioperative ischemia and reperfusion injury during CABG surgery requiring cardiopulmonary bypass (CPB). Thus, risk reduction strategies have become an essential focus of interest, especially among higher risk patients undergoing surgical coronary revascularization.

Proinflammatory complement activation produced during cardiac surgery with extracorporeal circulation and incidental ischemia-reperfusion injury contributes to perioperative myocardial damage in patients undergoing CABG surgery requiring CPB [6–9]. The Pexelizumab for Reduction in Myocardial Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial was designed as an international, prospectively randomized study to assess the efficacy of complement inhibition with pexelizumab in patients requiring on-pump CABG, with and without concomitant valve surgery. By preventing the cleavage of complement component C5, pexelizumab is thought to reduce myocardial injury and death caused by both the inflammatory reaction instigated by C5a generation, and direct cell lysis resulting from production of the terminal complement complex, C5b-9 [10].

In the phase III PRIMO-CABG trial, the primary analysis did not demonstrate a statistically significant reduction in the composite endpoint of death or MI, or both (death/MI), through day 30 in the CABG-only population (namely, 2,746 patients undergoing CABG surgery only) receiving pexelizumab versus placebo (9.8% versus 11.8%; p = 0.07) [9]. However, in the overall study population (3,099 patients undergoing CABG with or without a concurrent valve procedure), pexelizumab significantly reduced death/MI through day 30 (11.5% versus 14%; p = 0.030), compared with placebo. Similarly, pexelizumab significantly reduced death/MI through day 4 compared with placebo in both the CABG-only patients (24% risk reduction [RR]; p = 0.008) and in the overall study population (26% RR; p = 0.014). A treatment-independent analysis revealed the incidence of MI through day 4 was associated with a higher 6-month mortality, a finding that supported similar results from other CABG studies [11, 12].

The PRIMO-CABG trial enrolled patients 18 years and older who presented with at least one of seven prespecified baseline risk factors (diabetes mellitus, prior CABG, urgent intervention, female sex, history of neurologic event, history of congestive heart failure, and two or more previous MIs or a recent MI). The objective of this post hoc analysis was to quantify the incidence of death/MI in patients with multiple protocol specified risk factors (two or more, and three or more) from the overall patient population of the PRIMO-CABG trial.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
The PRIMO-CABG trial was conducted at 205 sites in seven North American and Western European countries. Patients were eligible for enrollment in the PRIMO-CABG trial if they were scheduled for CABG requiring CPB with or without concurrent valve surgery, were 18 years or older, and had one or more of the following preoperative baseline risk factors: urgent intervention defined according to the American College of Cardiology/American Heart Association guidelines [4] as requiring hospitalization due to medical factors, but able to proceed with surgery within a normal scheduling routine; diabetes mellitus; female sex; prior CABG; history of a neurologic event (cerebrovascular accident, transient ischemic attack, or carotid endarterectomy); history of congestive heart failure (New York Heart Association class III or IV); or history of two or more MIs (excluding patients who have had an MI within 48 hours of CABG) or a history of a recent MI that occurred 48 hours or more but less than 4 weeks before CABG. Exclusion criteria included planned aortic dissection repair or required aortic root reconstruction, salvage intervention, current cardiogenic shock, acute left ventricular septal or papillary muscle rupture, uncontrolled diabetes mellitus (plasma blood glucose > 400 mg/dL within 3 days before surgery), history of renal failure (serum creatinine > 3.0 mg/dL), history of chronic hepatic failure or cirrhosis, history of malignancy excluding basal cell carcinoma and malignancies in remission for at least 2 years, known or suspected hereditary complement deficiency, any active infection that was clinically significant in the opinion of the investigator, participation in another investigational drug study or exposure to another investigational agent within 30 days, and known or suspected pregnancy or breast-feeding, or the intention of becoming pregnant during the study period. The Institutional Review Boards or equivalent at each site approved the protocol, and all patients provided written informed consent.

Study Design
Patients were randomly assigned in a double-blind fashion to receive either an intravenous pexelizumab bolus (2.0 mg/kg) followed by a 24-hour infusion (0.05 mg · kg^-1 · hr^-1) or placebo (bolus followed by 24-hour infusion). Pexelizumab or placebo bolus was administered as soon as possible after general anesthesia induction, but not later than 10 minutes before CPB. Patients were followed up for adverse events and clinical endpoints. Death, defined as all-cause mortality, was assessed through postoperative day 180. Incidence of MI was defined as a peak creatine kinase myocardial band isoform (CK-MB) of 100 ng/mL or greater by postoperative day 4 independent of Q-wave evidence; CK-MB of 70 ng/mL or greater by postoperative day 4 with evidence of a Q-wave MI; new Q-wave evidence of MI by postoperative day 30 that was not present by postoperative day 4; and MI independent of Q-wave evidence identified by investigator and confirmed by the clinical events committee by postoperative day 30. A clinical events committee masked to treatment adjudicated all MIs. Serum samples were collected at 4, 8, 12, 16, 24, 72, and 96 hours postoperatively for subsequent CK-MB analysis at a central core laboratory. Electrocardiograms were recorded upon patient enrollment and at 2, 4, 14, 30, 90, and 180 days postoperatively, and were interpreted at a central laboratory whose personnel were masked to treatment. In addition, patients were seen 14, 30, 90, and 180 days after CABG surgery to document clinical events.

Statistical Analyses
In this post hoc analysis, the effect of pexelizumab on the incidence of death/MI through day 30 in patients with two or more and three or more of the prespecified risk factors was examined. Homogeneity of treatment effect on death/MI was also examined in subpopulations of patients with protocol-specified risk factors.

Comparison of incidence rates between the treatment groups was performed by (Mantel-Haenszel) ² testing. Comparison of the incidence rates was made by means of relative risks and their associated 95% confidence limits. Statistically significant differences were defined by p value of 0.01 or less. Patients whose mortality status was unknown at day 30, and who had not experienced an MI by day 30, were considered missing. Additionally, survival analysis and event-free survival analysis were performed using stratified Kaplan-Meier methodology. The SAS version 8.2 and S-Plus version 2000 software (SAS Institute, Cary, North Carolina) were used for all statistical analyses. No adjustments were made for multiple comparisons.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Randomization, Demographics, and Safety
Between January 2002 and February 2003, a total of 3,099 patients was randomly assigned (2,410 patients at 164 sites in North American and 689 patients at 41 sites in Western Europe). Of these patients, 2,018 (65%) had two or more prespecified risk factors and 895 (29%) had three or more risk factors. The incidence of specific risk factors was similar in the pexelizumab and placebo groups (Table 1). Although a higher proportion of women were randomly assigned to the pexelizumab group than to the placebo group, this numerical difference was not statistically significant. Urgent intervention was the most common risk factor (64%), followed by diabetes (41%), history of congestive heart failure (30%), and female sex (27%).

View larger version (12K): [in this window] [in a new window]   Fig 1. Effect of pexelizumab treatment through postoperative day 30. Data shown are for patients with (A) two or more risk factors and (B) three or more risk factors who underwent coronary artery bypass graft (CABG) surgery with and without concurrent valve surgery, and (C) for patients with two or more and three or more risk factors who underwent CABG-only surgery. (MI = myocardial infarction.)

View larger version (15K): [in this window] [in a new window]   Fig 2. Survival through day 180 in patients with (A) two or more risk factors, and (B) three or more risk factors. (RR = risk reduction.)

View larger version (21K): [in this window] [in a new window]   Fig 3. Event-free survival analysis for patients with (A) two or more risk factors, and (B) three or more risk factors.

View larger version (18K): [in this window] [in a new window]   Fig 4. Homogeneity of the treatment effects of pexelizumab on death/MI through day 30 in patients with various risk factors. (CABG = coronary artery bypass grafting; CHF = congestive heart failure; Hx = history; MI = myocardial infarction.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Over the past several years, the risk profile of CABG patients has shifted toward higher risk populations predisposed to increased perioperative morbidity and mortality [1, 5, 13]. The presence of an increased frequency of comorbid risk factors has led to a 30% rise in predicted operative risk in the past decade [1]. Although recent advances in myocardial preservation, pharmacologic intervention, modification of CPB circuits, and even off-pump CABG techniques allow most patients to undergo cardiac surgery without significant mortality, in certain populations, substantial morbidity and mortality may still occur. Perioperative complications involving cardiac dysfunction secondary to direct myocardial damage, pulmonary failure, neurologic injury, renal insufficiency, bleeding, and severe infection can affect length of stay and cost of hospitalization [14, 15], and can ultimately contribute to death [3, 4].

Several risk reduction strategies involving new surgical techniques (for example, off-pump CABG [16]) and pharmacologic interventions (for example, thyroxin [17] and free radical scavengers [18]) have been introduced in an attempt to reduce the incidence of adverse cardiovascular outcomes after CABG surgery.

Specific pharmacologic attempts to reduce myocardial damage secondary to ischemia reperfusion injury have been studied in multicenter, prospective randomized trials [9, 19]. Although the PRIMO-CABG trial did not meet its primary composite endpoint of death/MI reduction in the CABG-only population, the trial did demonstrate that pexelizumab, a C5 complement inhibitor, significantly reduced death/MI by 18% in the overall study population of 3099 patients who underwent CABG surgery with and without a concurrent valve procedure. In this present post hoc analysis, pexelizumab was found to significantly reduce the incidence of death/MI by 28% in patients with two or more risk factors and by 44% in patients with three or more risk factors. This significant reduction in death/MI by pexelizumab appears to be present despite the additional confounding effect of concomitant valve procedures to an already high risk group of patients. Complement inhibition represents a novel therapeutic approach for providing a sustained beneficial effect on reducing morbidity and mortality in higher risk patients undergoing CABG surgery requiring CPB.

The etiology of postoperative organ dysfunction after cardiac surgery is multifactorial and can involve preexisting comorbidities, hemodynamic instability, and nonphysiologic perfusion during CPB, as well as direct organ injury from intravascular embolization [20]. During cardiac surgery, surgical trauma and exposure of circulating blood to the extracorporeal circuit [21] and endotoxin [22] promote the production of proinflammatory mediators, which can contribute to postoperative morbidity and mortality [23]. Complement activation plays an important role in perioperative systemic inflammation [7, 24]. The generation of C5 cleavage products, C5a and C5b-9, during CPB correlates directly with clinical morbidity attributed to the systemic inflammatory response [7, 24, 25]. Perhaps more importantly, there is evidence that supports a significant role for perioperative systemic and local complement activation, which is initiated by extracorporeal circulation and subsequently by reperfusion upon myocardial revascularization, leading to adverse effects on the heart and other organ systems during CABG surgery [26–29]. Although inflammation may be promoted by different stimuli during CPB (contact activation) and ischemia-reperfusion injury (hypoxia and reoxygenation) during CABG, the damaging role of complement-mediated tissue injury is common to both mechanisms. Without CPB, selective aspects of systemic inflammation may be reduced. However, complement activation leading to myocardial ischemia-reperfusion injury will remain an unavoidable concern. Thus, inhibition of complement activation in cardiac surgical patients may afford organ protection and ultimately reduce morbidity.

We have previously shown that pexelizumab, a novel 25-kDa recombinant, humanized, single-chain monoclonal antibody, binds to human C5 with picomolar affinity and blocks C5 cleavage in the classical, alternative and lectin complement pathways [10]. This has resulted in a favorable treatment effect of pexelizumab in reducing perioperative myocardial injury [7, 8] and death [8] among patients undergoing CABG requiring CPB. In this current analysis, we identified a clinical benefit of pexelizumab on reducing morbidity and mortality events in a subset of higher risk patients having at least two of the seven prespecified risk factors. This benefit was maintained through postoperative day 180 and was associated with a favorable safety profile. Analysis for the homogeneity of the treatment effect indicated that the benefit observed with pexelizumab in higher risk patients was not driven by outcomes in a subgroup with one particular risk factor. The clinical significance of these results becomes apparent with the recognition that higher risk patients may represent the majority of those presenting for CABG surgery, with the number expected to rise in the future, based on recent trends [1]. Of the entire population of 3,099 patients in the PRIMO-CABG trial, 65% had two or more risk factors and 29% had three or more risk factors, as prespecified in the study protocol. Higher risk patients undergoing CABG surgery requiring CPB, including patients with preoperative organ dysfunction, those patients requiring urgent surgical intervention or repeat revascularization, and those who have experienced a recent MI may have decreased functional reserve, and may therefore be predisposed to increased postoperative morbidity and mortality [1].

The findings presented may be clinically meaningful and suggest that higher risk patients may benefit from terminal complement blockade during CABG surgery. There are certain limitations of this analysis: (1) results have been taken from a study where the primary endpoint was not met, and (2) the present results represent a post hoc analysis that was not prespecified, and is therefore subject to statistical error. The interesting hypothesis raised by these findings will be further examined in PRIMO-CABG II, a current second phase III trial that will examine the clinical benefits of pexelizumab in higher risk patients having two or more risk factors, who are undergoing CABG with or without valve surgery.

In summary, higher risk cardiac surgical patients are predisposed to increased perioperative morbidity and mortality. In this trial, the C5 complement inhibitor pexelizumab significantly reduced death/MI through postoperative day 30 in patients with multiple inclusion risk factors, who underwent CABG surgery with or without concomitant valve procedure requiring CPB. Based on the finding of this subanalysis, a second pexelizumab phase III clinical study called PRIMO-CABG II is under way and will focus on higher risk patients undergoing CABG surgery requiring CPB.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Funding for the PRIMO-CABG study was provided by the study's joint sponsors, Procter & Gamble Pharmaceuticals, Cincinnati, Ohio, and Alexion Pharmaceuticals, Cheshire, Connecticut. Data for the current manuscript were provided by the sponsors to the authors at their request for their independent analysis and interpretation.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Axel Haverich Stanton K. Shernan Jerrold H. Levy John C. Chen Michel Carrier Kenneth M. Taylor Mark F. Newman Peter X. Adams Edward D. Verrier Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haverich, A. Articles by Verrier, E. D. Search for Related Content PubMed PubMed Citation Articles by Haverich, A. Articles by Verrier, E. D. Related Collections Cardiac - other