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Original Article
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Volume 330:956-961 April 7, 1994 Number 14
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Use of a Monoclonal Antibody Directed against the Platelet Glycoprotein IIb/IIIa Receptor in High-Risk Coronary Angioplasty
The EPIC Investigators

 

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ABSTRACT

Background Platelets are believed to play a part in the ischemic complications of coronary angioplasty, such as abrupt closure of the coronary vessel during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal-antibody Fab fragment (c7E3 Fab) directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. This receptor is the final common pathway for platelet aggregation.

Methods In a prospective, randomized, double-blind trial, 2099 patients treated at 56 centers received a bolus and an infusion of placebo, a bolus of c7E3 Fab and an infusion of placebo, or a bolus and an infusion of c7E3 Fab. They were scheduled to undergo coronary angioplasty or atherectomy in high-risk clinical situations involving severe unstable angina, evolving acute myocardial infarction, or high-risk coronary morphologic characteristics. The primary study end point consisted of any of the following: death, nonfatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intraaortic balloon pump for refractory ischemia. The numbers of end-point events were tabulated for 30 days after randomization.

Results As compared with placebo, the c7E3 Fab bolus and infusion resulted in a 35 percent reduction in the rate of the primary end point (12.8 vs. 8.3 percent, P = 0.008), whereas a 10 percent reduction was observed with the c7E3 Fab bolus alone (12.8 vs. 11.5 percent, P = 0.43). The reduction in the number of events with the c7E3 Fab bolus and infusion was consistent across the end points of unplanned revascularization procedures and nonfatal myocardial infarction. Bleeding episodes and transfusions were more frequent in the group given the c7E3 Fab bolus and infusion than in the other two groups.

Conclusions Ischemic complications of coronary angioplasty and atherectomy were reduced with a monoclonal antibody directed against the platelet IIb/IIIa glycoprotein receptor, although the risk of bleeding was increased.

Percutaneous coronary angioplasty is associated with improvement in the symptoms of ischemia and the quality of life,1,2 but acute complications remain a major drawback. The treated vessel closes abruptly during or soon after the procedure in 4 to 9 percent of cases, causing considerable morbidity and an approximately 10-fold increase in mortality3,4,5,6,7. Characteristics that identify patients at high risk for acute complications include the presence of a clinical syndrome associated with coronary thrombus (such as unstable angina or recent myocardial infarction), diabetes, female sex, and complex coronary morphologic features (an angulated arterial segment, thrombus, or bifurcation lesion)3,7,8,9,10.

Although aspirin reduces the risk of abrupt vessel closure and acute myocardial infarction in patients undergoing angioplasty,11,12 its effects on platelet function are relatively weak, and ischemic events continue to occur in 10 to 20 percent of patients at high risk who have been treated with aspirin8. The integrin glycoprotein IIb/IIIa receptor on the surface of the platelet, the final common pathway of platelet aggregation,13 binds circulating adhesive macromolecules, particularly fibrinogen and von Willebrand factor, which can then cross-link receptors on adjacent platelets, leading to platelet aggregation.

In 1985 Coller produced a mouse monoclonal antibody, known as 7E3, against this platelet receptor,14 and its antithrombotic effects were demonstrated in animal models15. In pilot studies in patients16 this agent inhibited platelet aggregation by more than 80 percent, thus showing its promising biologic and clinical effects. The current study was designed to determine whether the biologic properties of c7E3 Fab would translate into clinical benefit in the setting of coronary angioplasty or atherectomy.

Methods

Study Population

Patients scheduled to undergo coronary angioplasty or directional atherectomy were eligible for enrollment if they were at high risk for abrupt vessel closure and were not at high risk for bleeding. They were considered to be at high risk for vessel closure if they had one of three clinical features: (1) acute evolving myocardial infarction within 12 hours after the onset of symptoms that necessitated direct or "rescue" percutaneous intervention; (2) early postinfarction angina or unstable angina with at least two episodes of angina at rest associated with changes on resting electrocardiography during the previous 24 hours, despite medical therapy; or (3) clinical or angiographic characteristics indicating high risk, according to the criteria of the American Heart Association and the American College of Cardiology17 as modified by Ellis et al.7. Patients were excluded if they were 80 years old or older, were known to have a bleeding diathesis, had undergone major surgery within the preceding six weeks, or had had a stroke within the preceding two years. Approval was obtained from the institutional review board of each study center, and informed consent from each patient. Patients were recruited between November 1991 and November 1992; 2099 patients were enrolled at 56 institutions in the United States (see the Appendix).

Study Protocol

All the patients were treated with aspirin and heparin. Aspirin was administered orally in a dose of 325 mg at least two hours before angioplasty or atherectomy and daily thereafter. Heparin was given intravenously in an initial bolus dose of 10,000 to 12,000 units followed by incremental bolus doses of up to 3000 units at 15-minute intervals, but no more than 20,000 units was given during the procedure; the goal was to keep the activated clotting time between 300 and 350 seconds during the operation18,19,20. Heparin was continued by constant infusion for at least 12 hours to maintain the activated partial-thromboplastin time at 1.5 to 2.5 times the control value. The only medication required at discharge was aspirin in a dose of 325 mg per day. The chimeric 7E3 Fab (Centocor, Malvern, Pa.) used in the study is a Fab fragment of a human-mouse genetic reconstruction of a murine monoclonal IgG molecule that binds selectively to the glycoprotein IIb/IIIa platelet receptor. It was supplied as a sterile, nonpyrogenic solution containing 2 mg of monoclonal Fab per milliliter of 0.15 M sodium chloride, 0.01 M sodium phosphate, and 0.001 percent polysorbate 80 (pH 7.2).

Patients were randomly assigned to one of the following three treatment groups according to a double-blind study design: c7E3 Fab in a bolus dose of 0.25 mg per kilogram of body weight, followed by an infusion of 10 µg per minute; c7E3 Fab in a bolus dose of 0.25 mg per kilogram, followed by a placebo infusion; or a placebo bolus and a placebo infusion. The bolus dose was started at least 10 minutes before the procedure and given over a 5-minute period, and the infusion was continued for 12 hours unless a clinical contraindication developed.

Blood samples were obtained 30 minutes and 2, 12, and 24 hours after treatment began and then daily until hospital discharge and were carefully examined for evidence of thrombocytopenia. A predesigned algorithm was used to evaluate and treat life-threatening bleeding and thrombocytopenia,21 although no specific hemoglobin value was used to determine whether red-cell transfusions should be given. Vascular sheaths were maintained for at least six hours after the end of the infusion of the study drug and were left in place at least four hours after the end of the heparin infusion and until an acceptable activated partial-thromboplastin time was achieved to maintain hemostasis.

Study End Points

The primary end point of the trial was a prespecified composite of any of the following events in the first 30 days after randomization: death from any cause, nonfatal myocardial infarction, coronary-artery bypass grafting or repeat percutaneous intervention for acute ischemia, and insertion of a coronary endovascular stent because of procedural failure or placement of an intraaortic counterpulsation balloon pump to relieve refractory ischemia. Events were classified by the consensus of at least two members of an independent clinical-end-points committee blinded to the patients' treatment groups throughout the study.

If a patient entered the trial within 24 hours after an acute evolving myocardial infarction, one of two enzymatic criteria was required for the diagnosis of a subsequent nonfatal infarction: the activity of creatine kinase or its MB isozyme had to be at least three times the upper limit of normal, representing an increase of at least 33 percent from the previous "valley" (defined as a 25 percent decrease from a previous peak value but remaining at least twice the upper limit of normal); or the activity of creatine kinase or the MB isozyme increased by at least 100 percent and remained three times the upper limit of normal after a 50 percent decrease from a previous peak level and a valley level less than twice the upper limit of normal. The MB isozyme value was used (in more than 95 percent of patients) unless it was not available, in which case the value for total creatine kinase was used.

If a patient entered the trial more than 24 hours after an acute infarction or without a recent infarction, one of two criteria had to be met for a diagnosis of in-hospital myocardial infarction: a new Q wave with a duration of at least 0.04 second or a depth of more than one fourth the amplitude of the corresponding R wave in two or more contiguous leads; or an MB isozyme level more than three times the upper limit of normal, representing an increase of 50 percent or more over the previous valley level. After hospital discharge, either a new Q wave with the same adverse characteristics or a creatine kinase or MB isozyme level more than twice the upper limit of normal was required.

Other components of the primary end point were an unplanned repeat angioplasty to treat recurrent ischemia, urgent coronary surgery to treat recurrent ischemia or failure of an angioplasty, placement of an intracoronary stent to treat imminent or complete abrupt closure of the vessel undergoing angioplasty, and placement of an intraaortic balloon pump for recurrent ischemia when a repeat revascularization procedure was contraindicated.

Bleeding events were classified as major, minor, or insignificant according to the criteria of the Thrombolysis in Myocardial Infarction Study Group22. To estimate the total number of units of blood lost in patients who received blood transfusions, the number of units transfused was added to the observed drop in the hematocrit divided by 323.

Data Management and Statistical Analysis

After randomization by telephone, the patients were stratified according to their study center and whether they were having an acute evolving myocardial infarction. On the basis of data from previous trials, this trial was planned to include 2100 patients to detect a reduction of 33 percent in the primary end point (the event rate in the placebo group was predicted to be 15 percent), with a power of 0.8 and an alpha level of 0.05.

Data were collected by study coordinators on case-report forms and monitored by blinded study monitors before data entry. The trial sponsor (Centocor) and the investigators remained blinded to the randomization code and study results until all end points had been agreed on by the clinical-end-points committee and all details of the analysis plan were finalized.

The primary end point of the trial was analyzed by evaluating the time to the first occurrence of any one of the components of the composite end point that occurred within the first 30 days after enrollment. The results in the three treatment groups were displayed as Kaplan-Meier survival curves24 and compared according to the intention-to-treat principle. For the primary end point, a log-rank test for trend was performed in which the group assigned to the bolus of c7E3 Fab ranked between the group assigned to both the bolus and infusion of c7E3 Fab and the group given only placebo25. The analysis plan then called for pairwise log-rank comparisons between the placebo group and each of the two c7E3 Fab groups if the result of the test for trend was significant. Interim analyses were performed when data were available for one third and approximately two thirds of the patients. The nominal alpha level used for judging the significance of the test for trend and the pairwise group comparisons at each interim analysis was prespecified to maintain an overall type I error rate of 0.05. In the final analysis, the level of significance used in comparisons of the primary end point was 0.036. Differences among the treatment groups with respect to each component of the composite end point were also examined in the final analysis, although these comparisons were made for explanatory purposes. The data were presented with nominal two-tailed P values (unadjusted for multiple comparisons); readers can therefore make appropriate adjustments for multiplicity when interpreting the results. The prespecified final analysis also compared the treatment groups with respect to measures of bleeding complications, using conventional chi-square testing. Odds ratios and confidence intervals for the treatment effect in major subgroups (classified according to sex, age, weight, and clinical features at entry) were calculated, with the primary outcome used as a binary end point.

Results

There were no substantial differences among the treatment groups in their base-line clinical characteristics (Table 1). When the c7E3 Fab groups were compared with the placebo group, a graded effect of c7E3 Fab was found (P = 0.009), with a 10 percent reduction in the rate of the composite end point in the group given the c7E3 Fab bolus alone (P = 0.43) and a 35 percent reduction in the rate in the group given both this bolus and the infusion (P = 0.008) (Table 2). A similar graded effect was observed for each of the most important individual end points relating to ischemia, including the spectrum of nonfatal myocardial infarctions. Three of the deaths among the patients assigned to the c7E3 Fab bolus and infusion occurred after randomization but before drug administration; these deaths were included in the analysis according to the intention-to-treat principle.

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  		Table 1. Base-Line Characteristics and Procedures Performed in 2099 Patients at High Risk for Ischemia during Coronary Surgery, According to Treatment Group.

 
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  		Table 2. Primary Outcome Events in the Treatment Groups.

 
The times of nonfatal ischemic events differed among the three groups, as shown in Figure 1 for urgent repeat angioplasty, an event whose beginning and end could be determined accurately. In the placebo group, more ischemic events occurred during the first six hours after the procedure than later (P<0.03), whereas in the group given the c7E3 Fab bolus, events were delayed for several hours, corresponding to the time of maximal receptor blockade. There was a marked delay in the onset of ischemic events in the group given the c7E3 Fab bolus and infusion, as well as a marked reduction in their absolute frequency.


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  		Figure 1. Probability of No Urgent Repeated Percutaneous Revascularization Procedures in the Three Treatment Groups (Kaplan-Meier Plots).

Events began to occur shortly after the index procedure in the placebo group, between 6 and 12 hours after the procedure in the group given the bolus of c7E3 Fab, and even later in the group given both the bolus and the infusion. The y axis is truncated at 97 percent to demonstrate the differences in this end point, which occurred with low frequency.

 
The rates of bleeding complications during hospitalization are shown in Table 3. The group given the c7E3 Fab bolus and infusion had a substantial increase in both the rate of major bleeding and that of transfusion, with a more moderate increase seen in the group given the bolus alone. The majority of bleeding episodes occurred during coronary-artery bypass grafting or at the site of vascular puncture in the groin. The rates of surgery for bleeding were similar (1.4 percent in the placebo group, 2.6 percent in the group given the c7E3 Fab bolus only, and 1.7 percent in the group given both the bolus and the infusion). Similarly, six patients had an intracranial hemorrhage -- two patients assigned to placebo only, one patient assigned to the c7E3 bolus, and three patients assigned to the bolus and infusion; one of these last three patients did not receive the drug because the hemorrhage occurred after randomization but before angioplasty.

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  		Table 3. Bleeding Complications and Hematologic Values in the Treatment Groups.

 
When the treatment effect was evaluated in subgroups defined according to whether patients were enrolled with an acute ischemic syndrome or unstable angina or with high-risk anatomical features, the odds ratio for the primary end point was less than 1.0 in all subgroups (Table 4). Similarly, the treatment effect was homogeneous across the subgroups defined by age and sex.

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  		Table 4. Event Rates of Primary End Point and Transfusion in Subgroups Defined before Entry.

 
As a function of body weight, the hazard ratio for the primary end point was less than 1.0 across the study population, although the treatment effect was more pronounced in heavier patients. The risk of major bleeding was increased in lighter patients given c7E3 Fab (whether the bolus only or both the bolus and the infusion). In the lightest third of the patients, major bleeding occurred in 21 percent of those given both the bolus and the infusion of c7E3 Fab, 15 percent of those given the bolus only, and 7 percent of those given placebo, whereas in the heaviest third the corresponding rates of bleeding were 9, 7, and 6 percent.

Discussion

This study confirms the importance of platelet aggregation in the occurrence of acute ischemic events in patients undergoing percutaneous transluminal coronary angioplasty26. The administration of c7E3 Fab directed against the platelet glycoprotein IIb/IIIa receptor as a bolus and infusion resulted in a 35 percent reduction in the composite-event rate, primarily in the rate of nonfatal myocardial infarction and the need for emergency angioplasty or bypass surgery. This beneficial effect was achieved at the cost of a significant increase in bleeding complications and transfusions. Judgment about the clinical usefulness of this approach in patients at high risk for ischemic complications during or after percutaneous revascularization depends on the value of averting ischemic events relative to the value of reducing the need for blood products. In the high-risk patients enrolled in this trial, the balance appeared to be favorable.

The composite end point serves as an overall estimate of the effect of this therapeutic approach on ischemic events in the period encompassing angioplasty. One of the most important findings of this trial is the consistency in the reduction of events across the various end points. This consistency is further demonstrated by the closeness of the hazard ratios across the range of patient characteristics in many subgroups (Table 4). Nominal statistical significance for a treatment effect with regard to each end point or within each subgroup would not be expected in view of the size of the study population27. Together with the positive results of a recent pilot trial in which the same antibody was given to patients with refractory unstable angina,28 the beneficial effect of glycoprotein IIb/ IIIa-receptor blockade on clinical end points in the setting of high-risk angioplasty is convincing.

The classification of nonfatal myocardial infarction has become a major issue in the evaluation of percutaneous coronary interventions. Elevations of creatine kinase MB isozyme activity above the upper limit of normal commonly occur in 4 to 21 percent of patients,29,30,31,32 yet when they are not accompanied by discrete clinical events, their association with long-term adverse outcomes is not clear. Thus, preventing isolated enzyme elevations may not be prognostically meaningful. To ensure objectivity in this subtle area, we systematically collected enzyme values and electrocardiograms, set up a blinded end-point committee, and required at least a threefold increase in myocardium-specific enzyme activity to classify an event as a myocardial infarction. Treatment with c7E3 Fab reduced all types of myocardial infarctions, including those associated with moderate and large enzyme elevations and Q-wave development, and also reduced the need for emergency coronary revascularization.

The blood loss observed in this trial was substantial and resulted in a significant increase in the use of blood products. The doubling of the transfusion rate in patients who received both a bolus and an infusion of c7E3 Fab occurred primarily as a result of bleeding at the femoral puncture site and did not lead to a marked difference among the three treatment groups in nadir hematocrits or the rate of life-threatening complications. The trends remained the same whether or not surgically treated patients were included in the analysis. Our previous experience has demonstrated that a refined protocol for the management of bleeding and the administration of transfusions in patients given thrombolytic therapy can effectively reduce the need for blood products33.

The relation between treatment benefit and the risk of bleeding as a function of body weight was more complex than expected. Although the primary-event rate and the risk of major bleeding did not vary substantially with weight in the placebo group in our study, it was clear that weight was inversely related to the number of primary-outcome events and major episodes of bleeding in the group given the bolus and infusion of c7E3 Fab. Future studies and clinical practice using potent, parenterally administered antithrombotic agents in patients with indwelling tubes or catheters must focus on weight-adjusted dosing with antithrombotic drugs, more detailed evaluation of the mechanisms by which antithrombotic therapy prevents ischemic complications, and protocols that define approaches to reduce bleeding that will be applied consistently at all participating centers.

These findings have many implications for future scientific inquiry. The broad consistency of the treatment effect across the study population is strong evidence that platelet thrombosis plays an important part in the abrupt closure of coronary lesions treated by angioplasty. The apparent delay of adverse events by the bolus of c7E3 Fab and the prevention of events by the bolus and infusion imply that in most situations the surface of the disrupted artery has lost much of its thrombogenicity 18 to 24 hours after the procedure. This finding suggests that fu-ture therapies must take into account the need for sustaining an antithrombotic effect in patients at high risk for abrupt vessel closure.

In summary, this trial demonstrates a beneficial effect of substantial and sustained blockade of the glycoprotein IIb/IIIa receptor in patients undergoing high-risk percutaneous revascularization procedures, although this benefit was achieved at the risk of increased bleeding. The relative value of a reduction in ischemic events as compared with an increase in bleeding events is at the crux of the decision about the clinical usefulness of glycoprotein IIb/IIIa-receptor blockade. Previous surveys of cardiologists' attitudes and clinical practice have demonstrated that they generally regard the transfusion of blood products as a much less serious clinical event than either an acute myocardial infarction or emergency repeat revascularization34. The prognostic implications of either of the latter two adverse events are serious, and fortunately the risks associated with transfusion continue to decline35,36,37. Future efforts to employ practice algorithms to avert bleeding and transfusions and to determine doses of antithrombotic agents more effectively, including their antithrombin and antiplatelet effects, should further enhance the clinical benefits observed in this trial.

Supported by a grant from Centocor, Inc., Malvern, Pa.


Source Information

From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, N.C. Dr. Califf, as the corresponding author, assumes overall responsibility for the contents of the manuscript.The principal investigators and study coordinators of the EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications) Study Group are listed in the Appendix.

Address reprint requests to Dr. Robert M. Califf at Box 31123, Duke University Medical Center, Durham, NC 27710.

References

  1. Gruentzig AR, King SB III, Schlumpf M, Siegenthaler W. Long-term follow-up after percutaneous transluminal coronary angioplasty: the early Zurich experience. N Engl J Med 1987;316:1127-1132. [Abstract]
  2. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. N Engl J Med 1992;326:10-16. [Abstract]
  3. Lincoff AM, Popma JJ, Ellis SG, Hacker JA, Topol EJ. Abrupt vessel closure complicating coronary angioplasty: clinical, angiographic and therapeutic profile. J Am Coll Cardiol 1992;19:926-935. [Abstract]
  4. Tenaglia AN, Fortin DF, Frid DJ, et al. Long-term outcome following successful reopening of abrupt closure after coronary angioplasty. Am J Cardiol 1993;72:21-25. [CrossRef][Medline]
  5. Detre KM, Holmes DR Jr, Holubkov R, et al. Incidence and consequences of periprocedural occlusion: the 1985-1986 National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1990;82:739-750. [Free Full Text]
  6. Ellis SG, Roubin GS, King SB III, et al. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation 1988;77:372-379. [Free Full Text]
  7. Ellis SG, Bates ER, Schaible T, Weisman HF, Pitt B, Topol EJ. Prospects for the use of antagonists to the platelet glycoprotein IIb/IIIa receptor to prevent post-angioplasty restenosis and thrombosis. J Am Coll Cardiol 1991;17:Suppl B:89B-95B.
  8. Tenaglia AM, Fortin DF, Frid DJ, et al. Individualizing the risk of angioplasty abrupt vessel closure. J Am Coll Cardiol (in press).
  9. Moushmoush B, Kramer B, Hsieh AM, Klein LW. Does the AHA/ACC task force grading system predict outcome in multivessel coronary angioplasty? Cathet Cardiovasc Diagn 1992;27:97-105. [Medline]
  10. Myler RK, Shaw RE, Stertzer SH, et al. Unstable angina and coronary angioplasty. Circulation 1990;82:Suppl II:II-88. 
  11. Schwartz L, Bourassa MG, 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]
  12. Barnathan ES, Schwartz JS, Taylor L, et al. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987;76:125-134. [Free Full Text]
  13. Harker LA. Role of platelets and thrombosis in mechanisms of acute occlusion and restenosis after angioplasty. Am J Cardiol 1987;60:Suppl:20B-28B. [Medline]
  14. Coller BS. A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb/IIIa complex. J Clin Invest 1985;76:101-108.
  15. Coller BS, Scudder LR. Inhibition of dog platelet function by in vivo infusion of F(ab')2 fragments of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor. Blood 1985;66:1456-1459. [Free Full Text]
  16. Ellis SG, Navetta FI, Tcheng JT, et al. Safety and antiplatelet effect of murine monoclonal antibody 7E3 Fab directed against platelet glycoprotein IIb/IIIa in patients undergoing elective coronary angioplasty: an initial experience. Coron Artery Dis 1993;4:167-175. [Medline]
  17. Ryan TJ, Faxon DP, Gunnar RM, et al. Guidelines for percutaneous transluminal coronary angioplasty: a report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1988;78:486-502. [Free Full Text]
  18. Dougherty KG, Marsh KC, Edelman SK, Gaos CM, Ferguson JJ, Leachman DR. Relationship between procedural activated clotting time and in-hospital post-PTCA outcome. Circulation 1990;82:Suppl IV:IV-189. 
  19. Rath B, Bennett DH. Monitoring the effect of heparin by measurement of activated clotting time during and after percutaneous transluminal coronary angioplasty. Br Heart J 1990;63:18-21. [Free Full Text]
  20. Ogilby JD, Kopelman HA, Klein LW, Agarwal JB. Adequate heparinization during PTCA: assessment using activated clotting times. Cathet Cardiovasc Diagn 1989;18:206-209. [Medline]
  21. Sane DC, Califf RM, Topol EJ, Stump DC, Mark DB, Greenberg CS. Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management. Ann Intern Med 1989;111:1010-1022.
  22. Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial -- phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1-11. [Abstract]
  23. Landefeld CS, Cook EF, Flatley 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. [CrossRef][Medline]
  24. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
  25. Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: John Wiley, 1980.
  26. Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. Specific platelet mediators and unstable coronary artery lesions: experimental evidence and potential clinical implications. Circulation 1989;80:198-205. [Free Full Text]
  27. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98. [Free Full Text]
  28. Simoons ML, de Boer MJ, van den Brand MJBM, et al. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Circulation 1994;89:596-603. [Free Full Text]
  29. Klein LW, Kramer BL, Howard E, Lesch M. Incidence and clinical significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty. J Am Coll Cardiol 1991;17:621-626. [Abstract]
  30. Hunt AC, Chow SL, Shiu MF, Chilton DC, Cummins B, Cummins P. Release of creatine kinase-MB and cardiac specific troponin-I following percutaneous transluminal coronary angioplasty. Eur Heart J 1991;12:690-693.
  31. Pauletto P, Piccolo D, Scannapieco G, et al. Changes in myoglobin, creatine kinase and creatine kinase-MB after percutaneous transluminal coronary angioplasty for stable angina pectoris. Am J Cardiol 1987;59:999-1000. [CrossRef][Medline]
  32. Spadaro JJ, Ludbrook PA, Tiefenbrunn AJ, Kurnik PB, Jaffe AS. Paucity of subtle myocardial injury after angioplasty delineated with MB CK. Cathet Cardiovasc Diagn 1986;12:230-234. [Medline]
  33. Wall TC, Califf RM, Ellis SG, et al. Lack of impact of early catheterization and fibrin specificity on bleeding complications after thrombolytic therapy. J Am Coll Cardiol 1993;21:597-603. [Abstract]
  34. Califf RM, Harrelson-Woodlief L, Topol EJ. Left ventricular ejection fraction may not be useful as an end point of thrombolytic therapy comparative trials. Circulation 1990;82:1847-1853. [Free Full Text]
  35. Donahue JG, Munoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992;327:369-373. [Abstract]
  36. Dodd RY. The risk of transfusion-transmitted infection. N Engl J Med 1992;327:419-421. [Medline]
  37. Nelson KE, Donahue JG, Munoz A, et al. Transmission of retroviruses from seronegative donors by transfusion during cardiac surgery: a multicenter study of HIV-1 and HTLV-I/II infections. Ann Intern Med 1992;117:554-559.
Appendix

The following are the principal investigators and study coordinators of the EPIC Study Group: Presbyterian Hospital, Albuquerque, N.M. -- N. Shadoff and N. Valett; University of Michigan Medical Center, Ann Arbor -- E. Bates and A. Galeana; St. Joseph Hospital, Atlanta -- W. Knopf, J. Shaftel, and M.J. Bender; Johns Hopkins Hospital, Baltimore -- T. Aversano and J. Raqueno; University of Maryland Hospital, Baltimore -- P. Gurbel and J. Cowfer; St. Francis Hospital, Beech Grove, Ind. -- M. Cohen and P. Cross; Brigham and Women's Hospital, Boston -- J. Bittl and K. Eddings; Deborah Heart Center, Brown Mill, N.J. -- M. Taylor and K. DeRosa; DePaul Hospital, Cheyenne, Wyo. -- L. Hattel, L. Cooper, and B. Eshelman; Northwestern University, Chicago -- D. Fintel and P. Niemyski; Rush-Presbyterian-St. Luke's Medical Center, Chicago -- L. Klein, H. Kennedy, and T. Thornton; Christ Hospital, Cincinnati -- D. Kereiakes, L. Martin, L. Anderson, and N. Higby; Cleveland Clinic, Cleveland -- S. Ellis and K. Brezina; Riverside Methodist Hospitals, Columbus, Ohio -- B. George, A. Chapekis, and D. Smith; Baylor University, Dallas -- A. Anwar, T.L. Gerber, and G.L. Pritchard; San Francisco Heart Institute, Daly City, Calif. -- R. Myler, R. Shaw, M. Murphy, and K. Ward; Geisinger Medical Center, Danville, Pa. -- N.P. Madigan, J. Blankenship, M. Halbert, and C. Flanagan; Iowa Heart Center Mercy Hospital, Des Moines -- M. Tannenbaum, M. Polich, and C. Stevenson; Duke University, Durham, N.C. -- J. Tcheng, S. Hoffman, and R.M. Moore; St. Vincent Health Center, Erie, Pa. -- J. Smith and P. Henry; Evanston Hospital, Evanston, Ill. -- T.J. McDonough and S. Weszt; Moses Cone Hospital, Greensboro, N.C. -- B. Brodie and D. Muncy; Baylor University Methodist/Ben Taub General Hospital, Houston -- N. Kleiman, K. Trainor, D. Rose, and S. Johnson; Texas Heart Institute, Houston -- J. Willerson, J.J. Ferguson, and M. Harlan; University of Florida Medical Center, Jacksonville -- T.A. Bass and G. Rohman; Lakeland General Hospital, Lakeland, Fla. -- K. Browne and C. Ciesla; Lancaster General Hospital, Lancaster, Pa. -- S. Worley and J. Tuzi; Dartmouth-Hitchcock Medical Center, Lebanon, N.H. -- B. Hettleman, W.C. Burke, G. Olsen, and S.J. Kennedy; University of Louisville, Louisville, Ky. -- J.D. Talley, Z.A. Yussman, and M. Rawert; Loyola University Hospital, Maywood, Ill. -- E.D. Grassman and L. Wrona; Baptist Memorial, Memphis, Tenn. -- J. Samaha and B. Ehemann; East Jefferson Hospital, Metairie, La. -- S.D. Bleich and R. Leonhard; St. Luke's Medical Center, Milwaukee -- F. Cummins and J. Nonnweiler; St. Patrick Hospital, Missoula, Mont. -- M. Sanz and D. Mayer; Yale University Medical Center, New Haven, Conn. -- M.W. Cleman, V.J. Pascale, and S. McConnell; Creighton University Cardiac Center, Omaha, Nebr. -- M. Del Core and L. Stengel; Florida Hospital, Orlando, Fla. -- R.J. Ivanhoe and N. Granger; Lutheran General Hospital, Park Ridge, Ill. -- M.J. Rosenberg and A. Schaechter; Sacred Heart, Pensacola, Fla. -- G. Aycock and T. Wilcox; Graduate Hospital, Philadelphia -- R. Gottlieb and H. Hunter; Philadelphia Heart Institute, Philadelphia -- W. Unterecker and B. Hart; Arizona Heart Institute and Foundation, Phoenix -- R. Heuser and S. Hoopmann; North Memorial Medical Center, Robbinsdale, Minn. -- G. Hanovich and A. Antolick; Rochester General Hospital, Rochester, N.Y. -- G. Gacioch, V. Chiodo, and K. Karski; William Beaumont Hospital, Royal Oak, Mich. -- G. Timmis and M. Safian; St. Louis University, St. Louis -- F. Aguirre and T. Stonner; St. John's Hospital, Springfield, Ill. -- G.J. Taylor, K. Womack, and B. Ruyle; South Miami Hospital, Miami -- D. Krauthamer and G. Welcom; Tampa General Hospital, Tampa, Fla. -- M. Weston and K. Dillon; Harbor-UCLA Medical Center, Torrance, Calif. -- W.J. French and G.T. Reynolds; Mother Frances Hospital, Tyler, Tex. -- F. Navetta, G. Murphy, R. LeBoeuf, and S. Spencer; and Washington Hospital Center, Washington, D.C. -- J.J. Popma and L. Sweet.

Executive Committee -- E.J. Topol, R.M. Califf, C.R. Smith, H. Weisman, and K.L. Lee; Coordinating Center -- J. Miller, K. Sigmon, R.M. Califf, J. Tcheng, K.L. Lee, M. Lui, A. Kosloff, and J. DiFulvio (Durham, N.C.); and A.L. Wang, K. Anderson, H. Weisman, R. Dann, W. Kingma, D. Norton, B. Myer, R. Masek, M. Lewandowski, S. Broderick, M. Musco, M. Schorr, P. Hartman, and L. McCardle (Malvern, Pa.); Safety Data Monitoring Committee -- D. Faxon (chairman), P. Armstrong, J. Gore, J. Loscalzo, L. McCullough, and J. Verter; Economics and Quality of Life -- D.B. Mark, L. Davidson-Ray, N. Clapp-Channing, and L.C. Lam; Clinical Events Committee -- R.A. Waugh (chairman), C.B. McCants, Jr., M.C. Hindman, G. Dehmer, W.B. Hillegass, D.J. Frid, D.F. Fortin, B.C. Brott, T.L. Forest, D.M. Unks, and M.E. Hamer; ECG Core Laboratory -- G.S. Wagner and K. Gates; and Thrombocytopenia Core Laboratory -- D. Sane.


 

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