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Circulation. 1999;99:2720-2732

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(Circulation. 1999;99:2720-2732.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Abciximab Facilitates the Rate and Extent of Thrombolysis

Results of the Thrombolysis In Myocardial Infarction (TIMI) 14 Trial

Elliott M. Antman, MD; Robert P. Giugliano, MD, SM; C. Michael Gibson, MS, MD; Carolyn H. McCabe, BS; Patrick Coussement, MD; Neal S. Kleiman, MD; Alec Vahanian, MD; A. A. Jennifer Adgey, MD; Ian Menown, MD; Hans-Jürgen Rupprecht, MD; R. Van der Wieken, MD; John Ducas, MD; Joel Scherer, MD; Keaven Anderson, PhD; Frans Van de Werf, MD, PhD; Eugene Braunwald, MD; for the TIMI 14 Investigators1

From Brigham and Women's Hospital (E.M.A., R.P.G., C.H.M., E.B.), Boston, Mass; Allegheny General Hospital (C.M.G.), Pittsburgh, Pa; Universitair Ziekenhuis Gasthuisberg (P.C., F.V.d.W.), Leuven, Belgium; Methodist Hospital (N.S.K.), Houston, Tex; Hopital Tenon (A.V.), Paris, France; Royal Victoria Hospital (A.A.J.A., I.M.), Belfast, United Kingdom; Medizinische Klinik II (H.-J.R.), Mainz, Germany; OLVG afdeling Cardiologie (R.V.d.W.), Amsterdam, Netherlands; University of Manitoba Health Sciences Centre (J.D.), Winnipeg, Canada; Eli Lilly, Inc (J.S.), Indianapolis, Ind; and Centocor (K.A.), Malvern, Pa.

Correspondence to Elliott M. Antman, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}bustoff.bwh.harvard.edu


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
Background—The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI.

Methods and Results—Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 µg · kg-1 · min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U · kg-1 · h-1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U · kg-1 · h-1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U · kg-1 · h-1) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and 90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70).

Conclusions—Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.


Key Words: thrombolysis • myocardial infarction • platelet aggregation inhibitors • platelets


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
Currently used thrombolytic reperfusion regimens produce an important survival benefit in patients with ST-segment elevation acute myocardial infarction (MI), but they also have several limitations.1 Depending on the agent used, patency of the infarct-related artery is established within 90 minutes after the initiation of treatment in only 60% to 80% of patients.1 2 Full antegrade perfusion (TIMI grade 3 flow) is achieved in only 30% to 55% of patients.1 2 After initially successful thrombolysis, {approx}5% to 10% of patients experience reocclusion of the culprit coronary artery.1 2 When it occurs, reocclusion may be associated with recurrent infarction and an increased risk of mortality and morbidity.1 3 4 Obstructive arterial thrombi that are platelet rich are resistant to thrombolysis and have an increased tendency to produce reocclusion after initial reperfusion.5 Although aspirin acts synergistically with thrombolytics to reduce mortality and may also be helpful in preventing reocclusion, it is a relatively weak antiplatelet agent.6 7 Despite the inhibition of cyclooxygenase by aspirin, platelet activation continues to occur through thromboxane A2-independent pathways, leading to platelet aggregation and increased thrombin formation.8

The activation of platelets by several agonists results in the expression of functional receptors for fibrinogen on the platelet surface, referred to as glycoprotein (GP) IIb/IIIa receptors. The GP IIb/IIIa inhibitor abciximab produces an antithrombotic effect by direct inhibition of the binding of natural ligands such as fibrinogen to the GP IIb/IIIa receptor, leading to a dose-dependent inhibition of platelet aggregation.9 Because abciximab is a much more potent inhibitor of platelet function than aspirin, it has the potential to promote a greater degree of thrombolysis and prevent rethrombosis in the short-term management of patients with ST-elevation MI.9 10 11

Preclinical studies have shown that GP IIb/IIIa inhibition accelerates thrombolysis and prevents reocclusion in several animal species with experimentally induced platelet-rich coronary thromboses that were treated with alteplase.5 12 13 14 15 Analyses from previous clinical trials16 17 18 suggested that administration of abciximab to support direct coronary intervention or rescue coronary intervention after failed thrombolysis for ST-elevation MI was helpful in reducing death and cardiac ischemic events. Pilot angiographic observations suggest that abciximab facilitates dissolution of intracoronary thrombi without a significant risk of distal embolization, no reflow, or abrupt closure.12 19

The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 study evaluated prospectively the safety of administering murine Fab fragments of a monoclonal antibody against the GP IIb/IIIa receptor (m7E3) after standard-dose alteplase in the treatment of acute MI.20 m7E3 inhibited platelet aggregation in a dose-dependent fashion, ultimately achieving >=80% inhibition at a dose of 0.25 mg/kg. There was no increase in bleeding events in patients receiving m7E3, and no intracranial hemorrhages were observed. TIMI grade 2 or 3 flow was seen in the infarct-related artery at follow-up angiography at day 5 in 5 (56%) of 9 control patients and 34 (92%) of 37 patients receiving m7E3 (P=0.02).

The observations noted above served as the foundation for testing the hypothesis that abciximab is a potent and safe addition to thrombolytic regimens for ST-elevation MI. To accomplish this, TIMI 14, a phase II, multicenter angiographic study, had as its primary objective an evaluation of the rate of TIMI 3 flow at 90 minutes for reperfusion regimens of abciximab alone and in combination with reduced doses of alteplase or streptokinase. Secondary objectives were to evaluate the safety of the new reperfusion regimens, make efficacy observations with a variety of angiographic criteria (including TIMI flow grade at 60 minutes and TIMI frame counts at 60 and 90 minutes), and make pilot observations on the rate of clinical events such as mortality, recurrent MI, recurrent ischemia, and development of severe pump dysfunction.


*    Methods
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 up arrowAbstract
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 *Methods
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 down arrowAppendix 1
 down arrowReferences
 
The trial was conducted between March 1997 and July 1998 at 63 enrolling centers in the United States, Canada, United Kingdom, Belgium, Netherlands, France, and Germany. It was supported by the central units and Angiographic Core Laboratory described in the Appendix.

Eligibility Criteria
Patients were eligible for inclusion if they were between 18 and 75 years of age, had a qualifying episode of ischemic discomfort of >=30 minutes' duration within the prior 12 hours, and, as reported by the enrolling clinical center, exhibited >=0.1-mV ST-segment elevation in 2 contiguous leads. Patients were excluded if they had any of the following findings:

  1. Cardiovascular: left bundle-branch block, intraventricular conduction defect, or paced rhythm obscuring identification of the infarct location; MI treated either with thrombolytic therapy or percutaneous coronary intervention within the prior 7 days; previous CABG surgery, cardiogenic shock, or pulmonary edema requiring intubation.

  1. Bleeding risks: single reliable measurement of systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg at any time from initial medical contact to randomization; known prior history of stroke, transient ischemic attack, or central nervous system structural damage; active bleeding or history of hemorrhagic diathesis; major surgery within prior 2 months; therapeutic anticoagulation (INR >1.4) in the absence of heparin.

  1. Prior or concomitant therapy: known allergy to abciximab or aspirin; treatment with abciximab or any other GP IIb/IIIa inhibitor within prior 7 days; treatment with >=6000 U heparin in the hour before randomization.

  1. General: inability to undergo cardiac catheterization; suspected cocaine or amphetamine-induced MI.

Study Protocol
The study consisted of randomized, open-label dose-finding and dose-confirmation phases. During both phases, all patients were given aspirin (150 to 325 mg PO or 250 to 500 mg IV) and were then randomized into the treatment groups described below (Figure 1Down).



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  		Figure 1. Design of dose-finding phase. Eligible patients with ST-elevation MI (ST{uparrow}) were randomized to 1 of 4 treatment groups: a control group that did not receive abciximab and was treated with 100 mg of tissue plasminogen activator (alteplase) in an accelerated-dose fashion and 3 experimental groups each receiving abciximab as an initial bolus of 0.25 mg/kg followed by a 12-hour infusion (inf) of 0.125 µg · kg-1 · min-1. Experimental regimens used in combination with abciximab consisted of no lytic, reduced-dose streptokinase ({downarrow} dose SK), and reduced-dose alteplase ({downarrow} dose alteplase). Control patients received standard (STD) heparin, whereas patients in the experimental groups received low-dose heparin (see text for further discussion). ASA indicates acetylsalicylic acid.

Dose-Finding Phase
Randomization occurred at an equal rate for all treatment groups by use of a centralized telephone system. The control group did not receive abciximab but was treated with 100 mg of alteplase with a front-loaded regimen (15-mg bolus, initial infusion of 0.75 mg/kg up to 50 mg over 30 minutes, followed by infusion of 0.50 mg/kg up to 35 mg over 60 minutes) and standard-dose heparin consisting of a bolus of 70 U/kg (maximum 4000 U) and initial infusion of 15 U · kg-1 · h-1 (maximum 1200 U/h). The 3 experimental groups all received an initial bolus of abciximab 0.25 mg/kg followed by a 12-hour infusion of 0.125 µg · kg-1 · min-1 and either received no lytic (abciximab alone), reduced-dose streptokinase, or reduced-dose alteplase (Table 1DownDown). Abciximab was to be administered before or concurrent with the thrombolytic in the reduced-dose streptokinase and reduced-dose alteplase groups. Abciximab-treated patients received low-dose heparin with a bolus of 60 U/kg (maximum 4000 U) and infusion of 7 U · kg-1 · h-1 (maximum 800 U/h). For all groups, heparin infusions were adjusted according to a nomogram to a target activated partial thromboplastin time (aPTT) of 50 to 70 seconds.


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  		Table 1. Baseline Characteristics


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  		Table 1B. Continued

Fourteen different reperfusion regimens were evaluated during the dose-finding phase. These included the alteplase-alone and abciximab-alone arms and the 12 reduced-dose lytic regimens combined with abciximab shown in Table 1Up. For each lytic, testing proceeded in an ascending dose–ranging fashion. The 4 streptokinase regimens were infusions of 500 000 U, 750 000 U, 1.25 MU, and 1.5 MU over the times shown in Table 1Up. To minimize the risk of bleeding, heparin was eliminated at the 1.5-MU dose of streptokinase. Eight alteplase regimens were tested that represented total doses of 20, 35, 50, and 65 mg. For the 35- and 50-mg doses, regimens that used a bolus and bolus plus infusion were evaluated. We evaluated the impact of varying the duration of the infusion in the 50-mg dose tier by comparing infusions of alteplase over 30 or 60 minutes. To test the benefit of a higher abciximab dose, in 1 group receiving 50 mg of alteplase over 60 minutes, the abciximab bolus dose was increased to 0.3 mg/kg and heparin reduced to a very-low-dose regimen of a bolus of 30 U/kg (maximum 2000 U) and initial infusion of 4 U · kg-1 · h-1 (maximum 400 U/h).

Dose-Confirmation Phase
After evaluation of the angiographic findings and safety observations from the dose-finding phase, a regimen of 50 mg of alteplase administered as a bolus of 15 mg and infusion of 35 mg over 60 minutes was selected for testing in the dose-confirmation phase. During the dose-confirmation phase, patients were randomized into 3 groups consisting of the accelerated-dose alteplase control group, as described for the dose-finding phase, and 2 experimental groups that were treated with the 50-mg alteplase regimen described above and abciximab (0.25 mg/kg bolus followed by a 12-hour infusion of 0.125 µg · kg-1 · min-1) and either a low-dose (60-U/kg bolus and infusion of 7 U · kg-1 · h-1) or very-low-dose (30-U/kg bolus and infusion of 4 U · kg-1 · h-1) heparin regimen (Figure 2Down). During the dose-confirmation phase, 1 patient was randomized to the control group for every 2 patients randomized to each of the experimental groups, and randomization into the experimental groups proceeded in a sequential fashion.



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  		Figure 2. Design of dose-confirmation phase. Patients were randomized to a control group (described in Figure 1Up) or a 50-mg alteplase regimen combined with abciximab and either low-dose or very-low-dose heparin. Abbreviations as in Figure 1Up.

During both the dose-finding and dose-confirmation phases, use of ß-blockers, nitrates, calcium antagonists, and other medications was at the treating physician's discretion, as was the decision for referral for CABG surgery.

Angiographic Procedures
For timing the performance of coronary angiograms, time 0 was considered to be the start of administration of the first drug of the assigned reperfusion regimen. Coronary angiography of the infarct-related artery was performed as soon as possible after initiation of the reperfusion regimen but in no case >90 minutes later. Standardized views and techniques of injection were used by investigators. Except in cases of rapid and progressive hemodynamic deterioration, coronary interventional procedures were performed at the treating physician's discretion after the 90-minute angiogram. When rescue interventional procedures were performed, supplemental heparin dosing was administered via a standardized nomogram, guided by measurements of activated clotting time (ACT), with a target of 250 seconds in the control group and 200 seconds in all groups receiving abciximab. Arterial access sheaths were removed when the aPTT was <=50 seconds or the ACT was <=170 seconds.

Clinical Procedures
ECGs were obtained at admission, for any episodes of recurrent ischemic discomfort >=5 minutes during the index hospitalization, 12 to 24 hours after any revascularization procedure, and at the time of hospital discharge. Creatine kinase (CK) and isoenzyme (CK-MB) levels were measured on admission and at 6, 12, and 24 hours for the first 24 hours and were repeated for episodes of recurrent ischemic discomfort >=30 minutes in duration or after revascularization procedures during the index hospitalization. Platelet counts were measured at admission; 60 minutes and 3, 12, and 24 hours after administration of study drug; and then daily until hospital discharge or day 3, whichever came first. In the event of a platelet count <100 000/mL that represented >=25% decrease from baseline, platelet counts were repeated. If true thrombocytopenia was confirmed, abciximab was discontinued. Hemoglobin and hematocrit levels were obtained at admission, 24 and 48 hours after administration of study drug, and at hospital discharge.

All patients were followed up for clinical events during the index hospitalization and through 30 days.

Study End Points
Efficacy
The primary angiographic efficacy end point was the achievement of TIMI grade 3 flow at 90 minutes in the infarct-related artery. All angiograms were evaluated by the Angiographic Core Laboratory, which was blinded to treatment assignment, using previously established procedures for determination of TIMI flow grade21 and TIMI frame count.22 Patients were considered angiographically evaluable if they received the specified reperfusion regimen and had an evaluable 90-minute angiogram. In patients receiving abciximab and a thrombolytic drug, the angiographically evaluable cohort was restricted to patients who received both abciximab and the thrombolytic drug within 15 minutes of each other. Prespecified secondary angiographic efficacy end points were TIMI grade 2 or 3 flow in the infarct-related artery at 60 and 90 minutes and TIMI frame counts at 60 and 90 minutes.22

Clinical efficacy end points were analyzed for all randomized patients (intention-to-treat cohort) by a Clinical Events Committee using standardized definitions. These end points included all-cause mortality, recurrent MI, recurrent ischemia >=5 minutes, severe recurrent ischemia requiring urgent revascularization, severe pump failure, the performance of rescue percutaneous coronary interventions, and CABG. The definitions of recurrent MI and severe pump failure were as previously described.23 24 Severe recurrent ischemia requiring urgent revascularization was considered to be present if the patient experienced >=1 episode of rest pain of >=5 minutes' duration or had Canadian Heart Association class III or IV angina that resulted in either an urgent percutaneous coronary intervention or CABG. In the absence of pain, the following were considered evidence of severe ischemia: new ST shifts >=0.1 mV on 12-lead ECG or lasting >20 minutes on ambulatory ECG monitoring; acute pulmonary edema, ventricular arrhythmias, or hemodynamic instability presumed to be ischemic in origin; TIMI 0 or 1 flow on the initial angiogram that was followed by rescue angioplasty; or revascularization after a recurrent MI.

Safety
The primary safety end point was major hemorrhage, which was defined as any intracranial, retroperitoneal, or intraocular hemorrhage or any clinically overt hemorrhage associated with a drop in hemoglobin >=5 g/dL. An additional end point was thrombocytopenia (platelet count <100 000/mL and a decrease of >=25% from baseline) that was not due to interaction in the blood-drawing tube with an anticoagulant such as EDTA, citrate, or heparin (ie, pseudothrombocytopenia). Severe thrombocytopenia was defined as a platelet count <50 000/mL. All patients who received any element of the assigned reperfusion regimen were included in safety analyses (safety-evaluable cohort); these events were also reviewed and classified by the Clinical Events Committee.

Statistical Considerations
Historical data suggest that {approx}50% of angiographically evaluable patients achieve TIMI grade 3 flow at 90 minutes after receiving a front-loaded 100-mg alteplase regimen.25 Patients enrolled in the experimental reperfusion regimen groups were compared with this historical rate. The protocol specified that in order for abciximab without thrombolytics to be considered a candidate for future study, the rate of TIMI 3 flow at 90 minutes should be comparable to 50%, whereas it needed to exceed 50% in regimens that combined abciximab with a thrombolytic. To guide the Operations Committee in identifying promising new reperfusion regimens during the dose-finding phase, the rates of TIMI 3 flow in each of the treatment groups were monitored by use of a sequential probability ratio test (SPRT).26 The prespecified SPRT boundaries were 30% (H0) and 50% (Ha) TIMI 3 flow with types I and II error rates of 0.0001% and 10%, respectively, for the abciximab-alone group and boundaries of 60% (H0) and 80% (Ha) TIMI 3 flow with types I and II error rates of 1% and 2.5%, respectively, for groups in which abciximab was combined with a thrombolytic. On the basis of the operating characteristics of the SPRT, it was estimated that 35 to 70 patients per treatment group would provide sufficient information to determine whether a given regimen was likely to be considered a candidate for additional testing.

Statistical comparisons were made by {chi}2 analysis for categorical variables and either Student's t test or Wilcoxon signed rank test, as appropriate, for continuous variables. Screening for any significant differences in TIMI frame counts among the treatment groups was performed in a protected fashion. This was accomplished first by performing a generalized log-rank {chi}2 procedure to test for any difference between treatment groups. If significant, this was followed by log-rank tests on pairwise comparisons between treatment groups. Owing to the exploratory nature of the comparisons in the trial, nominal probability values without adjustment for multiple comparisons were taken as an indication of the statistical significance of comparisons between groups or trends among groups.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
A total of 888 patients were enrolled in the trial, 677 in the dose-finding phase and 211 in the dose-confirmation phase. Baseline characteristics of patients are shown in Table 1Up. The median age of the patients enrolled was 58 years; 77% were male, and 37% had an anterior MI. The median time from the onset of pain to treatment was 3.0 hours; 75% of patients were treated in <5 hours. In 99% of patients, abciximab was administered either before or with the lytic.

Angiographic Observations
Of the 888 patients, 791 (89%) were considered angiographically evaluable at 90 minutes. The reasons for exclusion from the angiographically evaluable cohort at 90 minutes were failure to receive the reperfusion regimen as specified in the protocol (n=38 [4.3%]), lack of angiography for clinical reasons, performance of the angiogram >15 minutes outside the 90-minute time frame (n=59 [6.6%]), and technically inadequate imaging (n=2 [0.2%]). A total of 408 patients (45.9%) were considered angiographically evaluable at 60 minutes.

Dose-Finding Phase
Angiographic data for all groups during the dose-finding phase are summarized in Table 2DownDown. Patients treated with alteplase alone (n=152) achieved a 57% TIMI 3 flow rate at 90 minutes, whereas patients treated with abciximab alone (n=31) achieved a 32% TIMI 3 flow rate. Doses of streptokinase between 500 000 U and 1.25 MU given with abciximab produced TIMI 3 flow rates of 34% to 46%. The regimen of 1.5 MU of streptokinase plus abciximab was terminated prematurely after only 5 angiographically evaluable patients had been studied because of unacceptable bleeding (see below).


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  		Table 2. Angiographic Observations During Dose-Finding Phase


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  		Table 2B. Continued

Reperfusion regimens consisting of total alteplase doses of 20, 35, 50, or 65 mg produced 90-minute TIMI 3 flow rates that were at least comparable to and in many cases exceeded those observed with full-dose alteplase alone (Table 2Up). An increase in the abciximab bolus to 0.3 mg/kg did not appear to offer any incremental benefit in establishing TIMI 3 flow (Table 2Up).

The most promising regimen appeared to be 50 mg of alteplase given as a 15-mg bolus and 35-mg infusion over 60 minutes. Compared with full-dose alteplase alone, the 50-mg alteplase regimen noted above produced substantial increases in the rates of both TIMI 3 flow (76% versus 57%; P=0.08) and infarct-related artery patency (TIMI 2/3 flow, 93% versus 78%; P=0.09) at 90 minutes.

Insight into the rate and extent of thrombolysis when abciximab was combined with reduced-dose alteplase was gained by comparing observations made at 60 and 90 minutes after the start of the reperfusion regimens. The data shown in Figure 3Down are plotted for patients in the dose-finding phase who received varying total doses of alteplase stratified by the administration schedule of the lytic. Increasingly higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with more prolonged duration of administration of alteplase, progressing from a bolus to a bolus followed by a 30-minute infusion and then a bolus followed by a 60-minute infusion (P=0.02 by {chi}2 for trend at 60 minutes and P=0.0002 by {chi}2 for trend at 90 minutes). Compared with a 45% TIMI 3 flow rate at 60 minutes in the alteplase control arm, at the end of the 60-minute infusion schedule, TIMI 3 flow was 63%. At 90 minutes, it reached 74% compared with 57% in the alteplase control group.



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  		Figure 3. Impact of alteplase administration schedule on reperfusion of infarct-related artery. Percentage of patients (% Pts) achieving TIMI grade 3 flow at 60 minutes (shaded bars) and 90 minutes (solid bars) for different reperfusion regimens containing alteplase and abciximab tested during the dose-finding phase is shown. Increasingly higher rates of TIMI 3 flow at both 60 and 90 minutes were seen with more prolonged duration of administration of alteplase. inf indicates infusion.

Dose-Confirmation Phase
On the basis of the angiographic observations noted above and an acceptable safety profile (see below), a regimen of 50 mg of alteplase administered as a bolus of 15 mg and infusion of 35 mg over 60 minutes in combination with abciximab was selected for the dose-confirmation phase. TIMI 3 flow rates at 60 and 90 minutes in patients collectively enrolled in the alteplase control arm from the dose-finding and dose-confirmation phases are shown in Figure 4Down. These are compared with the 50-mg alteplase regimen from the dose-finding phase and during the dose-confirmation phase, in conjunction with the low-dose and very-low-dose heparin regimens. Rates of TIMI 3 flow similar to those originally observed in the dose-finding phase were seen at both 60 and 90 minutes with the 50-mg alteplase regimen and low-dose heparin in the dose-confirmation phase. The pooled data for the 50-mg alteplase regimen with low-dose heparin showed a significant increase in the rate of TIMI 3 flow at 60 minutes from 43% in the control arm to 72% (P=0.0009), representing a relative 67% increase. The very-low-dose heparin group had a 68% rate of TIMI 3 flow at 60 minutes. At 90 minutes, pooled data from the 50-mg alteplase regimen with low-dose heparin showed a 77% rate of TIMI 3 flow, which was significantly higher than the 62% rate observed in the alteplase control group (P=0.01). In the very-low-dose heparin regimen, the TIMI 3 flow rate at 90 minutes was 69%, a value intermediate between alteplase without abciximab and the 50-mg alteplase regimen with low-dose heparin.



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  		Figure 4. Facilitation of rate and extent of thrombolysis with abciximab. Percentage of patients (% Pts) with TIMI grade 3 flow at 60 minutes (shaded bars) and 90 minutes (solid bars) is shown for control group of 100 mg of alteplase in an accelerated-dose regimen and a 50-mg regimen of alteplase (15-mg bolus followed by infusion of 35 mg over 60 minutes) in combination with abciximab and either low-dose heparin (center portion of chart) or very-low-dose heparin (right). Similar rates of TIMI 3 flow were observed for the regimen of 50 mg of alteplase in combination with abciximab and low-dose heparin during both the dose-finding and dose-confirmation phases. Pooled data (ALL) for 50-mg alteplase regimen with low-dose heparin showed a significant increase in the rate of TIMI 3 flow at both 60 and 90 minutes compared with the control group.

TIMI frame counts at 60 and 90 minutes for 4 representative groups of reperfusion regimens are shown in Figure 5Down. The dashed vertical line at 28 frames is the upper 95% CI for normal flow, and the dashed line at 40 frames is the break point between TIMI 3 and TIMI 2 flow. It is in the zone between these 2 values that some distinctions between groups can be observed. The group receiving 50 mg of alteplase as a bolus of 15 mg and infusion of 35 mg over 60 minutes in combination with abciximab and low-dose heparin was shifted up and to the left compared with the full-dose alteplase control arm at both 60 and 90 minutes, indicating a higher proportion of patients with lower frame counts. These differences were statistically significant (P=0.001 at 60 minutes and P=0.005 at 90 minutes). At 90 minutes, the median TIMI frame count in the 50-mg alteplase regimen was normal at 28 frames compared with 36 frames in the alteplase control arm. A composite of all the streptokinase plus abciximab groups is shifted below the alteplase control arm, indicating higher frame counts (median frame count, 45 frames). This is followed by the abciximab-alone group, which had the highest frame counts.



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  		Figure 5. TIMI frame count for representative reperfusion regimens. Distribution plots are shown for cumulative percentage of patients with a given TIMI frame count corrected for vessel length (cTFC) at 60 minutes (A) and 90 minutes (B). Generalized log-rank {chi}2 test (df=3) was associated with a P value <0.001 for both the 60-and 90-minute TIMI frame counts, indicating significant differences were present among treatment groups. A significantly greater proportion of patients treated with 50 mg of alteplase (tPA) in combination with abciximab (Abx) and low-dose heparin had lower frame counts (ie, faster flow) than the control group of 100 mg of alteplase at both 60 and 90 minutes. Reperfusion regimens combining streptokinase (SK) plus abciximab or abciximab alone had higher frame counts.

Safety Observations and Other Clinical Events
Safety observations along with other clinical events from the dose-finding phase are summarized in Table 3DownDown. The overall rate of major hemorrhage was 7%. The rate of major hemorrhage was 6% in the alteplase control group, 3% in the abciximab-alone group, and 7% in all alteplase-plus-abciximab groups combined. The rate of major hemorrhage was 10% for all streptokinase-plus-abciximab groups combined. There was a dose-related increase in the rate of major hemorrhage as ascending doses of streptokinase were combined with abciximab, eventually culminating in a substantially higher rate as full-dose streptokinase was combined with abciximab even in the absence of heparin. Approximately two thirds of hemorrhages were at instrumented sites. The overall rate of intracerebral hemorrhage was 1.1%; no important differences in this complication were observed among reperfusion regimens. The overall rates for mortality, recurrent MI, and development of severe pump failure were 4%, 3%, and 1%, respectively, with no major differences observed across groups. Revascularization for severe recurrent ischemia was performed in 31% of patients overall but was highest in the abciximab-alone group at 59%. Similarly, the rate of rescue PTCA, which was 19% overall, was highest in the abciximab-alone group, at 41%. Thrombocytopenia occurred in 5 (3%) of the 163 patients in the alteplase-alone control group and in 30 (6%) of the 514 patients who received a reperfusion regimen containing abciximab (P=NS). Severe thrombocytopenia (<50 000/mL) occurred in 1 (0.6%) of the 163 patients in the alteplase-alone control group and in 6 (1.2%) of the 514 patients who received a reperfusion regimen containing abciximab (P=NS).


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  		Table 3. Clinical Events Through 30 Days: Dose-Finding Phase


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  		Table 3B. Continued

Figure 6Down depicts the safety experience in the cohort of patients collectively enrolled in the control alteplase arm compared with the collective experience in the 50-mg alteplase plus abciximab combined with low-dose and very-low-dose heparin regimens. The rate of major hemorrhage was 6% in the alteplase-alone control group, 7% in the low-dose heparin group, and 1% in the very-low-dose heparin group; mortality rates were 3%, 5%, and 0%, respectively.



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  		Figure 6. Safety observations with selected reperfusion regimens. Stacked bar graph on left shows rate of major hemorrhage (divided into intracranial hemorrhage [ICH], spontaneous [Spont], and instrumented [Instr] categories) for patients in the 100-mg alteplase control regimen in combination with standard-dose (STD) heparin vs patients in 50-mg alteplase regimen in combination with abciximab (Abx) and either low-dose or very-low-dose heparin. Mortality rate in same 3 groups is depicted on right.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowAppendix 1
 down arrowReferences
 
The thrombus obstructing the infarct-related artery in ST-elevation MI consists of multiple elements, including platelets, thrombin, and a fibrin mesh. The dynamic interplay between factors promoting thrombosis versus those promoting thrombolysis is shifted in favor of thrombosis. Although thrombolytic agents target the fibrin mesh component of the thrombus, their use is associated with both heightened thrombin activity and platelet activation.27 28 29 Thrombin not only promotes further thrombus deposition but is one of the most potent stimuli for activation of platelets.30 In response to stimulation by thrombin, platelets express GP IIb/IIIa receptors on their surface, promoting cross-linking by ligands such as fibrinogen, thereby providing a greater surface area for formation of the prothrombinase complex and additional thrombin generation.9 Other consequences of platelet activation that promote thrombus formation include release of plasminogen activator inhibitor-1 (PAI-1) and vasoconstrictor substances.9 Thus, the platelet-rich thrombus is not only more resistant to thrombolysis, but additional platelet activation after initially successful thrombolysis may promote reocclusion. From a mechanistic perspective, a powerful antiplatelet agent used in combination with a thrombolytic agent not only offers the potential for enhancing thrombolysis and reducing the risk of reocclusion but also permits this to be accomplished with reduced doses of thrombolytics and heparin.

The evaluation in TIMI 14 of various reperfusion regimens to achieve TIMI 3 flow lends strong support to the hypothesis that GP IIb/IIIa inhibition with abciximab may play an important role in reperfusion of thrombotically occluded coronary arteries. It is now well established that the principal goal of reperfusion regimens is to achieve a high rate of TIMI 3 flow, which maximizes the mortality reduction achieved in patients with ST-elevation MI.31 Abciximab alone produced TIMI 3 flow rates that exceeded previously reported rates for patients receiving aspirin and heparin either before administration of thrombolytics or in preparation for primary angioplasty.21 32 The TIMI 3 flow rates with abciximab alone were similar to those previously reported for full-dose streptokinase alone.1 21 When abciximab was combined with doses of streptokinase that did not result in unacceptable bleeding risks, modest increases in TIMI 3 flow were observed compared with full-dose streptokinase alone in previous studies.1 21

Of particular importance is the observation that abciximab augmented the rate and extent of thrombolysis with reduced doses of alteplase. The increase in TIMI 3 flow at 60 minutes from 43% with alteplase alone to 72% using a 50-mg regimen of alteplase over 60 minutes combined with abciximab represents a 67% relative increase and a 29% absolute difference in TIMI 3 flow rates.

On the basis of data from angiographic observations at 90 minutes, it may be estimated that a 20% absolute increment in TIMI 3 flow must be observed to translate into a 1% absolute mortality reduction mediated via enhanced reperfusion of the infarct-related artery and myocardial salvage.1 33 The absolute increment in TIMI 3 flow observed with the 50-mg alteplase-plus-abciximab regimen compared with the 100-mg accelerated-dose alteplase regimen exceeded the predicted 20% minimum at 60 minutes. Further evidence of the substantial improvement in flow in the infarct-related artery is the near normalization of the TIMI frame count in the 50-mg alteplase-plus-abciximab regimen by 60 minutes.

Insight into the mechanism of facilitation of thrombolysis when abciximab is combined with alteplase may be gained by considering the multiple effects of abciximab on clot formation and structure. Inhibition of GP IIb/IIIa receptors prevents aggregation of platelets, leading to reductions in both thrombus mass and the platform for further thrombin generation.9 Evidence exists that abciximab inhibits the release reaction from platelet-dense granules and {alpha}-granules, leading to a decrease in the local concentration of inhibitors of thrombolysis such as PAI-1 and {alpha}-2 plasma inhibitor.34 Clot structure is weakened by the ability of abciximab to block binding of activated factor XIII to platelets, diminishing cross-linking of fibrin strands and of {alpha}-2 plasma inhibitor to fibrin.35 Platelet-mediated clot retraction and gel elastic modulus are also reduced.36 37 38 By diminishing the tendency to thrombus growth and increasing clot porosity, abciximab may promote penetration of thrombolytic agents deeper into the clot, allowing more rapid and more extensive thrombolysis.9

The effects of abciximab on clot formation and structure noted above likely contributed to the enhanced coronary blood flow observed with reduced doses of alteplase (Table 2Up). When combined with abciximab, administration of only half the usual 100-mg dose of alteplase produced significantly higher rates of TIMI 3 flow. Of note, alteplase regimens of a bolus alone or a bolus and short infusion (30 minutes) did not appear to be as effective as regimens that used a bolus and longer infusion (60 minutes). These data suggest that even in the presence of abciximab, a sufficient concentration of a thrombolytic agent must be maintained for a long-enough period to enhance lytic efficiency. In the case of an agent with a relatively short plasma half-life, such as alteplase, this requires a more protracted infusion.

Safety Considerations
When used with low-dose heparin, abciximab and reduced-dose alteplase were associated with a bleeding risk similar to standard thrombolytic therapy. However, a larger sample size from registries and phase III trials is needed for a more statistically robust estimate of the risk of intracranial hemorrhage with the new reperfusion regimen. Very-low-dose heparin regimens consisting of an {approx}50% reduction in the initial bolus and 75% reduction in the initial infusion rate compared with standard weight-adjusted regimens may decrease the risk of bleeding even further. The low rate of major hemorrhage in the very-low-dose heparin group in TIMI 14 underscores the need for continued evaluation of the optimum dose of heparin when new reperfusion regimens for ST-elevation MI are being developed. On the other hand, streptokinase in combination with abciximab showed dose-related bleeding, ultimately producing unacceptable risks of bleeding when full-dose streptokinase was administered, even when heparin was omitted from the reperfusion regimen. The increased risk of major bleeding when streptokinase was administered with abciximab in TIMI 14 and when streptokinase was administered with eptifibatide by other investigators39 suggests that the combination of streptokinase with GP IIb/IIIa inhibitors may be associated with increased risk of bleeding. A likely explanation for this observation is the more profound systemic disturbances of the hemostatic system and generation of fibrinogen degradation products that occur with a less fibrin-specific thrombolytic agent such as streptokinase compared with alteplase.

Clinical Implications
The reperfusion era in the treatment of MI began with streptokinase, and the next major advance was the introduction of alteplase, first in the standard-dose regimen21 and later in the accelerated-dose regimen.25 33 Newer thrombolytics are clearly more convenient and can be delivered either as a single40 41 or double bolus42 but appear to be comparable to accelerated-dose alteplase. The angiographic data from TIMI 14 strongly suggest that abciximab in combination with a reduced dose of a thrombolytic represents a further advance in reperfusion therapy.


*    Acknowledgments
 
This study was supported by a grant from Centocor (Malvern, Pa) and Eli Lilly, Inc (Indianapolis, Ind).


*    Footnotes
 
1 Additional contributing authors were Elliot Barnathan, MD, Harlan Weisman, MD, and the TIMI 14 Investigators and Research Coordinators (see Appendix). Back


*    Appendix 1
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *Appendix 1
down arrowReferences
 
TIMI 14 Participants
Study Chairman's Office
Harvard Medical School, Brigham and Women's Hospital, Boston, Mass. Study Chairman: Eugene Braunwald, MD; Principal Investigator: Elliott M. Antman, MD; Project Director: Carolyn H. McCabe, BS; Coinvestigator: Robert P. Giugliano, MD, MS.

Leuven Coordinating Center
Leuven, Belgium. European Cochairman: Frans Van de Werf, MD, PhD; Coinvestigator: Patrick Coussement, MD.

Angiographic Core Laboratory
West Roxbury, Mass. Principal Investigator: C. Michael Gibson, MD, MS; Quantitative Angiography Technician: Kathryn Ryan, BS; Data Manager: Sabina Murphy, MPH.

Sponsors
Centocor, Malvern, Pa: Keaven Anderson, PhD, Elliot Barnathan, MD, Richard P. Schwarz, Jr, PhD, Ann Wang.

Eli Lilly, Inc, Indianapolis, Ind: Joel Scherer, MD, Shirley Paddock, RPh, Kimberly Hadley, BS.

Data Coordinating Center
COVANCE, Princeton, NJ. Global Program Director: Lillian Dampman, PhD; Project Director: Kevin Vernarec; Project Manager–Europe: Olive Fogarty; Director of Statistics–Nashville: Ramesh Amatya, PhD; Statistician: Steven Zweig; Site Coordinator: Patti Sciarrotta; Clinical Research Associates: Dipali Nanavati, CCRA; Kevin Dopke, MS; Senior Project Associate, Drug Management Systems: Erik Hostert.

Drug Distribution Center–North America
COVANCE Pharmaceutical Packaging Services, Allentown, Pa. Senior Clinical Coordinator: Margie Schneider; Distribution Coordinator: Charles Rissmiller.

Drug Distribution Center–Europe
PENN Pharmaceuticals, Gwent, United Kingdom. Project Manager: Debbie Williams.

Operations Committee
Chairman: Eugene Braunwald, MD. Other members: individuals from the Study Chairman's Office, Leuven Coordinating Center, Sponsors, and Data Coordinating Center.

Steering Committee
The members of the steering committee include the members of the Operations Committee and the principal investigators from the TIMI 14 clinical centers and the Angiographic Core Laboratory.

Clinical Centers in Order of Number of Patients Enrolled (Principal Investigator is First Individual Listed)
United States (372 patients)
Methodist Hospital and Ben Taub Hospital, Houston, Tex: Neal S. Kleiman, MD; research coordinator, Kelly Maresh, RN. Iowa Heart Center/Mercy Hospital Medical Center, Des Moines, Iowa: Magdi G.H. Ghali, MD; research coordinator, Teresa Coulson. Montefiore Medical Center, Bronx, NY: Coinvestigators, Mark Greenberg, MD; Hiltrud Mueller, MD; research coordinators, Joseph Cosico, RN; Kelly Schneider, RN. Baystate Medical Center, Springfield, Mass: Marc J. Schweiger, MD; research coordinator, Barbara Burkott, BSN, RN. Sarasota Memorial Hospital, Sarasota, Fla: Martin J. Frey, MD; research coordinator, Holly Taylor, RN. Rhode Island Hospital, Providence, RI: George McKendall, MD; research coordinators, Mary Jane McDonald, RN; Janet Raymond; Mary Grogan, RN. Alta Bates Medical Center, Berkeley, Calif: Robert M. Greene; research coordinators, Eileen Healy, RN; Vickie Perry, RN. Robert Wood Johnson Medical School, New Brunswick, NJ: Sebastian T. Palmeri, MD; research coordinator, Laurie Casazza, RN. Maine Medical Center, Portland, Me: Costas T. Lambrew, MD; research coordinator, Susan Bosworth-Farrell, RN. St. Luke's-Roosevelt Hospital Center, New York, NY: Coinvestigators, Judith S. Hochman, MD; James Slater, MD; research coordinators, Mary McAnulty, RN; Jeanine Libert, Dorothy Burch. Massachusetts General Hospital, Boston, Mass: Ik-Kyung Jang, MD; research coordinator: Jeanne Melley, RN. The Mount Sinai Medical Center, New York, NY: Srinivas Duvvuri, MD; research coordinators, Denise Ratner, Pauline Humphries, Eppie Brown, Traci King. Columbia/JFK Medical Center, Atlantis, Fla: Joshua Keival, MD; research coordinator, Jill Kinley, ARNP; Jamie Kosik. Broward General Medical Center, Ft. Lauderdale, Fla: Alan L. Niederman, MD; research coordinator, Terri Kellerman. LDS Hospital, Salt Lake City, Utah: Principal investigators, Jeffrey L. Anderson, MD; J. Brent Muhlestein, MD; research coordinators, Ann Allen, RN; Staci Hall. Sacred Heart Health System, Pensacola, Fla: Andrew Kees, MD; research coordinator, Elizabeth Steck, RN, BSN. Utah Valley Regional Medical Center, Provo, Utah: Charles F. Dahl, MD; research coordinator, Michelle LeBaron. University of Vermont, Burlington, Vt: Matthew W. Watkins, MD; research coordinator, Michaelanne Rowen, RN. John L. McClellan Veteran's Memorial Hospital, Little Rock, Ark: J. David Talley, MD; research coordinators, Millie Rawert, BSN; Mindy Dearen. Sharp Memorial Hospital, San Diego, Calif: David G. Marsh, MD; research coordinators, Beth Penny, RN; Sue Harte, CFNP. Saint Francis Medical Center, Proctor Hospital, Peoria, Ill: Paul J. Schmidt, MD; research coordinator, Cindy Ness, RN. Lancaster General Hospital, St Joseph Hospital, Lancaster, Pa: Paul N. Casale, MD; research coordinator, Lisa Hollywood, RN. Brigham and Women's Hospital, Boston, Mass: Robert Piana, MD; research coordinators, Michele Po, Ed Chao. Medical College of Virginia Hospitals of VCU, Richmond, Va: George W. Vetrovec, MD; research coordinator, Roberta P. O'Brien. University of Alabama, Birmingham, Ala: William Rogers, MD; research coordinators, Nancy L. Grady, RN; Kerri Mulrooney, RN. University of Miami/Jackson Memorial Hospital, Miami, Fla: R.F. Sequeira, MD; research coordinators, Gayatri Girwar, MD; Sergio Medrano, MD. Lakeland Regional Medical Center, Lakeland, Fla: Kevin F. Browne, MD; research coordinators, Beth Evans, Mary Telatnik, RN. Munroe Regional Medical Center, Ocala, Fla: Robert L. Feldman, MD; research coordinator, Brandi Merchant, LPN. Winthrop University Hospital, Mineola, NY: Richard M. Steingart, MD; research coordinator, Suzanne Bilodeau-Parker, RN. The Ohio State University Medical Center, Columbus, Ohio: Raymond D. Magorien, MD; research coordinators, Laurie McCloud-Clouse, RN; Ann Marie Nordgren, RN. Baptist Hospital, Pensacola, Fla: William Pickens, MD; research coordinator, Elizabeth Steck, RN, BSN. Pitt County Memorial Hospital, Greenville, NC: Joseph Babb, MD; research coordinators, Carmen R. Corbitt, RN, BSN, CCRN; Doris R. Francis, RN. Trinity Mother Frances Hospital, Tyler, Tex: Frank Navetta, MD; research coordinator, Greg Murphy, RPh. St. Elizabeth's Medical Center, Boston, Mass: Douglas, M. Losordo, MD; research coordinators, Suzanne Farley-Keane, RN; Kathleen Osborne. Geisinger Medical Center, Danville, Pa: James C. Blankenship, MD; research coordinator, Saundra L. Demko.

Belgium (120 patients)
Universitair Ziekenhuis Gasthuisberg, Leuven: Coinvestigators, Frans Van de Werf, MD, PhD; Patrick Coussement, MD; research coordinator, Patrick Coussement, MD. Dienst Hartcatheterisatie, Ziekenhuis Oost-Limburg, Genk: Mathias Vrolix, MD; research coordinator, LieveVan Dienst. Algemeen Ziekenhuis, Brugge: Etienne Van der Stichele, MD; research coordinator, Joerl Voet, MD. Onze Lieve Vrouwe Ziekenhuis, Aalst: Guy Heyndrickx, MD; research coordinator, Frank Staelens. Cliniques Universitaires St. Luc, Bruxelles: Jaques Col, MD; research coordinator, Reine Lauwers. Imeldaziekenhuis, Bonheiden: Guido Verstreken, MD; research coordinator, Marcel Cuypers.

France (116 patients)
Hopital Tenon, Paris: Alec Vahanian, MD; research coordinator, Reza Farnoud. Hopital St. Jacques, Besancon: Jean Pierre Bassand, MD; research coordinator, Denis Pales Espinosa. Center de Hospitalier Universitaire de Caen, Caen: Giles Grollier, MD; Coinvestigator, Emmanuel Lecluse, MD; research coordinator, Mireille Bourse. Center Hospitalier Universitaire Pontchaillou, Rennes: Herve LeBreton, MD; research coordinator, Heautot Herve Le Breton.

United Kingdom (107 patients)
Royal Victoria Hospital, Belfast: Coprincipal investigators, A.A. Jennifer Adgey, Ian Menown; research coordinators, Bernie Smith, Leslie Swailes. Western Infirmary, Glasgow: W. Stuart Hillis, MD; coinvestigators, Douglas Muir, MD; Gerard McCann, MD.

Germany (89 patients)
Medizinische Klinik II, Mainz: Hans-Jürgen Rupprecht, MD; research coordinator, Felix Post, MD. Universitats-Krankenhous Eppendorf, Hamburg: Chrispoh A. Nienaber, MD; research coordinator, Tim Rehders, MD. Klinikum der Stadt Ludwigshafen, Ludwigshafen: Ralph Zahn, MD; research coordinator, Caroline Bergmeier, MD. Klinikum Sud, Nurnberg: Martin Gottwik, MD; research coordinator, Riego, MD. Medizinische Klinik, I, Aachen: Jürgen Vom Dahl, MD; research coordinator, Christian Koch, MD. Klinik fur Kardiologie, Munchen: Rainer Von Essen, MD; research coordinator, Axel Reimer, MD.

Netherlands (58 patients)
OLVG afdeling Cardiologie, Amsterdam: R. Van der Wieken, MD; Coinvestigator, Arthur Scholte, MD; research coordinator, Gerde Kuiper. Afdeling Cardiologie, Eindhoven: Herman Rudolf Michels, MD; research coordinators, Henricus Heymen, MD; Muriel Van Tol, MD.

Canada (26 patients)
University of Manitoba Health Sciences Center, Winnipeg, MB: John Ducas, MD; research coordinator, Usha Schick. CUSE-Site Fleurimont, Sherbrooke, QC: Vincent Dangoisse, MD; research coordinator, Jackie Dangoisse. Mount Sinai Hospital, Toronto, ON: Allan G. Adelman, MD; research coordinator, Susan Webber. Royal Columbian Hospital, New Westminster, BC: Coinvestigator, Mark Henderson, MD; R.A. Kuritzky, MD; research coordinators, Karen Stevens, Karen Wedding.

Received November 9, 1998; revision received March 22, 1999; accepted March 23, 1999.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 up arrowAppendix 1
 *References
 

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