HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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): Peter K. Smith Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lincoff, A. M. Articles by Topol, E. J. Search for Related Content PubMed PubMed Citation Articles by Lincoff, A. M. Articles by Topol, E. J.

Ann Thorac Surg 2000;70:516-526
© 2000 The Society of Thoracic Surgeons

---

Original articles: cardiovascular

Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials^*

^a Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^b Department of Biostatistics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^c Eli Lilly and Company, Indianapolis, Indiana, USA
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA
^e Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
^f Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA
^g Centocor, Malvern, Pennsylvania, USA

Address reprint requests to Dr Lincoff, Department of Cardiology, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195

	Abstract

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Background. Abciximab during percutaneous coronary revascularization reduces ischemic complications, but concern exists regarding increased bleeding risk should emergency coronary surgical procedures be required.

Methods. Outcomes were assessed among 85 patients who required coronary artery bypass grafting operations after coronary intervention in two randomized placebo-controlled trials of abciximab. Comparisons were made between patients in the pooled placebo and abciximab groups.

Results. The incidence of coronary surgical procedures was 2.17% and 1.28% among patients randomized to placebo and abciximab, respectively (p = 0.021). Platelet transfusions were administered to 32% and 52% of patients in the placebo and abciximab groups, respectively (p = 0.059). Rates of major blood loss were 79% and 88% in the placebo and abciximab groups, respectively (p = 0.27); transfusions of packed red blood cells or whole blood were administered in 74% and 80% of patients, respectively (p = 0.53). Surgical reexploration for bleeding was required in 3% and 12% of patients, respectively. Death and myocardial infarction tended to occur less frequently among patients who had received abciximab.

Conclusions. Urgent coronary artery bypass grafting operations can be performed without an incremental increase in major hemorrhagic risk among patients on abciximab therapy.

	Introduction

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Plaque rupture and vascular thrombosis are key initiating factors in the pathogenesis of ischemic complications of percutaneous coronary revascularization. Strategies to achieve potent inhibition of platelet activity at the injured coronary plaque focus on the platelet membrane integrin glycoprotein (GP) IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor and cross-links adjacent platelets as the final

common pathway of platelet aggregation. Abciximab (ReoPro, Centocor, Malvern, PA) is a human-murine chimeric monoclonal Fab antibody fragment that binds with high affinity and a slow dissociation rate to the GP IIb/IIIa receptor and potently inhibits platelet aggrega-tion [1]. Large-scale placebo-controlled trials have demonstrated that abciximab reduces the incidence of ischemic complications by as much as 60% among patients undergoing percutaneous coronary revascularization for both stable and unstable ischemia [2–5].

Concerns have been raised, however, about the risk of excessive perioperative blood loss in patients requiring emergency coronary artery bypass graft operation (CABG) for failed angioplasty after administration of abciximab. This antibody fragment is cleared rapidly from the plasma, but it remains bound to circulating platelets for as long as 21 days [6]. Thus, after discontinuation of an abciximab infusion, platelet aggregation and bleeding times remain abnormal for 12 to 48 hours [1]. These effects are compounded by the routine administration of aspirin during coronary intervention, even among patients treated with abciximab. Isolated reports of small numbers of patients have suggested that abciximab was associated with excessive perioperative blood loss [7], although others have concluded that bleeding risk may not be elevated during emergency CABG if abciximab-treated patients are administered prophylactic platelet transfusions [8–10]. Therefore, to assess whether patients who undergo CABG after administration of abciximab are at increased risk for blood loss, we analyzed outcomes among patients enrolled in two recent trials of abciximab during coronary intervention who required urgent coronary surgical procedures.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Study population
This report describes the 85 patients who underwent CABG in the Evaluation in PTCA (percutaneous transluminal coronary angioplasty) to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) and Evaluation of Platelet IIb/IIIa Inhibition in STENTing (EPISTENT) trials during the index hospitalization. Details of these two trials have been previously reported [3, 4]. The EPILOG trial enrolled 2,792 patients who were to undergo elective or urgent percutaneous coronary revascularization at 69 clinical sites between February and December 1995. The EPISTENT trial enrolled 2,399 patients who had target lesions suitable for allocation to either stenting or balloon angioplasty at 63 sites between July 1996 and September 1997. Relevant exclusions for both trials were for acute myocardial infarction, warfarin therapy or prothrombin time more than 1.2 times control, cerebrovascular accident within the prior 2 years or with residual neurologic deficit, intracranial structural abnormality, hemorrhagic diathesis or active internal bleeding, or major surgical procedure or gastrointestinal or genitourinary bleeding within the previous 6 weeks.

Study protocols
Patients were treated with oral aspirin at least 2 hours before the index procedure and for at least 6 months thereafter. In the EPILOG trial, patients were randomized to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus, target activated clotting time [ACT] 300 seconds), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus, target ACT 200 seconds). In the EPISTENT trial, patients were randomized to undergo stenting plus placebo with standard-dose, weight-adjusted heparin, stenting plus abciximab with low-dose, weight-adjusted heparin, or balloon angioplasty plus abciximab with low-dose, weight-adjusted heparin. Abciximab was administered as a 0.25 mg/kg bolus before the start of the interventional procedure, followed by an infusion of 0.125 µg/kg - min^-1 (maximum, 10 µg/min) for 12 hours. Ticlopidine was to be given after stenting in the EPISTENT trial, and 53% of patients received at least one dose before initiation of study drug. Administration of dextran was prohibited; warfarin or low-molecular-weight heparin were permitted only for suboptimal angiographic results and were not to be started until after the interventional procedure.

Guidelines were provided for management of patients requiring emergency CABG [11]. Unblinding of study drug was permitted. Abciximab or placebo infusion was to be discontinued once a decision was made to proceed with the operation. The administration of platelet transfusions to reverse the inhibitory effect of abciximab or aspirin was to be considered; if the decision was made to give platelets, initial transfusion of a "pack" of 8 to 10 random donor units was recommended. Intraoperative heparin dosing, ACT targets, and use of hemostatic agents were left to the discretion of the physicians caring for the patients. It was recommended that red blood cell transfusions be administered according to the clinical guidelines of the American College of Physicians [12].

Data collection and study end points
Data for all patients in the trials were prospectively collected using case report forms by study coordinators at the clinical sites and verified with source medical records by study monitors. For this analysis, a supplemental two-page case report form was also completed post hoc at the clinical sites for patients requiring CABG during the index hospitalization, providing details of the operative procedure, perioperative blood loss, intraoperative heparin dosing and ACT measurements, use of agents for reversal of anticoagulation, and surgical reexploration for bleeding. In-hospital myocardial infarction was defined by new significant electrocardiographic Q-waves or elevation in creatine kinase-MB isoenzyme to at least three times the upper limit of normal. Major bleeding was defined according to the criteria used by the Thrombolysis in Myocardial Infarction (TIMI) Study Group [13] as intracranial hemorrhage or blood loss resulting in a decrease in hemoglobin by more than 5 g/dL. To account for the influence of whole blood or red blood cell transfusions on measured hemoglobin values, estimated decreases in hemoglobin were adjusted according to the technique of Landefeld [14] as (baseline hemoglobin - predischarge hemoglobin) + number of transfused units.

Statistical analysis
Continuous variables are expressed as medians and interquartile ranges, categorical variables as counts and percentages. Comparisons were made between patients in the pooled placebo and pooled abciximab groups of the two trials. Continuous variables were compared using the unpaired Student’s t test if normality could be assumed or the Wilcoxon two-sample test if not normally distributed. Differences between categorical variables were assessed using the ² or Fisher’s exact test. Clinical event rates at 30 days were calculated using the Kaplan-Meier method and compared with the log-rank test. Two-sided probability values are reported.

	Results

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Patient population
Of the 5,191 patients enrolled in the two trials, 85 patients (53 in the EPILOG trial and 29 in the EPISTENT trial) required CABG during the initial hospitalization and form the basis of this study. The incidence of coronary operations was 2.17% (38 of 1,748 patients) among patients randomized to placebo and 1.28% (44 of 3,443 patients) among patients randomized to abciximab (41% relative risk reduction, p = 0.021). Supplemental case report forms could not be completed because of lost hospital charts for 2 patients, 1 receiving placebo in the EPILOG trial and 1 receiving abciximab in the EPISTENT trial.

The timing of initiation of CABG relative to discontinuation of abciximab or placebo infusion is illustrated in Figure 1. The initial surgical skin incision was performed within 6 hours of stopping the study drug in the majority of patients; fewer than a quarter had an elapsed time of more than 24 hours. Baseline and demographic characteristics are summarized in Table 1. Patients in the abciximab group tended to be older and more frequently were female and diabetic.

View larger version (24K): [in this window] [in a new window]   Fig 1. Histogram chart of timing of initiation of coronary artery bypass grafting operation relative to discontinuation of abciximab administration.

Surgical procedural details and outcomes
Study drug randomization (placebo versus abciximab) was unblinded in 14 patients. Details of perioperative heparin anticoagulation are summarized in Table 2. Preoperative heparin doses were lower in the abciximab group, reflecting the low-dose, weight-adjusted heparin regimen used with abciximab during the index percutaneous coronary revascularization procedure; preoperative ACT values were accordingly lower in the abciximab-treated patients as well. Loading doses of heparin in the operating room were virtually identical in the two groups, but patients who had been treated with abciximab tended to receive less heparin in the cardiopulmonary bypass pump and lower total intraoperative heparin doses. Nevertheless, the first ACT values on cardiopulmonary bypass and highest ACT values were greater in the abciximab-treated patients. Median total protamine dose was 300 mg in both groups. The final recorded ACT values in the operating room were comparable between the two groups.

View larger version (26K): [in this window] [in a new window]   Fig 2. Box-and-whisker plot of the volume of perioperative mediastinal- and chest-tube drainage in the placebo and abciximab groups. The box spans the interquartile range (25th to 75th percentiles), whereas the line within the box denotes the median. Whiskers extend from the 10th to the 90th percentiles. The diamond symbol represents the mean.

View larger version (37K): [in this window] [in a new window]   Fig 3. Number of transfused packed red blood cell or whole blood units in the placebo and abciximab groups.

View larger version (24K): [in this window] [in a new window]   Fig 4. Box-and-whisker plot of the maximum decrease in hemoglobin levels, adjusted for transfusion [14], in the placebo and abciximab groups. See Figure 2 for explanation of box-and-whisker plot.

	Comment

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Although blockade of the platelet GP IIb/IIIa receptor with abciximab reduces ischemic complications of percutaneous coronary intervention, this therapy may produce a potent hemostatic defect. The current study shows, however, that CABG can be safely performed in patients who have recently received abciximab, without an increase in major hemorrhagic risk. Among the 85 patients requiring urgent CABG in the EPILOG and EPISTENT trials, more than three quarters underwent operation within 24 hours of discontinuation of abciximab, a period during which substantial inhibition of platelet aggregation by this agent would be expected to persist. Nevertheless, in this detailed analysis of surgical outcomes among these patients, antecedent abciximab therapy was not associated with a major increase in perioperative blood loss. Platelet transfusions were administered more frequently (in part prophylactically) to patients who had received abciximab than placebo, an intervention recommended by the trial protocols, but the need for other blood products, such as packed red blood cells, whole blood, cryoprecipitate, or autotransfusions, was not increased after abciximab therapy. A total of 5 of 43 patients who had received abciximab did require surgical reexploration for bleeding (compared with only 1 of 37 placebo-treated patients), but surgical cross-clamp, cardiopulmonary bypass, and closure times were not prolonged and the use of optimal mammary artery conduits was not impaired. Ischemic events tended to be less frequent in the patients who had received abciximab, suggesting that abciximab may have had a protective effect on the myocardium in this setting.

A variety of coagulopathies occur during and after cardiopulmonary bypass that may contribute to perioperative bleeding complications. Moreover, among patients undergoing percutaneous coronary revascularization, aspirin reduces ischemic events [15] and is used universally. This practice may account at least in part for the high rates of bleeding and blood product transfusions among patients requiring emergency surgical procedures for failed coronary angioplasty [16, 17]. Notably, virtually all patients in this current study received aspirin, with ticlopidine administered to approximately 20% of patients as well; major blood loss (defined as a fall in hemoglobin of > 5 g/dL) occurred in nearly 80%, and blood transfusions were required in 74% of even those randomized to placebo.

The extent to which potent platelet inhibition by GP IIb/IIIa receptor blockade would increase bleeding risk beyond that of aspirin (with or without ticlopidine) was therefore unclear. Abciximab and other agents of this class unquestionably produce a profound inhibition of platelet aggregation with marked prolongation of bleeding times. Importantly, however, although abciximab attaches avidly to the platelet GP IIb/IIIa receptor and is detectable bound to circulating platelets for at least 21 days [6], this antibody fragment is cleared rapidly from the plasma with a half-life of only approximately 25 minutes [18]. Thus, the antiplatelet effect of abciximab can be reversed with platelet transfusions. After transfusion, abciximab redistributes from old to new platelets, reducing the mean level of receptor blockade, with near normalization of bleeding times and partial recovery of platelet aggregation [19].

In the first trial of this agent (the EPIC [Evaluation of c7E3 for Prevention of Ischemic Complications] trial), clinical outcomes among 58 patients who required CABG for failed angioplasty were largely concordant with that in the present study. Rates of major blood loss and red blood cell transfusions, relatively gross measurements of hemorrhagic risk, were high among all patients undergoing emergency CABG in the EPIC trial, and trended only modestly higher among patients receiving abciximab [8]. That study was limited, however, by the lack of detailed data about the coronary operative procedure, and mortality rates trended higher in the abciximab group. In a series of 11 patients undergoing CABG after abciximab therapy, Gammie and associates [7] described excessive perioperative blood loss and transfusion requirements when the operation was performed within 12 hours of drug discontinuation, but prophylactic platelet transfusions had not been administered. In contrast, Juergens and colleagues [9] found that routine platelet transfusions in 4 patients were associated with low rates of bleeding after abciximab and CABG. Yet concerns about increased bleeding, procedural complications, blood product requirements, and costs with abciximab continue to be expressed [20, 21].

The current study therefore evaluated the influence of abciximab on blood loss during and after urgent CABG among a contemporary cohort of patients treated in hospitals experienced with the use of this agent. Given that major blood loss and transfusion rates, the safety end points typically used in trials of this type, are high among all patients requiring emergency CABG and are therefore insensitive to incremental hemorrhagic risk, we used supplemental case report forms to collect additional detailed data about the operative procedure and blood loss. Compared with their counterparts randomized to receive placebo, patients treated with abciximab tended to have a greater incidence of risk factors for surgical bleeding [22], including female sex, advanced age, and diabetes mellitus. Nevertheless, with platelet transfusions administered to slightly more than half of patients who had received abciximab during angioplasty, GP IIb/IIIa blockade was not associated with substantial increases in major blood loss, red blood cell or cryoprecipitate transfusions, or cardiopulmonary bypass or surgical closure times. A modest abciximab-related increase in hemorrhagic risk in these patients was suggested by some of the trends in these data, however, including the higher incidence of reoperation for bleeding and the greater decrease in hemoglobin values among those who had received this agent. Thus, although antecedent abciximab therapy likely confers some degree of hemorrhagic challenge to patients undergoing urgent CABG, that bleeding risk appears to be relatively modest, amenable to surgical management, and unassociated with appreciable mortality or morbidity.

Among the patients undergoing operation within 12 hours of cessation of study drug infusion, during the period of most intense residual platelet inhibition by abciximab, an incremental bleeding risk associated with this agent was particularly apparent. Importantly, however, both hemorrhagic and ischemic events were frequent after treatment with either abciximab or placebo in these patients, suggesting a high risk profile caused at least in part by the complications of the interventional procedure that led to the need for emergency CABG. These findings do not support a practice of delaying operations for patients who have received abciximab, as the incremental blood loss associated with this agent is relatively modest and does not outweigh the potential ischemic consequences of deferring prompt revascularization in critically ill patients.

The optimal level of anticoagulation with heparin during CABG with abciximab is not known. Excessive conjunctive heparin doses clearly potentiate the hemorrhagic risk of abciximab therapy during coronary angioplasty [2, 23], and the bleeding risk associated with this agent in that setting may be virtually eliminated by reduced heparin dosing and intraprocedural ACT levels [3]. Thus, some investigators have advocated that intraoperative heparin doses also be markedly decreased to reduce serious bleeding in abciximab-treated patients who require emergency CABG [10]. Lowering heparin doses during cardiopulmonary bypass may be problematic, however, as intracardiac thrombosis has been described when reduced heparin doses were administered during cardiopulmonary bypass [24]. The effectiveness of abciximab in preventing thrombosis during coronary operation is unknown. Therefore, the EPILOG and EPISTENT trial protocols did not suggest reduction in intraoperative heparin dosing should emergency CABG be required, and median loading doses were the same in the placebo and abciximab groups. Peak intraoperative ACTs were higher in the abciximab-treated patients, reflecting the known 30-second to 40-second prolongation caused by this agent [25]. Subsequent heparin doses tended to be lower in the abciximab group, with equalization of final ACT values between patients who had received placebo and abciximab, suggesting effective titration of heparin on the basis of the ACT measurements. Thrombotic complications did not occur with this strategy for heparin administration. Blood loss was greater overall among patients with higher intraoperative ACT values, but was not related to heparin dose per se, nor did the gradient of bleeding risk with abciximab appear to be influenced by ACT or heparin dose. Therefore, these data do not support a recommendation that intraoperative heparin doses be lowered when abciximab-treated patients require cardiac operation.

The optimal timing for platelet transfusion is also unclear. In the EPIC report, thrombocytopenia after CABG occurred less frequently among patients who had received abciximab rather than placebo (24% versus 60%, respectively; p = 0.0097), suggesting a protective influence of abciximab on platelet clearance in the cardiopulmonary bypass pump [8]. Animal data exist to support this concept [26], and another study indicated that the reversible GP IIb/IIIa inhibitor eptifibatide may preserve hemostasis in patients undergoing cardiac operation [27]. A significant reduction in rates of thrombocytopenia was not observed among abciximab-treated patients in the current study, although severe thrombocytopenia tended to be less frequent. It therefore may be reasonable to defer the decision to administer platelets until after cardiopulmonary bypass is completed, reserving transfusions for patients who show evidence of bleeding. It is worthwhile to note that 48% of abciximab-treated patients in the current study did not receive platelet transfusions, and indices of blood loss were not higher among these patients as compared with those in whom transfusions had been administered (data not shown). Use of one of several current or emerging point-of-care platelet function tests may also be helpful in identifying patients at risk for perioperative platelet-related bleeding [28].

Limitations
This study is subject to the limitations of a post hoc evaluation of a subgroup of patients within a randomized trial. In particular, given the small sample size, this analysis is underpowered to detect small differences in bleeding rates or transfusion requirements or may overemphasize the differences seen. Uniform protocols were not used in these studies for heparin administration or platelet transfusions, and precise guidelines for management of these issues during emergency CABG in abciximab-treated patients therefore cannot be proposed. Nevertheless, the findings of this study reflect the safety profile that can be achieved in this setting using real-world strategies for intraoperative heparin dosing and platelet transfusions.

Conclusions
Abciximab potently reduces ischemic complications of percutaneous coronary revascularization, including the need for emergency CABG, and thereby in effect reduces the bleeding complications that would otherwise result from such unplanned coronary operation. In the event that CABG is urgently required after coronary intervention, hemorrhagic risk may be modestly increased by abciximab, but is unlikely to be associated with excess mortality or important morbidity. Conventional procedures for intraoperative ACT-guided heparin dosing and selective application of platelet transfusions appear appropriate for the management of these patients. Antecedent treatment with abciximab should not be considered a contraindication to necessary emergency surgical revascularization.

	Acknowledgments

 
Supported by Eli Lilly and Company (Indianapolis, IN) and Centocor, Inc (Malvern, PA).

	Footnotes

 
Doctors Mark B. Effron, LeRoy A. LeNarz, and Catherine F. Cabot are employees of Eli Lilly and Company or Centocor, Inc, sponsors of these trials. There are no other conflicts of interest associated with this paper.

^* A complete list of the principal investigators and study coordinators of the EPILOG (Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade) Study Group and the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibition in STENTing) Study Group can be found in the Appendices.

	Appendix 1

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Investigators of the EPILOG trial

Name Institution City/State/Province Country Enrollment Dean J. Kereiakes, John Paul Runyon Christ Hospital and University of Cincinnati Medical Center Cincinnati, OH US 238 Thomas Kelly Moses H. Cone Memorial Hospital Greensboro, NC US 176 George Timmis William Beaumont Hospital Royal Oak, MI US 148 Neal S. Kleiman Baylor University Medical Center Dallas, TX US 144 A. Michael Lincoff Cleveland Clinic Hospital Cleveland, OH US 125 Jeffrey Kramer Our Lady of Lourdes Medical School Cherry Hill, NJ US 124 David Talley University Hospital of Arkansas Little Rock, AR US 118 Frank I. Navetta Mother Frances Hospital Regional Health Care Center Tyler, TX US 88 Phillip Kraft Henry Ford Heart and Vascular Institute Detroit, MI US 85 James E. Tcheng Duke University Medical Center Durham, NC US 83 James Ferguson Texas Heart Institute Houston, TX US 73 Kevin Browne Lakeland Regional Medical Center Lakeland, FL US 71 James Blankenship Geisinger Medical Center Danville, PA US 70 Russell Ivanhoe Florida Hospital—Orlando Orlando, FL US 67 Neal Shadoff Presbyterian Hospital Albuquerque, NM US 62 Mark Taylor Deborah Heart and Lung Center Browns Mills, NJ US 56 Gerald Gacioch Rochester General Hospital Rochester, NY US 53 Eric Bates University of Michigan Medical Center Ann Arbor, MI US 53 H.A. Snyder Cooper Hospital—University Medical Center Audubon, NJ US 49 Theodore A. Bass University of Florida Medical Center Jacksonville, FL US 43 Philip Bear Methodist Hospital—Iowa Heart Des Moines, IA US 34 Larry Hattel United Medical Center Cheyenne, WY US 30 H. Vernon Anderson Hermann Hospital Houston, TX US 30 Bruce Hettleman Dartmouth-Hitchcock Medical Center Lebanon, NH US 30 Paul S. Teirstein Scripps Clinic and Research Foundation La Jolla, CA US 29 Ian Sarembock University of Virginia Charlottesville, VA US 28 Charles J. Davidson Northwestern Memorial Hospital Chicago, IL US 26 Frank V. Aguirre St. Louis University Hospital St. Louis, MO US 25 Michael Azrin University of Connecticut Health Center Farmington, CT US 25 Seth Worley Lancaster General Hospital Lancaster, PA US 24 Jean-François Marquis Ottawa Civic Hospital—Ottawa Heart Institute Ottawa, ON, Canada CA 24 Douglas J. Spriggs Morton Plant Hospital Clearwater, FL US 23 Michael Azrin Hartford Hospital Hartford, CT US 23 Mark W. Weston Tampa General Hospital Tampa, FL US 22 Barry S. George Riverside Methodist Hospital Columbus, OH US 21 Donald R. Ricci Vancouver General Hospital Vancouver, BC, Canada CA 21 Carl W. Hartman Sentara Norfolk General Hospital Norfolk, VA US 20 Anthony Farah Allegheny General Hospital Pittsburgh, PA US 20 Gary Sander Louisiana State University Medical Center New Orleans, LA US 20 Bernard M. Reen Presbyterian Hospital Charlotte, NC US 18 Richard Heuser Arizona Heart Institute and Foundation Phoenix, AZ US 18 Timothy Larkin Evanston Hospital Evanston, IL US 17 Jeffrey Popma Washington Hospital Center Washington, DC US 17 Mark L. Sanz St. Patrick Hospital Missoula, MT US 17 Jeffrey Burton University of Alberta Edmonton, AB, Canada CA 17 Robert I.G. Brown Royal Columbian Hospital New Westminster, BC, Canada CA 14 William J. French Harbor-UCLA Medical Center Torrance, CA US 13 Allan G. Adelman Mount Sinai Hospital Toronto, ON, Canada CA 13 Ronald Gottlieb Graduate Hospital Philadelphia, PA US 9 Spencer B. King Emory University Hospital Atlanta, GA US 9 Seth Worley St. Joseph Hospital Lancaster, PA US 7 John Ducas Health Sciences Center Winnipeg, MB, Canada CA 7 Judith S. Hochman St. Luke’s–Roosevelt Hospital New York, NY US 6 Blair J. O’Neill Victoria General Hospital—Halifax Halifax, NS, Canada CA 5 Po Kee Cheung Saint Boniface General Hospital Winnipeg, MB, Canada CA 5 Merril Knudtson Calgary Foothills Hospital Calgary, AB, Canada CA 4 Joseph Samaha Baptist Memorial Hospital East Memphis, TN US 4 Lloyd W. Klein Rush-Presbyterian-St. Luke’s Medical Center Chicago, IL US 3 David Almond Victoria Hospital Corporation London, ON, Canada CA 2 Michael J. Rosenberg Lutheran General Hospital Park Ridge, IL US 1 Michael Unks Keesler Medical Center Keesler AFB, MS US 1

^a All values are expressed as counts (percent of total). There were no significant differences between groups for any outcome variable.

	Appendix 2

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 
Investigators of the EPISTENT trial

Name Institution City/State/Province Country Enrollment John Ducas University of Manitoba Winnipeg, MB, Canada CA 153 Jeffrey H. Kramer Our Lady of Lourdes Medical Center Cherry Hill, NJ US 147 J. David Talley University Hospital of Arkansas Little Rock, AR US 142 Allan G. Adelman Toronto Hospital Toronto, ON, Canada CA 138 Neal S. Kleiman Baylor College of Medicine Houston, TX US 135 Eric Cohen Sunnybrook Health Science Centre Toronto, ON, Canada CA 132 A. Michael Lincoff Cleveland Clinic Foundation Cleveland, OH US 118 Jeffrey Burton University of Alberta Edmonton, AB, Canada CA 108 Thomas Kelly Moses H. Cone Memorial Hospital Greensboro, NC US 97 John C. Webb St. Paul’s Hospital Vancouver, BC, Canada CA 81 Donald R. Ricci Vancouver Hospital—Health Science Centre Vancouver, BC, Canada CA 76 Jean-François Tanguay Institute de Cardiologie de Montréal Montreal, QC, Canada CA 68 Gerald Timmis William Beaumont Hospital Royal Oak, MI US 65 Patrick S. Coleman Northern Californian Medical Association Santa Rosa, CA US 57 Blair J. O’Neill Victoria General Hospital—Halifax Halifax, NS, Canada CA 57 David Almond London Health Sciences Centre London, ON, Canada CA 52 Ronald Gottlieb Graduate Hospital Philadelphia, PA US 52 Michael Azrin University of Connecticut Health Center Farmington, CT US 48 James Blankenship Geisinger Medical Center Danville, PA US 47 Phillip Kraft Henry Ford Heart and Vascular Institute Detroit, MI US 47 Robert Brown Royal Columbian Hospital New Westminster, BC, Canada CA 45 Ian Sarembock University of Virginia Health Science Center Charlottesville, VA US 45 Kevin Browne Watson Clinic Lakeland, FL US 44 Bernard Reen Presbyterian Hospital Charlotte, NC US 43 Mark Thompson Rochester General Hospital Rochester, NY US 37 Theodore A. Bass University of Florida Medical Center Jacksonville, FL US 35 Jean-François Marquis Ottawa Civic Hospital Ottawa, ON, Canada CA 35 William French Harbor-UCLA Medical Center Torrance, CA US 30 Alan Gradman Western Pennsylvania Hospital Pittsburgh, PA US 27 Seth Worley Lancaster Heart Foundation Lancaster, PA US 20 Steven Yakubov Midwest Cardiology Research Foundation Columbus, OH US 20 Russell J. Ivanhoe Florida Hospital Orlando, FL US 19 Mark Taylor Deborah Heart and Lung Center Browns Mills, NJ US 19 Mark Tannenbaum Iowa Heart Center Des Moines, IA US 18 Judith Hochman St. Luke’s–Roosevelt Hospital Center New York, NY US 13 Eric Bates University of Michigan Hospitals Ann Arbor, MI US 12 Mark Gonzalez Orlando Regional Medical Center—Columbia Orlando, FL US 12 John Paul Runyon University of Cincinnati Medical Center Cincinnati, OH US 12 James Tcheng Durham Veterans Affairs Medical Center Durham, NC US 11 Richard Bach St. Louis University Hospital St. Louis, MO US 8 Michael Azrin Hartford Hospital Farmington, CT US 8 Frank E. Cummins Milwaukee Heart and Vascular Clinic Milwaukee, WI US 5 John P. Runyon Christ Hospital Cincinnati, OH US 4 Mark Sanz Western Montana Clinic Missoula, MT US 4 Mark W. Weston Tampa General Hospital Tampa, FL US 4 H. V. Anderson University of Texas Medical Center Houston, TX US 3 Timothy Larkin Evanston Hospital Evanston, IL US 3 Michael J. Rosenberg Lutheran General Hospital Park Ridge, IL US 3 Carl Hartman Sentara Norfolk General Hospital Norfolk, VA US 2 Charles Lucore Prairie Cardiovascular Consult Springfield, IL US 2 Brent Muhlestein Latter Day Saints Hospital Salt Lake City, UT US 2 Gary Sander Louisiana State University Medical Center New Orleans, LA US 2 Robert Chisholm St. Michael’s Hospital Toronto, ON, Canada CA 2 Michael Del Core Creighton Cardiac Center Omaha, NE US 1

^a All values are expressed as counts (percent of total). There were no significant differences between groups for any outcome variable.

	References

Top Abstract Introduction Material and methods Results Comment Appendix 1 Appendix 2 References

 

1. Tcheng J.E., Ellis S.G., George B.S., et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90:1757-1764.[Abstract/Free Full Text]
2. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956-961.[Abstract/Free Full Text]
3. EPILOG Investigators. Platelet glycoprotein IIb/IIIa blockade with abciximab with low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689-1696.[Abstract/Free Full Text]
4. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty- controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87-92.[Medline]
5. Brener S.J., Barr L.A., Burchenal J.E.B., et al. A randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 1998;98:734-741.[Abstract/Free Full Text]
6. Mascelli M.A., Lance E.T., Damaraju L., Wagner C.L., Weisman H.F., Jordan R.E. Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 1998;97:1680-1688.[Abstract/Free Full Text]
7. Gammie J.S., Zenati M., Kormos R.L., et al. Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998;65:465-469.[Abstract/Free Full Text]
8. Boehrer J.D., Kereikes D.J., Navetta F.I., Califf R.M., Topol E.J., EPIC investigators. Effects of profound platelet inhibition with c7E3 before coronary angioplasty on complications of coronary bypass surgery. Am J Cardiol 1994;74:1166-1170.[Medline]
9. Juergens C.P., Yeung A.C., Oesterle S.N. Routine platelet transfusion in patients undergoing emergency coronary bypass surgery after receiving abciximab. Am J Cardiol 1997;80:74-75.[Medline]
10. Kereiakes D.J. Prophylactic platelet transfusion in abciximab-treated patients requiring emergency coronary bypass surgery [Letter]. Am J Cardiol 1998;81:373.[Medline]
11. Sane D.C., Califf R.M., Topol E.J., Stump D.C., Mark D.B., Greenberg C.S. Bleeding during thrombolytic therapy for acute myocardial infarction. Ann Intern Med 1989;111:1010-1012.
12. American College of Physicians Clinical Guideline. Practice strategies for elective red blood cell transfusion. Ann Intern Med 1992;116:403-406.
13. Rao A.K., Pratt C., Berke A., et al. Thrombolysis in myocardial infarction (TIMI) trial. Phase I. J Am Coll Cardiol 1988;11:1-11.[Abstract]
14. Landefeld L.S., Cook E.F., Hatley M., Weisberg M., Goldman L. Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med 1987;82:703-713.[Medline]
15. Schwartz L., Bourassa M.G., Lesperance J., et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988;318:1714-1719.[Abstract]
16. Talley J.D., Weintraub W.S., Roubin G.S., et al. Failed elective percutaneous transluminal coronary angioplasty requiring coronary artery bypass surgery. In-hospital and late clinical outcome at 5 years. Circulation 1990;82:1203-1213.[Abstract/Free Full Text]
17. Phillips S.J., Kongtahworn C., Zeff R.H., et al. Disrupted coronary artery caused by angioplasty. Ann Thorac Surg 1989;47:880-883.[Abstract]
18. Kleiman N.S., Raizner A.E., Jordan R., et al. Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab. J Am Coll Cardiol 1995;26:1665-1671.[Abstract]
19. Wagner C.L., Cunningham M.R., Wyand M.S., Weisman H.F., Coller B.S., Jordan R.E. Reversal of the antiplatelet effects of chimeric 7E3 Fab treatment by platelet transfusion in cynomolgus monkeys [Abstract]. Thromb Haemost 1995;73:1313.
20. Alvarez J.M. Emergency coronary bypass grafting for failed percutaneous coronary artery stenting. J Thorac Cardiovasc Surg 1998;115:472-473.[Free Full Text]
21. Duke C., Gammie J.S. Surgical implications of platelet glycoprotein IIb-IIIa inhibition. J Thorac Cardiovasc Surg 1998;116:1083-1084.[Free Full Text]
22. Surgenor D.M., Churchill W.H., Wallace R.J., et al. Determinants of red cell, plasma, and cryoprecipitate transfusions during coronary artery bypass graft surgery. Transfusion 1996;36:521-532.[Medline]
23. Aguirre F.V., Topol E.J., Ferguson J.J., et al. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 1995;91:2882-2890.[Abstract/Free Full Text]
24. Cheung A.T., Levin S.K., Weiss S.J., Acker M.A., Stenach N. Intracardiac thrombus. Ann Thorac Surg 1994;58:541-542.[Abstract]
25. Moliterno D.J., Califf R.M., Aguirre F.V., et al. Effect of platelet glycoprotein IIb/IIIa integrin blockade on activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy (the EPIC trial). Am J Cardiol 1995;75:559-562.[Medline]
26. Uthoff K., Zehr K.J., Geerling B.A., Herskowitz A., Cameron D.E., Reitz B.A. Inhibition of platelet adhesion during cardiopulmonary bypass reduces postoperative bleeding. Circulation 1994;90(Suppl 2):II269-II74.
27. Suzuki Y., Miyamoto S., Niewiarowski S., Edmunds L.H., Jr Integrilin prevents prolonged bleeding times after cardiopulmonary bypass [Abstract]. Ann Thorac Surg 1998;66:1.[Abstract/Free Full Text]
28. Despotis G.L., Levine V., Saleem R., Joist J.H., Spitznagel E. DDAVP reduces blood loss and transfusion in cardiac surgical patients with impaired platelet function identified using a point-of-care test. Lancet 1999;354:106-110.[Medline]

This article has been cited by other articles:

				T. Lang, K. Johanning, H. Metzler, S. Piepenbrock, C. Solomon, N. Rahe-Meyer, and K. A. Tanaka The Effects of Fibrinogen Levels on Thromboelastometric Variables in the Presence of Thrombocytopenia Anesth. Analg., March 1, 2009; 108(3): 751 - 758. [Abstract] [Full Text] [PDF]

				J. M. O'Riordan, R. J. Margey, G. Blake, and P. R. O'Connell Antiplatelet Agents in the Perioperative Period Arch Surg, January 1, 2009; 144(1): 69 - 76. [Abstract] [Full Text] [PDF]

				C. M. Dyke, L. K. Jennings, G. Maier, C. Andreou, R. Daly, and M. R. Tamberella III Preoperative Platelet Inhibition With Eptifibatide During Coronary Artery Bypass Grafting With Cardiopulmonary Bypass Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 54 - 60. [Abstract] [PDF]

				C. K. Haan, S. O'Brien, F. H. Edwards, E. D. Peterson, and T. B. Ferguson Trends in emergency coronary artery bypass grafting after percutaneous coronary intervention, 1994-2003. Ann. Thorac. Surg., May 1, 2006; 81(5): 1658 - 1665. [Abstract] [Full Text] [PDF]

				R. Glaser, H. A. Glick, H. C. Herrmann, and S. E. Kimmel The Role of Risk Stratification in the Decision to Provide Upstream Versus Selective Glycoprotein IIb/IIIa Inhibitors for Acute Coronary Syndromes: A Cost-Effectiveness Analysis J. Am. Coll. Cardiol., February 7, 2006; 47(3): 529 - 537. [Abstract] [Full Text] [PDF]

				A. Shander, D. Moskowitz, and T. S. Rijhwani The Safety and Efficacy of "Bloodless" Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2005; 9(1): 53 - 63. [Abstract] [PDF]

				Committee Members, K. A. Eagle, R. A. Guyton, R. Davidoff, F. H. Edwards, G. A. Ewy, T. J. Gardner, J. C. Hart, H. C. Herrmann, L. D. Hillis, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery) J. Am. Coll. Cardiol., September 1, 2004; 44(5): 1146 - 1154. [Full Text] [PDF]

				K. A. Eagle, R. A. Guyton, R. Davidoff, F. H. Edwards, G. A. Ewy, T. J. Gardner, J. C. Hart, H. C. Herrmann, L. D. Hillis, A. M. Hutter Jr, et al. ACC/AHA 2004 Guideline Update for Coronary Artery Bypass Graft Surgery: Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery) Circulation, August 31, 2004; 110(9): 1168 - 1176. [Full Text] [PDF]

				M. B. Vroom Epidemiology and Pharmacotherapy of Acute Heart Failure Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2003; 7(1): 3 - 12. [PDF]

				R. H. Hongo, J. Ley, S. E. Dick, and R. R. Yee The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting J. Am. Coll. Cardiol., July 17, 2002; 40(2): 231 - 237. [Abstract] [Full Text] [PDF]

				M. Singh, H. H. Ting, P. B. Berger, K. N. Garratt, D. R. Holmes Jr, and B. J. Gersh Rationale for on-site cardiac surgery for primary angioplasty: a time for reappraisal J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1881 - 1889. [Abstract] [Full Text] [PDF]

				G. J. Despotis, M. S. Avidan, and C. W. Hogue Jr Mechanisms and attenuation of hemostatic activation during extracorporeal circulation Ann. Thorac. Surg., November 1, 2001; 72(5): S1821 - 1831. [Abstract] [Full Text] [PDF]

				N. J. Skubas and G. J. Despotis Optimal Management of Bleeding Complications After Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 217 - 228. [Abstract] [PDF]

				G. J. Despotis and L. T. Goodnough Management approaches to platelet-related microvascular bleeding in cardiothoracic surgery Ann. Thorac. Surg., August 1, 2000; 70(2): S20 - 32. [Abstract] [Full Text] [PDF]

				L. H. Edmunds Jr The quill passes Ann. Thorac. Surg., July 1, 2000; 70(1): 1 - 2. [Full Text] [PDF]

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): Peter K. Smith Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lincoff, A. M. Articles by Topol, E. J. Search for Related Content PubMed PubMed Citation Articles by Lincoff, A. M. Articles by Topol, E. J.