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Peter K. Smith
Michel Carrier
John C. Chen
Axel Haverich
Jerrold H. Levy
Philippe Menasché
Stanton K. Shernan
Peter X. Adams
Edward Verrier
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Ann Thorac Surg 2006;82:781-789
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Effect of Pexelizumab in Coronary Artery Bypass Graft Surgery With Extended Aortic Cross-Clamp Time

Peter K. Smith, MDa,*, Michel Carrier, MDb, John C. Chen, MDc, Axel Haverich, MDd, Jerrold H. Levy, MDe, Philippe Menasché, MDf, Stanton K. Shernan, MDg, Frans Van de Werf, MD, PhDh, Peter X. Adams, MDi, Thomas G. Todaro, MDj, Edward Verrier, MDk

a Duke University Medical Center, Durham, North Carolina
b Montréal Heart Institute, Montréal, Quebec, Canada
c University of Hawaii, Honolulu, Hawaii
d Hannover Medical School, Hannover, Germany
e Emory University Hospital, Atlanta, Georgia
f Hôpital Européen Georges Pompidou, Paris, France
g Brigham and Women's Hospital, Boston, Massachusetts
h University Hospital Gasthuisberg, Leuven, Belgium
i Alexion Pharmaceuticals, Cheshire, Connecticut
j Procter & Gamble Pharmaceuticals, Mason, Ohio
k University of Washington, Seattle, Washington

Accepted for publication February 2, 2006.

* Address correspondence to Dr Smith, Duke University Medical Center, PO Box 3442, Durham, NC 27710 (Email: smith058{at}mc.duke.edu).

Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.


Adult cardiac surgery: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
BACKGROUND: Prolonged cross-clamp time during cardiac surgery increases the risk of postoperative mortality and myocardial injury. This subanalysis from the pexelizumab for reduction of infarction and mortality in coronary artery bypass grafting surgery (PRIMO-CABG) trial, a phase III double-blind, placebo-controlled study of 3,099 patients undergoing on-pump coronary artery bypass graft surgery with or without valve surgery, assessed the impact of pexelizumab, an investigational C5 complement inhibitor, on postoperative outcomes after prolonged aortic cross-clamp time.

METHODS: The composite endpoint of death or myocardial infarction through postoperative day 30 and death alone through days 30, 90, and 180 were examined in subpopulations of patients across different cross-clamp times.

RESULTS: After prolonged cross-clamping (≥90 minutes), death, or myocardial infarction through day 30 and death through days 30, 90, and 180 were significantly increased in the intent-to-treat population and were even higher in patients with two or more prespecified risk factors, compared with all patients cross-clamped less than 90 minutes. Pexelizumab significantly reduced the incidence of death or myocardial infarction through day 30, and significantly reduced the incidence of mortality through day 180, in patients with two or more risk factors that required prolonged cross-clamp time. Pexelizumab also significantly reduced perioperative myocardial injury in all patients requiring prolonged cross-clamp time.

CONCLUSIONS: In this retrospective, subgroup analysis, pexelizumab reduced postoperative morbidity and myocardial injury in patients with multiple risk factors who underwent prolonged cross-clamp time during coronary artery bypass surgery. The clinical benefit of pexelizumab may be related to the effect of complement inhibition in the presence of potential ischemic-reperfusion injury associated with prolonged aortic cross-clamp time.


Drs Smith, Chen, Haverich, Levy, Menasché, Shernan, Van de Werf, Adams, Todaro, and Verrier disclose that they have financial relationships with Alexion and Proctor & Gamble.

 

During cardiac surgery, aortic cross-clamping results in myocardial ischemia that may be exacerbated by reperfusion when the clamp is released [1]. Prolonged cross-clamp time has been associated with extended intensive care unit stay [2] and increased morbidity [3] including pulmonary dysfunction [4], low cardiac output [5], myocardial injury [6], and multiorgan system failure [7], as well as intraoperative death [5] and mortality [7–9].

The correlation between longer cross-clamp time in cardiac surgery and increased myocardial injury, assessed by serum levels of troponin and creatine kinase-myocardial band (CK-MB), has also been well-established [10–12]. A previous report published in this journal [13] identified that 90 or more minutes of cross-clamp time during coronary artery bypass graft (CABG) surgery is an independent predictor of myocardial injury. In cases where prolonged aortic cross-clamping is anticipated, additional myocardial protection techniques, in conjunction with modified cardioplegia and hypothermia, specifically targeted toward protection against myocardial ischemia-reperfusion injury may be warranted [14].

Myocardial tissue injury can result from direct surgical trauma and from ischemia during aortic cross-clamping. In addition, exposure of circulating blood to the extracorporeal circuit (ECC) [15], and associated endotoxemia [16], can trigger systemic proinflammatory events including complement activation [17–19]. After cross-clamp release and subsequent reperfusion, the transition from a state of hypoxia to reoxygenation can exacerbate tissue injury as the vasculature and myocardium are exposed to reactive oxygen species and other proinflammatory mediators including activated terminal complement products.

The terminal complement products, C5a, and the terminal complement complex otherwise known as the membrane attack complex (C5b-9), both play a key role in inflammation-mediated tissue injury during ischemia-reperfusion. While C5a promotes direct leukocyte activation and chemotaxis, increases vascular permeability, and activates various proinflammatory cytokines, multiple target cell "hits" by the pore-forming terminal complement complex promotes water, electrolyte, and small molecule transcellular fluxes, ultimately resulting in cell lysis and irreversible tissue injury [20]. These local and systemic proinflammatory responses may alter tissue barrier function and cause widespread microvascular dysfunction [21], leading to postoperative morbidity and mortality.

The ability of pexelizumab, a specific C5 complement inhibitor, to reduce death or myocardial infarction (MI) (death-MI) in patients undergoing CABG was explored in the PRIMO-CABG trial [22]. Although the primary analysis did not demonstrate an important significant reduction in the composite endpoint of death-MI through day 30 in the CABG-only population who received pexelizumab versus placebo (9.8% vs 11.8%; p = 0.069), pexelizumab significantly reduced death-MI in the intent-to-treat population of patients undergoing CABG with or without concurrent valve surgery (11.5% vs 14%; p = 0.030), compared with placebo [22]. The decreased incidence of MI through day 4 after CABG was found to be associated with a significant reduction in postoperative mortality [22]. However, the impact of terminal complement inhibition on perioperative myocardial injury and postoperative outcomes in patients requiring prolonged aortic cross-clamp time has not been previously examined in a clinical trial setting.

The purpose of this subanalysis was to examine retrospectively the impact of cross-clamping 90 or greater minutes, which has previously been shown to cause significant myocardial injury [13], on clinical and other outcomes in all patients from the PRIMO-CABG trial who underwent CABG surgery with or without concomitant valve replacement. In addition, the impact of terminal complement inhibition with pexelizumab on perioperative myocardial injury and postoperative outcomes in patients requiring prolonged (≥ 90 minutes) cross-clamp time was evaluated.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Study Design
Patients were randomized 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/hour–1) or placebo (bolus followed by 24-hour infusion). Patients were included for planned coronary bypass grafting with or without valve replacement and had one or more predefined risk factors (diabetes, female gender, a history of New York Heart Association class III or IV congestive heart failure, a history of two or more MIs or a recent MI, a history of cerebral vascular accident or transient ischemic attack, urgent surgical intervention, or prior CABG). Pexelizumab or placebo bolus was administered as soon as possible after general anesthesia induction, but not later than 10 minutes prior to initiating cardiopulmonary bypass (CPB). Compared with placebo, pexelizumab administration resulted in complete inhibition of total serum complement hemolytic activity for 24 hours [22]. Patients were followed for in-hospital adverse events and clinical endpoints. Death, defined as all cause mortality, was assessed at postoperative days 4, 30, 90, and 180. Postoperative MI definition was based on a prespecified algorithm, which has been previously described [22], and was adjudicated by a clinical events committee that was blinded to treatment. Serum samples were collected at 4, 8, 12, 16, 24, 72, and 96 hours postoperatively for CK-MB analysis at a central core laboratory. Electrocardiograms recorded at the time of patient enrollment, and at 2, 4, 14, 30, 90, and 180 days postoperatively, were interpreted at a central laboratory whose personnel were blinded to treatment. In addition, patients were evaluated 14, 30, 90, and 180 days after CABG surgery to document adverse events. Institutional review board approval was obtained at all sites (Duke University IRB 3460-02-2R0), and individual consent waived for additional analysis of the primary data.

Statistical Analyses
The impact of cross-clamp time 90 or greater minutes on the incidence of postoperative adverse outcomes and peak CK-MB levels was examined by (Mantel-Haenszel) {chi}2 testing for the intent-to-treat population and for patients having two or more prespecified risk factors. The postoperative incidence of mortality, MI, and peak CK-MB values was compared based on cross-clamp time and across treatment groups. Folded empirical frequency distribution curves [23], were generated to compare the distribution of peak CK-MB levels across patient populations. The effect of treatment on patient survival was analyzed through day 180 using a log-rank test. The endpoints examined included the composite of death-MI through day 30, death (all-cause mortality) assessed at days 4, 30, 90, and 180, MI through day 4, and peak serum levels of CK-MB.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Requirement for Prolonged Cross-Clamp Time
Aortic cross-clamp data were available on 3,070 of the 3,099 patients. Approximately 1 in 5 patients required an aortic cross-clamp time equal to 90 or greater minutes. This value was similar for patients in the overall population (21%, 646 of 3,070) and for patients with two or more of the protocol specific risk factors (21%, 428 of 2,000). Median cross-clamp times were similar between treatments. Patients who required prolonged cross-clamp time 90 or greater minutes versus less than 90 minutes during CABG surgery were five times more likely to have undergone a concurrent valve procedure (33% vs 6%), and were also more likely to have undergone a prior cardiac procedure (14% vs 7%). In addition, prolonged cross-clamp time was associated with a greater number of total grafts (Table 1).


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  		Table 1. Surgical Procedures for Patients According to Cross-Clamp Time
 
Effect of Prolonged Cross-Clamp Time on Myocardial Injury
The frequency distribution of peak CK-MB release for the overall population, independent of treatment, was significantly shifted to the right (towards higher levels) as cross-clamp time increased (Fig 1). In addition, the curve shift with prolonged aortic clamping occurs across all percentiles of peak CK-MB, not only at levels associated with the diagnosis of MI as defined in the protocol [22].


Figure 1
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  		Fig 1. Treatment-independent effect of cross-clamp time on peak postoperative CK-MB levels. Plots show the peak CK-MB levels across the population for patients cross-clamped. (A) less than 30 minutes, (B) 30 to 90 minutes, and (C) 90 or greater minutes. Note: CK-MB data were available for 2,984 patients. (CK-MB = creatine kinase-myocardial band.)

 
Effect of Prolonged Cross-Clamp Time on Clinical Outcomes
In the placebo-treated patients, prolonged cross-clamp time was associated with increased day 30 death-MI, MI through day 4, and death through days 4, 30, 90, and 180 (Table 2). This effect was observed for all patients but was more pronounced in patients with two or more risk factors. The incidence of both postoperative mortality and myocardial injury increased with longer cross-clamp duration and was most notable when the cross-clamp time extended beyond 90 minutes (Fig 2), whereas 90 to 105 minutes cross-clamp time was associated with a 4.1% mortality rate compared with 2.2% for patients requiring less than 90 minutes of cross-clamp time (p = 0.056). These observations are consistent with unadjusted mortality outcome compared with cross-clamp time in 537,142 isolated CABG procedures performed from 2000 to 2004 and submitted to the STS National Adult Cardiac Database [24].


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  		Table 2. Treatment-Independent Effect of Cross-Clamp Time on Clinical Endpoints
 

Figure 2
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  		Fig 2. Mortality by aortic cross-clamp time. Data shown are for day 30 mortality ({square}) and mean peak CK-MB release ({diamondsuit}) across various cross-clamp intervals for patients in the current analysis. (CK-MB = creatine kinase-myocardial band.)

 
Effect of Pexelizumab on Myocardial Injury
A more detailed analysis revealed that, while increasing the cross-clamp time to 90 or greater minutes was associated with higher peak CK-MB concentrations (Figs 3 A, 3B, 3C), pexelizumab therapy resulted in a significant shifting of peak CK-MB toward lower levels (Fig 3C). Log-rank analysis of the population distribution curves revealed that pexelizumab significantly lowered peak CK-MB levels in all patients requiring 90 or greater minutes of cross-clamp time (p = 0.024). In addition, pexelizumab significantly reduced the percent of patients with peak CK-MB levels greater than or equal to 100 ng/mL (p = 0.042). Mean peak CK-MB levels were significantly reduced in all patients requiring prolonged aortic cross-clamp time, regardless of the number of prespecified risk factors (Fig 4A, 4B). A similar treatment effect was also seen for populations requiring a prolonged CPB time of 120 or greater minutes, but was not statistically significant (p = 0.058 for log-rank analysis: data not shown).


Figure 3
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  		Fig 3. Effect of treatment on the distribution of peak CK-MB levels. Distribution plots of peak postoperative CK-MB levels shown are for populations requiring the following cross-clamp time: (A) less than 30 minutes (x = placebo [n =177]; o = Pexelizumab [n = 171]), (B) 30 to 90 minutes (x = placebo [n = 999]; o = Pexelizumab [n = 1,013], and (C) 90 or greater minutes (x = placebo [n = 309]; o = Pexelizumab [n= 315]). (p values shown are for the log-rank analysis; CK-MB = creatine kinase-myocardial band.)

 

Figure 4
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  		Fig 4. Effect of Pexelizumab on mean peak CK-MB levels according to cross-clamp time. Data shown are mean values ± standard error for (A) the overall population and (B) patients with two or more risk factors. (*p < 0.05 compared with placebo; {blacksquare} = placebo; {square} = Pexelizumab.)

 
Effect of Pexelizumab on Clinical Outcomes
In patients with two or more risk factors, pexelizumab significantly reduced the combined incidence of death-MI through day 30, regardless of aortic cross-clamp time (Fig 5B). The day 30 death-MI was reduced 30.3% (p = 0.044) in the higher risk patients requiring prolonged cross-clamp time and to a lesser degree (25%) in the higher risk patients requiring prolonged CPB time (p = 0.059). In addition, pexelizumab significantly reduced mortality through day 30 (Fig 6B), and improved overall survival through day 180 in those patients who required 90 or greater minutes of cross-clamp time (Fig 7B). The relative reduction in mortality through day 30 in the pexelizumab versus placebo groups was greater when the aortic cross-clamp time was 90 or greater minutes than when it was less than 90 minutes (Fig 6A, 6B). A reduction in mortality with pexelizumab versus placebo was also observed through day 90 (6.0% vs 13.2%, relative reduction 54.4%, p = 0.013), and day 180 (7.9% vs 15.1%, relative reduction 47.9%, p = 0.023) in patients with two or more risk factors who were cross-clamped for 90 or greater minutes. There was a trend favoring pexelizumab for the reduction of death-MI (Fig 5A) and death alone (Fig 6A) through day 30, and for improving survival through day 180 (Fig 7A) in the overall intent-to-treat population, although it did not reach statistical significance.


Figure 5
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  		Fig 5. Effect of Pexelizumab on death-MI according to cross-clamp time. Data shown are mean values ± standard error for (A) the overall population and (B) patients with two or more risk factors. (*p < 0.05 compared with placebo; {blacksquare} = placebo; {square} = Pexelizumab; MI = myocardial infarction.)

 

Figure 6
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  		Fig 6. Effect of Pexelizumab on death according to cross-clamp time. Data shown are mean values ± standard error for (A) death for the overall population, and (B) death for patients with two or more risk factors. (*p < 0.05 compared with placebo; {blacksquare} = placebo; {square} = Pexelizumab.)

 

Figure 7
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  		Fig 7. Kaplan-Meier survival curves showing the effect of Pexelizumab on survival in patients requiring 90 or greater minutes of cross-clamp time. Data shown are for (A) the overall population and (B) patients with two or more risk factors. The p values are for the log-rank analysis of the curves.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
The PRIMO-CABG trial demonstrated that terminal complement inhibition with pexelizumab significantly reduced the composite endpoint of death-MI among patients undergoing CABG with and without valve surgery [22]. Additionally, a strong relationship between perioperative MI and death was demonstrated that was independent of terminal complement inhibition [22], and was associated with increased hospital cost [25]. This subanalysis of the PRIMO-CABG trial further identifies a favorable treatment effect of terminal complement inhibition when aortic cross-clamp time is prolonged, especially in patients with multiple risk factors.

In this subgroup analysis, both postoperative mortality and myocardial injury, as assessed by peak CK-MB release, directly correlated with aortic cross-clamping, most notably after a cross-clamp time of 90 or greater minutes. Furthermore, complement inhibition with pexelizumab reduced the incidence of death and myocardial injury in higher risk patients who required prolonged (≥90 minutes) cross-clamp time. Complement inhibition resulted in a relative reduction of CK-MB release in patients requiring prolonged cross-clamp time and this was especially prominent in patients with two or more risk factors, where a significant reduction in mortality was identified.

Although no studies to date have directly assessed the association between aortic cross-clamp time and degree of complement activation, the current analysis demonstrated a direct relationship. Longer ischemic periods resulting from prolonged cross-clamping were shown to be associated with greater myocardial injury. In patients requiring 90 or greater minutes of cross-clamp time, pexelizumab protected against myocardial injury, as indicated by a significant shift towards lower levels in peak CK-MB release, compared with placebo. Pexelizumab treatment resulted in lower CK-MB levels across the entire population requiring 90 or greater minutes of cross-clamp time, suggesting that complement-mediated tissue damage may not be restricted to patients who produce the highest levels of this injury marker.

The present findings may help elucidate how activation of the complement system contributes to perioperative tissue injury during CABG. It is possible that longer periods of ischemic time render the myocardium more vulnerable to activated complement attack, leading to a greater degree of tissue injury upon reperfusion. While this scenario infers that myocyte injury can be a direct result of reperfusion after prolonged ischemia, data presented here also suggest that a substantial component of the observed damage after reperfusion is mediated through terminal complement activation, because selectively blocking complement reduces overall myocardial tissue injury.

Several models for predicting cardiac surgery outcomes have been proposed [26], but these approaches lack intraoperative and postoperative variables that could improve predictive ability [8]. If one could accurately predict which patients will require extended cross-clamping during CABG surgery, additional protective measures could be applied. In some cases, it may be possible to anticipate which patients are more likely to require prolonged cross-clamp time. For example, this current dataset showed that patients who required 90 or greater minutes of cross-clamp time were more likely to have undergone repeat CABG surgery, four or more bypass grafts, or a concurrent valve procedure, compared with patients who required shorter periods of cross-clamp time.

There has been an increasing trend in the number of combined CABG plus valve procedures over the past decade, while the number of isolated CABG procedures has remained relatively stable [27]. Numerous studies have highlighted the changing demographics of patients presenting for CABG surgery [28–30], most notably including advanced age, impaired ventricular function, and increased comorbidity. The patient population enrolled in the PRIMO-CABG trial reflected these findings, with 65% of patients presenting with two or more risk factors and 29% presenting with three or more risk factors [31]. The increased risk of surgical patients may partially explain the finding from this subanalysis that 21% of patients in both the intent-to-treat group and the two or more risk factor group required extended cross-clamp time. As more complex patients become the predominant subjects for CABG surgery, approaches that improve clinical outcomes, such as substrate enhancement, thyroxin, heparin-coated circuits, and alternate arresting agents, and complement inhibition [32] will become increasingly vital as a tool in the surgical team's armamentarium.

It is important to note that this study was a subanalysis of the original PRIMO-CABG trial in which the primary endpoint was not met, and that findings are subject to statistical error. The decision to choose a 90-minute surgical ischemic time was based on published literature and the presence of a gradient of mortality seen in the randomized patients and seen in STS database observational data. Because of interaction between the duration of surgical ischemia, patient risk factors, and the type of surgery, it is not certain that the actual ischemic time alone is predictive. In addition, certain interactions between variables, such as the relationship between aortic cross-clamp time and the duration of CPB cannot be evaluated independently due to limitations in study design. While aortic cross-clamp time may directly correlate with ischemic myocardial injury, the duration of CPB may more closely relate to the further activation of complement and other proinflammatory mediators. In patients with multiple risk factors, the benefit of terminal complement inhibition was significant after prolonged cross-clamp time compared with prolonged CPB time. This suggests that complement-mediated myocardial damage may be driven by the duration of ischemia time. Therefore, after prolonged ischemia, the myocardium may become more vulnerable to complement-mediated attack upon reperfusion. It may well be the case that both CPB duration and ischemia time are important and that there are thresholds for CPB duration that exceed tolerance to complement activation in patients with preexisting organ dysfunction, as well as thresholds for aortic cross-clamping that exceed cardiac tolerance to complement activation.

An additional limitation is that the predefined risk factors are probably not of equal weight in predictive value, although they are treated equally and equally additive due to the study design. Correction by weighting may lead to differing results, and could add to the predictive value of ischemic time.

These findings indicate that in CABG surgery, prolonged aortic cross-clamp time was associated with greater myocardial injury and increased postoperative morbidity and mortality. Inhibiting terminal complement activation with pexelizumab reduced the degree of myocardial tissue injury after prolonged ischemia and improved postoperative outcomes in a subset of higher risk patients who were susceptible to increased postoperative morbidity and mortality after prolonged cross-clamp time. The potential benefits of terminal complement inhibition with pexelizumab are being 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.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR JOHN H. CALHOON (San Antonio, TX): Peter, this is a nice study. I think our group participated in it a little bit as well. One of my questions is, where do you think pexelizumab will fall into our armamentarium of antiinflammatory agents in taking care of our coronary patients in the future? Thank you. A very nicely done and presented paper.

DR SMITH: Thank you. That is obviously a very important question because the drug is not FDA-approved for use, because in the primary analysis of coronary bypass grafting patients alone, it did not achieve statistical significance. Accordingly, another trial has been designed to answer your question. So I can't answer it right now, although obviously the feeling is that higher risk patients and potentially those patients where one would anticipate prolonged cross-clamp time would be a population that would be affected positively by the drug. The randomized trial being performed now is 4,250 patients randomized that have two or more risk factors for starters, both coronary bypass grafting and (or) valve replacement. So it is a similar study design, the endpoints are the same, plus there is a heart failure outcome endpoint as well as a secondary endpoint. This trial is completed, all the patients have been enrolled, the data is locked, and we will be hoping to present this to the American College of Cardiology as a late-breaking trial. The results will be known within a month or so.

DR JOHN D. PUSKAS (Atlanta, GA): I enjoyed your presentation very much, Dr Smith. Can you share with us any insights that you might have about the use of this medication in off-pump cardiac surgery? Will it have any role at all?

DR SMITH: Again, that is possible. That has not been studied. The only other ongoing study is a study of acute myocardial infarction in the cath lab recognized within six hours; patients are being randomized to receive this drug. One would assume that in off-pump bypass some stimulus for complement activation would still be present, and certainly myocardial injury is occurring. So one would anticipate that there is a possibility the drug could be effective in that role, but it hasn't been studied yet. It probably should be.

DR ANDREA J. CARPENTER (San Antonio, TX): In the trial that just completed, or in this trial, were you able to separate out the use of aprotinin, Amicar, or no antifibrinolytics in these patients and how that may influence the complement activation with pexelizumab?

DR SMITH: To my knowledge, that has not been done yet. The use of aprotinin and these other drugs was not controlled, so that patients in both the placebo and treatment arms received these drugs. It has not been studied, to my knowledge, yet.

DR CARPENTER: Do you know, if it was recorded, whether they were given to individual patients?

DR SMITH: Yes, that I believe is known.

DR CARPENTER: We look forward to seeing the data.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
Funding for the PRIMO-CABG study was provided by the study's joint sponsors, Procter & Gamble Pharmaceuticals, Cincinnati, OH, and Alexion Pharmaceuticals, Cheshire, CT. Data for the current manuscript were provided by the sponsors to the authors at their request for their independent analysis and interpretation. The authors wish to thank Thomas Filloon, PhD, Procter & Gamble Pharmaceuticals, Cincinnati, OH, for his contribution to the statistical analysis and for his interpretations of the data and analytical methods used.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

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