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(Stroke. 2000;31:601.)
© 2000 American Heart Association, Inc.
Original Contributions |
Abciximab in Acute Ischemic Stroke
A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study
From the Department of Neurology, University of Iowa, Iowa City, and the Department of Neurology, CHUV, Lausanne, Switzerland.
Correspondence to H.P. Adams, Jr, MD, Department of Neurology, University of Iowa, Iowa City, IA 52242-1053. E-mail julien.bogousslavsky{at}chuv.hospvd.ch
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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Background and Purpose—Abciximab is a potent parenterally administered platelet glycoprotein IIb/IIIa antagonist. Because this agent has been shown to improve outcomes in coronary artery disease, there is interest to evaluate whether it could improve cerebral perfusion and outcomes after ischemic stroke. This study was designed to evaluate the safety of abciximab in acute ischemic stroke and to obtain pilot efficacy data.
Methods—We conducted a randomized, double-blind, placebo-controlled, dose-escalation trial. Seventy-four eligible and consenting patients presenting within 24 hours after ischemic stroke onset at 38 study sites were randomly allocated to receive either an escalating dose of abciximab (54 patients) or placebo (20 patients) in a ratio of 3:1. We studied 4 escalating doses of abciximab. Patients underwent a scheduled follow-up head CT scan 24 to 36 hours after the completion of study agent administration to monitor for bleeding complications and were evaluated through 3 months.
Results—There were no cases of major intracranial
hemorrhage. Asymptomatic parenchymal
hemorrhages were detected on post–study agent CT in 4 of 54
abciximab patients (7%) and in 1 of 20 placebo patients (5%). Six
additional abciximab patients had asymptomatic hemorrhagic
lesions detected by unscheduled brain imaging during their follow-up
period. Nine of 11 patients with asymptomatic
hemorrhage had a baseline National Institutes of Health Stroke
Scale score >14. At 3 months, there was a trend toward a higher rate
of minimal residual disability (Barthel Index 
95 or modified Rankin
scale 
1) among abciximab patients compared with those who received
placebo.
Conclusions—Abciximab appears to be safe when administered up to 24 hours after stroke onset, and it might improve functional outcome.
Key Words: platelet aggregation inhibitors • randomized controlled trials • stroke, ischemic
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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Intravenous recombinant tissue plasminogen activator (rtPA) is the only approved treatment for ischemic stroke in the United States and Canada. Although it is efficacious, the practical use of this agent is limited by the short treatment window of 3 hours from stroke onset and the risk of symptomatic parenchymal hemorrhage.1 2 3 4 5 Anticoagulants are not effective in this setting and may increase the risk of parenchymal hemorrhage.6 7 8 Thus, there is a need for safer therapy in patients presenting within 3 hours of onset and for safe and effective therapy in patients presenting beyond 3 hours from stroke onset. Recent clinical trials suggest that aspirin started within 48 hours of stroke onset may improve outcomes.7 9 Although these studies demonstrated a modest benefit of aspirin, they raise the issue that a more potent antiplatelet agent started within a few hours of stroke onset may be more effective.
Abciximab (ReoPro) is the Fab fragment of a chimeric human/mouse
monoclonal antibody directed against the platelet
glycoprotein IIb/IIIa (GP IIb/IIIa) receptor, the final
mediator of aggregation.10 Abciximab, in combination with
aspirin and adjusted-dose heparin, is approved for the prevention of
ischemic complications in patients undergoing
percutaneous coronary interventions and in
those with unstable angina not responding to conventional medical
therapy when a percutaneous coronary
intervention is planned within 24 hours.11 12 13 14 The
approved regimen consists of an intravenous bolus dose of
0.25 mg/kg followed by a continuous infusion of 0.125 µg ·
kg-1 · min-1
(maximum 10 µg/min) for 12 hours. This regimen immediately induces an
80% blockade of GP IIb/IIIa receptors, a reduction of ADP-induced
platelet aggregation to <15% of pretreatment levels, and
prolongation of the bleeding time to >30 minutes.15 16
These hemostatic effects persist for 4 to 6 hours after termination of
the intravenous infusion, and platelet function
gradually recovers over the next 24 to 48 hours.15 16
Abciximab is not specific for GP IIb/IIIa and exhibits cross-reactivity
with other integrins, such as
vß3 and
Mac-1.17 18
Angiographic studies in acute myocardial infarction have shown that the
combination of abciximab, aspirin, and adjusted-dose heparin reopens
40% to 50% of occluded coronary
vessels.19 20 21 Also, in the setting of myocardial
infarction, the combination of abciximab, aspirin, and adjusted-dose
heparin, supplemented by a reduced dose of rtPA or reteplase, yielded
coronary patency rates >80% (ie, Thrombolysis in
Myocardial Infarction [TIMI] flow II or III).19 20
Additional data suggest that GP IIb/IIIa antagonists may
improve flow in both the coronary and cerebral
microcirculations.22 23 24
In view of the success of abciximab in the treatment of acute coronary artery lesions, interest has grown in the use of this agent in acute ischemic stroke. There are also anecdotal reports of the successful use of this agent in cerebrovascular interventional procedures.25 26 However, the safety of abciximab in acute ischemic stroke has not been established. In the percutaneous coronary intervention trials, intracranial hemorrhage (ICH) occurred infrequently, with average rates of 0.15% and 0.10% among abciximab and placebo patients, respectively.11 12 13 14 We therefore performed a randomized, double-blind, placebo-controlled, dose-escalation study of abciximab in patients with acute ischemic stroke. This study examined safety in a broad range of stroke patients, including those presenting up to 24 hours from onset. Although efficacy trials with this agent will most likely focus on a narrower time interval from stroke onset, ie, 6 hours, obtaining safety data in a broader interval provides additional reassurance and would be important for possible extension of the therapeutic window beyond 6 hours in the future.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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Study Objectives
The primary objective of the study was to evaluate the risk of fatal and nonfatal major ICH within 5 days after treatment. The main secondary objectives were to assess (1) the rate of asymptomatic parenchymal hemorrhage detected by CT 24 to 36 hours after the end of treatment with study agent; (2) the rate of all ICHs through 3 months; (3) the rates of stroke progression, systemic hemorrhage, and thrombocytopenia within 5 days of treatment; (4) the rates of neurological improvement at 5 days and 3 months; (5) the rates of recurrent strokes within 3 months; and (6) disability outcomes at 3 months.
Patients
The study population consisted of adult ischemic stroke
patients evaluated within 24 hours from stroke onset at 38
participating sites (26 in the United States and 12 in Europe). The
interval from stroke onset was defined as the time elapsed between the
first symptoms and randomization. For patients whose stroke started
during their sleep, the time of onset was defined as when the patient
was last known to be intact. All patients had a head CT before
randomization and had to have a minimum National Institutes of Health
Stroke Scale (NIHSS) score of 4.27 Other reasons for
exclusion and the number of patients excluded in each category are
listed in the Results section. Patients could have >1 reason for
exclusion. Written informed consent was obtained for all study
participants.
Randomization and Dosing Regimens
Four dose tiers of abciximab were evaluated against placebo in a
dose-escalating sequence (Figure 1
). A
separate randomization was performed within each of the 4 strata
defined by time from stroke onset (<12 hours or 12 to 24 hours) and
stroke severity (prerandomization NIHSS score 4 to 14 or >14). If a
randomized patient was not treated, an additional patient was
randomized to balance the treatment experience of the trial. Before
dose escalation occurred, patients in all strata had to be enrolled at
a given dose tier. There was no stratification by study site.
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Treatment allocation was obtained by contacting a 24-h/d interactive
voice-response system located at the Randomization Center. Based on the
prespecified stratification criteria, each patient was assigned a study
agent kit containing either abciximab or an identical-appearing
placebo. The study agent was administered as an intravenous
bolus given over 1 minute during the first 2 dose tiers of the
study, whereas the bolus was followed by a 12-hour continuous
intravenous infusion for the last 2 dose tiers (Figure 1
). The day of randomization was defined as day 0.
Assessments
Neurological status was assessed by the NIHSS at baseline (ie,
prerandomization), daily until day 5 or hospital discharge if sooner,
and at 3 months (±14 days). The trial mandated a
non–contrast-enhanced head CT scan 24 to 36 hours after the end of
study agent administration. Additional brain imaging studies were
performed at the discretion of the treating physician, including for
cases of new or worsening neurological symptoms. Data on the reasons
for the additional scans were not collected. Patients underwent
telephone-based interviews at 10 days and 6 weeks after
randomization and had a clinic visit at 3 months. Disability outcomes
were rated according to the modified Rankin scale and Barthel Index
scores at 3 months.28 29 Laboratory surveillance included
platelet counts daily through day 3 and hemoglobin and hematocrit
measurements on day 1 and day 5.
End-Point Definitions
Fatal ICH was defined as autopsy- or imaging-confirmed
hemorrhage assessed to be the primary cause of death. Nonfatal
major ICH was defined as either symptomatic parenchymal
hemorrhage or CT evidence of
intraventricular, subdural, or subarachnoid
hemorrhage, with or without clinical symptoms.
Symptomatic parenchymal hemorrhage was defined as
CT-documented bleeding either in the area of the qualifying stroke and
causally related to neurological deterioration (4 points worsening on
the NIHSS compared with the previous examination or by global clinical
assessment) or in a different vascular territory and associated with
new neurological deficit. Asymptomatic hemorrhagic
transformation was defined as CT-documented bleeding in the area of the
qualifying stroke without neurological deterioration ascribed to the
bleeding. Nonintracranial hemorrhage was
assessed by the TIMI criteria.30 Thrombocytopenia was
classified as moderate (<100 000/mm3 and a 25%
decrease from baseline value) or severe
(<50 000/mm3). Stroke progression was defined
as neurological deterioration in the absence of ICH. Recurrent stroke
was defined as recurrence of neurological deficit within the
infarct territory after day 5 or deficit in a newly involved territory
at any time during the study without ICH or other causes for the
neurological symptoms. Neurological improvement was assessed at day 5
and 3 months and defined as either a 4-point improvement on the NIHSS
compared with the prerandomization score, an NIHSS score of 0, or
global clinical impression.
Ancillary Care
Patients were admitted to a monitored bed or skilled care unit
for the first 24 hours after randomization. They received customary
local care for treatment of their stroke, including rehabilitation and
management of comorbid diseases. Antiplatelet agents, NSAIDS, or
anticoagulants could not be administered until after the results of the
24- to 36-hour post–study agent CT were available. Subsequent therapy
for secondary prevention was at the discretion of the local
physician.
Safety Monitoring
An External Safety Monitoring Board (ESMB) composed of
clinicians and scientists not otherwise involved in the study reviewed
safety data before escalation to the next dose tier and after each
potential major ICH. Mandatory enrollment pauses were instituted before
dose escalation and after each potential major ICH, pending ESMB
review. These safety reviews were conducted without knowledge of
treatment assignment, but the ESMB had the prerogative to become
unblinded, if necessary. Upon ESMB recommendation, the Steering
Committee would either approve dose escalation, continue enrollment in
an ongoing dose tier, or halt/stop enrollment. The chairperson of the
Steering Committee, unaware of treatment allocation, reviewed all
expedited reports of serious adverse experiences in an ongoing
fashion.
Avoidance of Bias
All CT scans were reviewed by an independent neuroradiologist
blinded to treatment allocation, time period of the examination, and
clinical data. MRI studies performed outside the protocol to
investigate possible outcome events were also reviewed in a blinded
fashion by the same neuroradiologist. An independent reviewer
adjudicated all cases of death, ICH, stroke progression, and recurrent
stroke without knowledge of treatment allocation. Another independent
reviewer adjudicated cases of thrombocytopenia without knowledge of
treatment allocation. Results of these adjudicated reviews only were
used for final data analyses.
Statistical Analysis
Data from all sites were pooled by treatment within each dose
tier. Data from placebo patients in all dose tiers were pooled
together. Analyses were performed on the intent-to-treat
population consisting of all randomized patients, irrespective of
whether they received any study agent. Fisher’s exact test was used
for all statistical hypothesis testing. Subgroup analyses of
safety or efficacy based on either of the stratification variables
were not performed in view of the small sample size of the study.
Patients who died were assigned the worst score on all measurement
scales. Subgroup analyses for either safety or efficacy based
on either of the stratification variables (severity of stroke or
interval from stroke) were not performed because of the small numbers
of patients enrolled in the groups. A regression model with length of
stay as the dependent variable and age, sex, baseline NIHSS score,
time from stroke onset to randomization, and treatment received as the
independent variables was used to examine the effect of abciximab
on length of hospital stay.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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Between February and November 1998, 3440 patients were evaluated for possible enrollment in the study (Figure 1
). A total of 3177
patients were excluded for 1 of the following reasons: NIHSS <4
(1293 patients); American patients 3 hours from stroke onset or any
patient with stroke onset >24 hours earlier (749 patients); hemostatic
defect or increased hemorrhagic risk (418 patients); severe illness or
disability (383 patients); stratum complete for given dose tier or
enrollment pause for ESMB evaluation (364 patients); need for
antiplatelet agent, NSAID, or anticoagulant (89 patients); stupor
or coma (88 patients); participation in another trial (64 patients);
suspected subarachnoid hemorrhage (44 patients);
hypertension (37 patients); hypodensity involving the entire MCA
territory (21 patients) or mass effect (14 patients) on baseline CT;
cerebral venous thrombosis (14 patients); vasculitis (11 patients);
suspected septic embolism (5 patients); pregnancy or lactation (3
patients); unavailability of study agent at site (10 patients); alcohol
abuse or illicit drugs (2 patients); and previous administration of
abciximab (1 patient). Informed consent was obtained from 74 of the
remaining 263 eligible patients, 54 of whom were allocated to receive
abciximab and 20 to the placebo group.
Twenty-seven of 38 participating sites (71%) enrolled the 74 study
patients; 18 of these sites were in the United States and 9 in Europe.
Forty-nine patients were enrolled in the United States and 25 in
Europe. The baseline characteristics of the study patients, including
demographic variables, risk factors, and stroke features, are
described in Table 1. The average
age of the total study population, consisting of all abciximab and
placebo patients, was 66±15 years. There was no racial imbalance or
difference in mean body weight and blood pressure among the patient
groups. The majority of patients had cortical lesions involving the MCA
territory, and 50% had signs of early infarction on baseline CT. A
higher proportion of placebo than abciximab patients had cortical
lesions. Thirty-six of 74 patients (49%) had left-sided brain lesions,
37 (50%) had right-sided lesions, and 1 (1%) had bilateral
lesions.
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The median time since stroke onset for all 74 patients was 12 hours (range, 2 to 23 hours), and the median baseline NIHSS score was 15 (range, 4 to 25). The mean and median times from stroke onset to start of study agent for all 70 patients who received study agent were 13±6 hours and 12 hours, respectively (range, 2 to 24 hours). Seven of 74 patients (9%) had a baseline NIHSS score >20. The median time after stroke onset was longer in the 0.15-mg/kg bolus group than in the other abciximab dose groups and placebo patients. Two patients were treated within 3 hours of stroke onset: 1 abciximab patient in the 0.25-mg/kg bolus plus infusion group and 1 placebo patient. Four patients, 2 in the abciximab 0.15-mg/kg bolus group and 2 in the placebo group, did not receive study agent. In 1 abciximab and 2 placebo patients, the blood pressure became unacceptably high after randomization and could not be stabilized to initiate treatment within the planned time window. The fourth patient, in the abciximab group, inadvertently received a single 5-mg dose of warfarin in the interval between randomization and starting study agent. No patients were lost to follow-up.
Safety Outcomes
Twelve patients (16%) died during the course of the study:
2 within the first 5 days and 10 between day 6 and 3 months (Table 2). Nine of 54 abciximab patients (17%)
and 3 of 20 placebo patients (15%) died. The causes of death among
abciximab patients were as follows: direct consequence of the
qualifying stroke (3 patients at days 1, 5, and 7); sudden cardiac
death (1 patient at day 14); pneumonia (3 patients at days 13, 30, and
70); and withdrawal of life support after major sequelae from a very
severe initial stroke (2 patients at days 47 and 64). The 3 deaths
within the first week of enrollment were the result of brain edema
among patients with very severe strokes. The causes of death among
placebo patients were sudden cardiac death (2 patients at days 11 and
49) and pneumonia (1 patient at day 37). None of the deaths were judged
to be due to the study agent or ICH.
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There were no identified cases of fatal or nonfatal major ICH within either 5 days or 3 months of randomization. In a single instance, a local investigator judged 1 patient as having symptomatic parenchymal hemorrhage, but the patient’s scores on the NIHSS did not worsen. The blinded reviewer subsequently adjudicated this event as an asymptomatic hemorrhagic transformation of the infarction.
Asymptomatic parenchymal hemorrhages were detected on the post–study agent head CT in 4 of 54 abciximab patients (7%) and in 1 of 20 placebo patients (5%). One of the asymptomatic hemorrhages among abciximab patients occurred in the 0.20-mg/kg bolus dose group and 3 in the 0.25-mg/kg bolus plus infusion dose group.
Thirty-one of 54 abciximab patients (57%) and 9 of 20 placebo patients
(45%) underwent additional brain imaging studies (ie, CT or MRI)
during the course of the study. Asymptomatic hemorrhagic
lesions were detected in 6 abciximab patients on these additional
imaging studies: 1 at day 2 (0.25 mg/kg bolus plus infusion), 1 at day
3 (0.20 mg/kg bolus), 1 at day 5 (0.20 mg/kg bolus), 2 at day 6 (0.15
mg/kg bolus and 0.25 mg/kg bolus plus infusion), and 1 at day 35 (0.20
mg/kg bolus). Five of these 6 patients did not have parenchymal
hemorrhage on their post–study agent CT, and this examination
was not performed in the 0.25-mg/kg bolus plus infusion patient whose
hemorrhage was detected at day 6. Thus,
asymptomatic parenchymal hemorrhage was detected in
10 of 54 abciximab patients (19%) and in 1 of 20 placebo patients
(5%) through 3 months (P value for dose-relationship,
0.07). Five of the asymptomatic hemorrhages
occurred at the 0.25-mg/kg bolus plus infusion abciximab dose (Table 2).
The clinical characteristics and CT scan features of patients with
asymptomatic parenchymal hemorrhage are shown in
Table 3 and Figure 2, respectively. All parenchymal
hemorrhages involved areas of hemorrhagic transformation within
the original infarct. The median baseline NIHSS score for the 11
patients with asymptomatic hemorrhages was 17
(range, 9 to 23), and 9 of them had baseline scores >14 (range, 15 to
23; 4 patients had scores 20). The median time from stroke onset in
the 11 patients with asymptomatic hemorrhages was
8.5 hours (range, 1.8 to 18.1 hours), and 4 of them presented
beyond 12 hours from their stroke onset.
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Nonneurological bleeding occurred in 10 abciximab patients (19%) and in 4 placebo patients (20%). None of these hemorrhages were major. These bleeding episodes consisted of hematuria (6 patients), subcutaneous hematomas (2 patients), epistaxis (2 patients), gastrointestinal bleeding (1 patient), oropharyngeal bleeding (1 patient), and significant decreases in hemoglobin without an identifiable bleeding source (3 patients). Four of 54 abciximab patients (7%) had moderate thrombocytopenia during the first 5 days after treatment. There were no cases of severe thrombocytopenia. None of the patients with thrombocytopenia had parenchymal hemorrhage.
Efficacy Outcomes
Stroke progression during the first 5 days occurred in 6 of 54
abciximab patients (11%) and in 3 of 20 placebo patients (15%) (Table 2). Stroke recurrence during the first 3 months occurred
in 1 of 54 abciximab patients (2%) and in 1 of 20 placebo patients
(5%). There were no notable differences in overall neurological
improvement at day 5 and at 3 months between the 2 treatment groups,
except for the higher number of abciximab patients with NIHSS score 0
to 1 at day 5 (Table 2). However, differences in functional
outcome were observed between abciximab and placebo patients. Nineteen
of 54 abciximab patients (35%) and 4 of 20 placebo patients (20%) had
minimal residual disability (modified Rankin scale score 1) at 3
months. Twenty-seven of 54 abciximab patients (50%) and 8 of 20
placebo patients (40%) had Barthel index scores 95 at 3 months.
Length of Hospital Stay
A regression model adjusting for age, sex, baseline NIHSS, and
time from stroke onset showed a nonsignificant reduction in mean length
of hospital stay of 4 days in favor of abciximab (P=0.39).
The mean lengths of stay in abciximab and placebo patients were 13±16
days and 17±19 days, respectively. The median lengths of stay in
abciximab and placebo patients were 7 and 12 days, respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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This is the first in a series of planned studies to evaluate the potential usefulness of abciximab in the treatment of acute ischemic stroke. The primary objective of the study was to obtain preliminary safety data on abciximab in a broad spectrum of patients with acute ischemic stroke. Additional objectives were to select a dosing regimen for abciximab that could be evaluated in future studies and to obtain preliminary efficacy data. The stroke severity of patients in this trial compares favorably to that obtained in the National Institute of Neurological Disorders and Stroke rtPA trial, at least from the aspect of baseline NIHSS score.1
Symptomatic parenchymal hemorrhage is the most feared complication of reperfusion treatment for acute ischemic stroke. Abciximab, combined with aspirin and adjusted-dose heparin, is associated with a low risk of ICH in the setting of percutaneous coronary intervention. Before this study, there were no data on the risk of ICH after abciximab therapy for acute ischemic stroke. In this study, abciximab was used alone, without concomitant aspirin or heparin. Our results suggest that abciximab at doses used in treatment of coronary artery disease is relatively safe in acute ischemic stroke, even when a 24-hour treatment window is used.
There was a higher frequency of asymptomatic parenchymal hemorrhage in abciximab patients than in placebo patients. There was no apparent dose-relationship with abciximab for this finding, because 4 of the bleeds occurred in the 0.20-mg/kg bolus group and 5 in the 0.25-mg/kg bolus plus infusion group. The excess of total asymptomatic hemorrhages in the abciximab group might have been due in part to the higher proportion of these patients who underwent unscheduled brain imaging studies. When the rate of asymptomatic hemorrhage on scheduled post–study agent head CT is compared between abciximab patients (7%) and placebo patients (5%), the absolute difference is less striking. The majority of asymptomatic parenchymal hemorrhages occurred in patients with a baseline NIHSS score >14, an observation made in other studies.8 31 Whether these asymptomatic parenchymal hemorrhages could be a surrogate for major ICH in future trials or represent enhanced reperfusion is unknown.
Moderate thrombocytopenia occurred in 7% of abciximab patients. Thrombocytopenia is a well-recognized complication of abciximab and other GP IIb/IIIa antagonists.10 11 12 13 14 There were no adverse consequences related to this complication in this study. The differential diagnosis of thrombocytopenia in abciximab-treated patients includes true thrombocytopenia and platelet clumping.32 Although the numbers are small, the frequency of thrombocytopenia obtained in this trial was higher than that reported in the percutaneous coronary intervention trials.11 12 13 14 Whether this was a chance occurrence or because abciximab was given without concomitant aspirin or heparin is unknown and will require further evaluation.
A secondary objective of the study was to select a dose of abciximab for future studies. Data from the percutaneous coronary intervention studies provide insight on the most effective regimen of abciximab and the intensity of GP IIb/IIIa receptor blockade required to achieve efficacy. The 0.25-mg/kg bolus plus 12-hour infusion regimen has shown the best clinical efficacy in percutaneous coronary intervention, whereas a 0.25-mg/kg bolus–only dose yielded suboptimal results.11 The benefit of the 12-hour infusion may be related to passivation (ie, nonreactive state) of the vessel wall at the site of injury. We elected not to study a dose higher than the approved percutaneous coronary intervention regimen, a decision partly influenced by the observation that the dose of rtPA in stroke is lower than that in myocardial infarction. Also in myocardial infarction, a higher dose of abciximab has been associated with a higher bleeding rate.19 On the basis of these considerations, we would select the 0.25-mg/kg bolus plus 12-hour infusion regimen to be brought forward in future trials. After stroke, the infusion regimen could prevent delayed platelet aggregation in the microcirculation and reduce inflammation by binding to the Mac-1 integrin, thus halting progression of thrombosis or recurrent edema.18 23 24
Analysis of the pooled abciximab data provides some preliminary evidence that this agent might improve outcome after stroke. The proportion of patients with minimal residual disability at 90 days was higher in the abciximab group.
In summary, the results of this study suggest that abciximab deserves further evaluation in the setting of acute ischemic stroke. The absence of major ICH is encouraging. These initial results will help us in designing the most appropriate follow-up study.
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Appendix |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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Study Organization
Steering Committee
Harold P. Adams, Jr, MD (chair), University of Iowa, Iowa City, Iowa; Julien Bogousslavsky, MD (cochair), Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Elliot Barnathan, MD, Centocor Inc, Malvern, Pa; Thomas Brott, MD, Mayo Clinic Jacksonville, Jacksonville, Fla; Marc Fisher, MD, University of Massachusetts, Worcester, Mass; Anthony J. Furlan, MD, The Cleveland Clinic, Cleveland, Ohio; Carmelo Graffagnino, Duke University, Durham, NC; Jaap Kappelle, Academisch Ziekenhuis, Utrecht, Netherlands; Rashmi Kothari, MD, University of Cincinnati, Cincinnati, Ohio; Jacques R. Leclerc, MD, Lilly Research Laboratories, Indianapolis, Ind; Thierry Moulin, MD, University of Besancon, Besancon, France; John Polzer, DVM, MSc, Lilly Research Laboratories, Indianapolis, Ind; Jim Torner, PhD, University of Iowa, Iowa City, Iowa; Seth Worley, MD, Lancaster General Hospital, Lancaster, Pa.
External Safety Monitoring Board
Clarke E. Haley, Jr, MD (chair), University of Virginia Health
Sciences Center, Charlottesville, Va; James H. Day, MD, Temple
University Hospital, Philadelphia, Pa; Steven R. Levine, MD, Henry Ford
Health Science Center and Henry Ford Hospital, Detroit, Mich; John L.P.
"Seamus" Thompson, PhD, New York Neurological Institute, New York,
NY.
Adjudication of Clinical Outcome Events
David G. Sherman, MD, University of Texas Health Science Center,
San Antonio, Tex.
Adjudication of Thrombocytopenia
David C. Sane, MD, Wake Forest School of Medicine,
Winston-Salem, NC.
CT Scan Core Laboratory
Joan E. Maley, MD, University of Iowa, Iowa City, Iowa.
Principal Study Coordinators
Karla J. Grimsman, RN, University of Iowa, Iowa City, Iowa;
Malin Maeder, MD, Center Hospitalier Universitaire Vaudois, Lausanne,
Switzerland.
Randomization Center and Study Agent Management
Applied Clinical Concepts Inc, Durham, NC.
Data Management for the ESMB
William R. Clarke, PhD, Clinical Trials Data Management Center,
University of Iowa, Iowa City, Iowa.
Data Analysis and Programming
Keaven Anderson, PhD, Ruth Cook, MPH, and Susan FitzPatrick,
Biostatistics, Centocor Inc, Malvern, Pa.
Study Site Monitoring
Lilly Research Laboratories (US sites); Centocor Inc, Leiden
(European sites).
Site Principal Investigators
Number of patients enrolled per country is in parentheses.
Listing is based on number of patients enrolled per site in descending
order. Sites with equal enrollment are listed in alphabetical
order.
Belgium (3): Andre Peeters, UCL Saint-Luc, Brussels; Patrick Cras, University Hospital Antwerp, Antwerp; Serge Blecic, Hopital Erasme, Brussels; Patrice Laloux, Cliniques Universitaires de Mont-Godinne, Brussels.
France (5): Marcel Chatel, Helene Mahagne, Hopital Pasteur/St Roch, Nice; Thierry Moulin, Center Hospitalier Universitaire Jean Minjoz, Besancon.
Germany (5): Werner Hacke, Ruprecht Karls Universität, Heidelberg; H. Christoph Diener, Universität Essen, Essen.
Switzerland (4): Julien Bogousslavsky, Malin Maeder, Center Hospitalier Universitaire Vaudois, Lausanne.
Netherlands (8): L. Jaap Kappelle, Academisch Ziekenhuis Utrecht, Utrecht; Marinus Vermulen, Vincent I.H. Kwa, Academisch Medisch Centrum, Amsterdam; Cees L. Franke, Atrium Heerlen, Heerlen.
United States (49): Michael Jacoby, Mercy Ruan Neurology Clinic, Des Moines, Iowa; Richard Libman, Long Island Jewish Medical Center, New Hyde Park, NY; Chung Hsu, Washington University School of Medicine, St Louis, Mo; Rashmi Kothari, University of Cincinnati Medical Center, Bethesda North Hospital, St Elizabeth Medical Center, Francisca Hospital, Cincinnati, Ohio; Eric C. Raps and Scott E. Kasner, University of Pennsylvania Medical Center, Philadelphia, Pa; Phillip Scott, University of Michigan, Ann Arbor, Mich; Percy Karanjia, Marshfield Clinic, Marshfield, Wis; Darell Heiselman, Akron General Medical Center, Akron, Ohio; Carmelo Graffagnino, Duke University Medical Center, Durham, NC; Glenn Graham, Veterans Administration Medical Center, Albuquerque, NM; Paul T. Akins Mercy General Hospital, Sacramento, Calif; Tom Brott, James Meschia, Mayo Clinic Jacksonville, Jacksonville, Fla; Anthony J. Furlan, The Cleveland Clinic, Cleveland, Ohio; David Gordon, University of Mississippi, Jackson, Miss; Christy M. Jackson, UCSD Medical Center, San Diego, Calif; Sidney Starkman, UCLA Emergency Medical Center, Los Angeles, Calif; Robert Wityk, the Johns Hopkins Hospital, Baltimore, Md; Seth Worley, Lancaster General Hospital, Lancaster, Pa; Harold P. Adams, Jr, University of Iowa Hospitals and Clinics Medical Center, Iowa City, Iowa; John R. Belden, Maine Neurology, Portland, Me; John Dashe, Beth Israel Deaconess Medical Center, Boston, Mass; Marc Fisher, Memorial Health Care, Worcester, Mass; Camilo Gomez, University of Alabama, Birmingham, Ala; Te-Long Hwang, University of South Carolina, Columbia, SC; Draga Jichici, Allegheny University of Health Sciences, Hahnemann Division, Philadelphia, Pa; Daryl Thompson, St Louis University Health Sciences Center, St Louis, Mo.
Writing Committee
Harold P. Adams, Jr, MD, University of Iowa, Iowa City,
Iowa; Elliot Barnathan, MD, Centocor Inc, Malvern, Pa; Julien
Bo-gousslavsky, MD, Center Hospitalier Universitaire Vaudois,
Lausanne, Switzerland; Thomas Brott, MD, Mayo Clinic Jacksonville,
Jacksonville, Fla; Marc Fisher, MD, University of Massachusetts,
Worcester, Mass; Anthony J. Furlan, MD, The Cleveland Clinic,
Cleveland, Ohio; Werner Hacke, MD, Ruprecht Karls Universität,
Heidelberg, Germany; Jaap Kappelle, Academisch Ziekenhuis,
Utrecht, Netherlands; Rashmi Kothari, MD, University of
Cincinnati, Cincinnati, Ohio; Jacques R. Leclerc, MD, Lilly Research
Laboratories, Indianapolis, Ind; Thierry Moulin, MD, University of
Besancon, Besancon, France; John Polzer, DVM, MSc, Lilly Research
Laboratories, Indianapolis, Ind; Phillip Scott, MD, University of
Michigan, Ann Arbor, Mich; Jim Torner, PhD, University of Iowa, Iowa
City, Iowa.
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Acknowledgments |
|---|
This study was supported by a research grant from Centocor Inc, Malvern, Pa, and Lilly Research Laboratories, Indianapolis, Ind.
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Footnotes |
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Reprint requests to Julien Bogousslavsky, MD, Department of Neurology, CHUV CH-1011, Lausanne, Switzerland.
Elliot Barnathan is a full-time employee of Centocor Inc. Jacques R. Leclerc and John Polzer are full-time employees of Lilly Research Laboratories.
Received October 21, 1999; revision received December 20, 1999; accepted December 28, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
1. The National Institute of Neurological Disorders, and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.
2.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E,
von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, Hennerici M,
for the ECASS Study Group. Intravenous
thrombolysis with recombinant tissue
plasminogen activator for acute hemispheric
stroke. JAMA. 1995;274:1017–1025.
3.
The NINDS t-PA Stroke Study Group.
Intracerebral hemorrhage after
intravenous t-PA therapy for ischemic stroke.
Stroke. 1997;28:2109–2118.
4. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P, for the Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352:1245–1251.[Medline] [Order article via Infotrieve]
5.
Clark WM, Wissman S, Albers GW, Jhamandas JH,
Madden KP, Hamilton S, for the ATLANTIS Study Investigators.
Recombinant tissue-type plasminogen activator
(alteplase) for ischemic stroke 3 to 5 hours after symptom
onset: the ATLANTIS study: a randomized controlled trial.
JAMA. 1999;282:2019–2026.
6.
Sandercock PAG, van den Belt AGM, Lindley RI,
Slattery J. Antithrombotic therapy of acute ischemic stroke: an
overview of the completed randomized trials. J Neurol
Neurosurg Psychiatry. 1993;56:17–25.
7. Sandercock P, for the International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. Lancet. 1997;349:1569–1581.[Medline] [Order article via Infotrieve]
8.
The Publication Committee for the Trial of ORG
1072 in Acute Stroke Treatment (TOAST) Investigators. Low molecular
weight heparinoid ORG 1072 (Danaparoid), and outcome after
acute ischemic stroke: a randomized controlled trial.
JAMA. 1998;279:1265–1272.
9. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischemic stroke. Lancet. 1997;349:1641–1649.[Medline] [Order article via Infotrieve]
10.
Chong PH. Glycoprotein IIb/IIIa
antagonists in the management of
cardiovascular diseases. Am J Health Syst
Pharm. 1998;55:2363–2386.
11.
The 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.
12.
The EPILOG Investigators. Effect of the
platelet glycoprotein IIb/IIIa receptor
inhibitor abciximab with lower heparin dosages in
ischemic complications of percutaneous
coronary revascularization. N
Engl J Med. 1997;336:1689–1696.
13. The CAPTURE Investigators. Refractory unstable angina reduction of events by treatment with abciximab prior to coronary intervention. Lancet. 1997;349:1429–1435.[Medline] [Order article via Infotrieve]
14. The 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] [Order article via Infotrieve]
15.
Tcheng JE, Ellis SG, George BS, Kereiakis DJ,
Kleiman NS, Talley D, Wang AL, Weisman HF, Califf RM. Pharmacodynamics
of chimeric glycoprotein IIb/IIIa integrin antiplatelet
antibody Fab 7E3 in high-risk coronary angioplasty.
Circulation. 1994;90:1757–1764.
16.
Mascelli MA, Lance ET, Damajaru L, Wagner CL,
Weisman HF, Jordan RE. 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.
17.
Tam SH, Sassoli PM, Jordan RE, Nakada MT.
Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity
and functional blockade of glycoprotein IIb/IIIa and
vß3 integrins.
Circulation. 1998;141:1085–1091.
18. Altieri D, Edgington TS. A monoclonal antibody reacting with distinct adhesion molecules defines a transition in the functional state of the receptor CD11b/CD18 (Mac-1). J Immunol. 1998;141:2656–2660.[Abstract]
19.
Antman EM, Giugliano RP, Gibson CM, McCabe CH,
Coussement P, Kleiman NS, Vahanian A, Adgey AAJ, Menown I, Rupprecht
HJ, van der Wieken R, Ducas J, Scherer J, Anderson K, van de Werf F,
Braunwald E, for the TIMI 14 Investigators. Abciximab facilitates the
rate and extent of thrombolysis: results of the
Thrombolysis in Myocardial Infarction (TIMI) 14 Trial.
Circulation. 1999;99:2720–2732.
20. Ohman EM, Lincolff AM, Bode C, Bachinsky WB, Ardissino D, Betriu A, Schildcrout JS. Enhanced early reperfusion at 60 minutes with low-does retaplase combined with full-dose abciximab in acute myocardial infarction: preliminary results from the GUSTO-4 Pilot (SPEED) dose-ranging trial. Circulation. 1998;98(suppl I):I-504. Abstract.
21.
van den Merkhof LFM, Zijlstra F, Olsson H, Grip
L, Veen G, Bar FWHM, van den Brand MJBM, Simoons ML, Verheugt FWA.
Abciximab in the treatment of acute myocardial infarction eligible for
primary percutaneous transluminal coronary
angioplasty. J Am Coll Cardiol. 1999;33:1528–1532.
22.
Neumann FJ, Blasini R, Schmitt C, Alt E,
Dirschinger J, Gawaz M, Kastrati A, Schomig A. Effect of
glycoprotein IIb/IIIa receptor blockade on recovery of
coronary flow and left ventricular function after
placement of coronary-artery stents in acute myocardial
infarction. Circulation. 1998;98:2695–2701.
23. Kaku S, Umemura K, Mizuno A, Yano S, Suzuki KI, Kawasaki T, Nakashima M. Evaluation of a GPIIb/IIIa antagonist YM337 in a primate model of middle cerebral artery thrombosis. Eur J Pharmacol. 1998;345:185–192.[Medline] [Order article via Infotrieve]
24. Choudri TF, Hoh BL, Zerwes HG, Prestigiacomo CJ, Kim SC, Connolly ES, Kottirsch G, Pinsky DJ. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest. 1998;102:1301–1310.[Medline] [Order article via Infotrieve]
25. Wallace RC, Furlan AJ, Moliterno DJ, Stevens GHJ, Masaryk TJ, Perl J II. Basilar artery rethrombosis: successful treatment with platelet glycoprotein IIb/IIIa receptor inhibitor. Am J Neuroradiol. 1997;18:1257–1260.[Abstract]
26. Cecena FA, Hoelzinger DH, Miller JA, Abu-Shakra S. The platelet IIb/IIIa inhibitor abciximab as adjunctive therapy in carotid stenting of potential thrombotic lesions. J Intervent Cardiol. 1999;12:355–361.
27.
Brott T, Adams H Jr, Olinger CP, Marler JR,
Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V,
Rorick M, Moomaw CJ, Walker M. Measurements of acute cerebral
infarction: a clinical examination scale. Stroke. 1989;20:864–870.
28. Mahoney FI, Barthel DW. Functional evaluation: the BI. Md State Med J. 1965;14:61–65.[Medline] [Order article via Infotrieve]
29. Rankin J. Cerebral vascular accidents in people over the age of 60, II: prognosis. Scott Med J. 1957;2:200–215.[Medline] [Order article via Infotrieve]
30. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR, Knatterud G, Robertson TL, Terrin ML, for the TIMI Investigators. 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]
31. The NINDS t-PA Stroke Study group. Intracerebral hemorrhage after intravenous t-PA therapy for acute ischemic stroke. Stroke. 1997;28:2109–2118.
32. Christopoulos CG, Machin SJ. A new type of pseudothrombocytopenia: EDTA-mediated agglutination of platelets bearing Fab fragments of a chimaeric antibody. Br J Haematol. 1994;87:650–652.[Medline] [Order article via Infotrieve]
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|
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|
|
|
|
 |
|
 T. A. Waldmann, R. Levy, and B. S. Coller Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy Hematology, January 1, 2000; 2000(1): 394 - 408. [Abstract] [Full Text] [PDF]
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