Detection of neurological symptoms of stroke on awakening

Transcription

1 Treating Patients With Wake-Up Stroke The Experience of the AbESTT-II Trial Harold P. Adams, Jr, MD; Enrique C. Leira, MD; James C. Torner, PhD; Elliot Barnathan, MD; Lakshmi Padgett, PhD; Mark B. Effron, MD; Werner Hacke, MD; for the AbESTT-II Investigators Background and Purpose Approximately 10% to 20% of patients with a new stroke have symptoms present on awakening (wake-up stroke), but these persons are not treated with interventions to restore perfusion because the time of onset is not known. We elected to test the safety and possible efficacy of abciximab in treatment of enrolled subjects with wake-up stroke. Methods Abciximab in Emergency Stroke Treatment Trial-II (AbESTT-II) tested the usefulness of abciximab in improving outcomes after acute ischemic stroke and it prospectively tested an intervention in subjects that awakened with their stroke. We compared the outcomes among the subjects in the wake-up group with the other subjects in the trial. Results Of the 801 subjects randomized in the trial, 43 (22 abciximab and 21 placebo) had wake-up strokes. Those with wake-up strokes had similar baseline characteristics as the other subjects except for a higher rate of a new stroke found on CT. Recruitment of patients into the wake-up group was halted early because of the rate of bleeding with abciximab exceeded the prespecified safety margins (3 of 22 [13.6%]) within 5 days or at discharge versus 15 of 375 (4.0%) for the nonwake-up group (P 0.07). Favorable outcomes at 3 months, as defined by scores on the modified Rankin Scale, among the wake-up group (4 of 43 [9.3%]) were worse than the nonwake-up group (221 of 758 [29.2%]; P 0.005). Conclusions Although the baseline characteristics of the wake-up group of subjects were similar to those of persons enrolled in the nonwake-up group, their outcomes were much poorer. Patients with wake-up stroke may not tolerate reperfusion therapies even when started within a short time of awakening. (Stroke. 2008;39: ) Key Words: acute ischemic stroke chemical trials reperfusion therapy stroke on awakening Detection of neurological symptoms of stroke on awakening (wake-up stroke) is a relatively common situation. A statewide survey of patients admitted with stroke into hospitals in California noted that 8% of the cases had symptoms on awakening. 1 Other groups have described higher frequencies. Fink et al 2 reported that 100 of 364 patients with ischemic stroke (27%) awoke with their symptoms. Among 1248 patients with stroke admitted in a national data bank in Spain, 301 (24.1%) had symptoms on awakening. 3 A registry of the Canadian Stroke Network reported 13.5% of 2585 patients with acute stroke awakened with their neurological symptoms. 4 Recently, a Dutch study reported that 18% of 263 consecutive patients had symptoms of stroke present on awakening. 5 Because there is uncertainty about the time of onset of the stroke in this situation, patients with stroke on awakening have not been enrolled in clinical trials that include a short time window from onset of stroke until treatment. Consequently, there is no evidence to determine whether these patients can or cannot be treated with thrombolytic medications. Potential similarities or differences between those patients with stroke on awakening and those persons with events that have a relatively defined onset have been sought. Serena et al 3 noted no major differences in epidemiological factors, vital signs, stroke subtypes, or severity of stroke. They did find that those patients with wake-up stroke were less likely to have a normal baseline CT scan than those whose events occurred while they were awake (39.4% versus 60.8%). In another study, no major differences were noted in age, sex, stroke subtype, National Institutes of Health Stroke Scale scores, or findings on MRI between those patients with a stroke with a defined onset and those with wake-up events. 2 Nadeau et al 4 reported that patients with stroke on awakening had higher levels of blood pressure but similar levels of consciousness as other patients. Although they noted a mortality that was comparable to the patients with strokes that occurred during wakening, the patients with wake-up strokes had a higher rate of poorer functional outcomes. Recently, Todo et al 6 evaluated CT findings among patients with stroke Received October 30, 2007; final revision received January 17, 2008; accepted February 7, From the Department of Neurology (H.P.A., E.C.L.), Carver College of Medicine and the Department of Epidemiology (J.C.T.), College of Public Health, University of Iowa, Iowa City, Iowa; Centocor Research (E.B., L.P.), Malvern, Pa; Eli Lilly and Company (M.B.E.), Indianapolis, Ind; and the Department of Neurology (W.H.), University of Heidelberg, Heidelberg, Germany. Correspondence to Harold P. Adams, Jr, MD, Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA harold-adams@uiowa.edu 2008 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 3278 Stroke December 2008 on awakening and described the changes were akin to those found among patients with stroke that occurred in the previous 3 hours. They concluded that the imaging findings might suggest that many patients with wake-up strokes have their vascular events shortly before arising. These reports suggest that there may be some patients with acute ischemic stroke first recognized on awakening that might be eligible for treatment with early thrombolytic therapy or other interventions that might restore or improve circulation. An earlier dose-escalation study of abciximab, which had a 24-hour entry window, allowed enrollment of patients with wake-up stroke. 7 From this study, there were data about the potential safety of the abciximab in this population. Based on the previous reports and the results of the dose-escalation study, the usefulness of abciximab in emergency treatment of subjects with acute ischemic stroke first detected on awakening was analyzed in a large international trial, the Abciximab in Emergency Stroke Treatment Trial-II (AbESTT-II). The wake-up cohort was included in an ancillary part of the trial. Methods AbESTT-II was a randomized, double-blind, placebo-controlled international trial of early administration of abciximab for treatment of subjects with acute ischemic stroke. Subjects were enrolled in 119 sites from December 2003 through September The appendix listing the sites and investigators and the details of the design of the trial, including the role of the sponsors, are contained in another publication. 8 The primary efficacy outcome was the rate of favorable outcomes at 3 months as determined by the by a dichotomous scoring of the modified Rankin Scale as adjusted by the baseline score on the National Institutes of Health Stroke Scale (NIHSS). 9 For example, a higher standard (modified Rankin Scale 0) for a favorable response was required for subjects with minor strokes (NIHSS 4 to 7) than for those with more severe strokes. The primary safety measure was the rate of symptomatic (fatal or nonfatal) intracranial hemorrhage within 5 days of entry. The definitions of the safety and efficacy outcomes are included in the papers describing the major results of the previous studies. 8,10 Symptomatic intracranial hemorrhage was defined as neurological worsening associated with the finding of intracranial bleeding on a brain imaging study. No particular CT pattern of bleeding was required for the diagnosis of hemorrhagic transformation. A causal link was required. All cases of symptomatic intracranial hemorrhage were confirmed by an independent adjudication panel. A physician safety monitor, who was unaware of treatment allocation, reviewed cases of serious adverse experiences as they were reported. He was charged to contact the independent safety committee if the number of events exceeded that what was anticipated. The safety committee used sequential probability ratio testing to define what would be considered acceptable boundaries for the number of symptomatic intracranial hemorrhages based on the number of subjects enrolled. If there was a concern that there was an excess of intracranial hemorrhage or another safety issue, the safety committee could also review efficacy data to look at a risk benefit assessment. AbESTT-II enrolled subjects into 2 cohorts. Subjects were assigned treatment using the stratification variables of study center, NIHSS score, and study cohort. The primary cohort included those subjects who could be treated within 5 hours of onset of stroke (randomization 4.5 hours). This group was selected because of the findings of a dose confirmation study (AbESTT) suggested that the primary potential benefit from treatment with abciximab was in this population. 10 The companion population included those subjects who could be treated 5 to 6 hours after stroke (randomization 4.5 hours and 5.5 hours) or those who could be treated within 3 hours (randomization 2.5 hours) of awakening. The original goal was to randomize 1200 subjects in the primary population, but the trial was halted in September 2005 because an interim analysis did not demonstrate an acceptable risk benefit ratio for treatment with abciximab and only 439 subjects (221 abciximab and 218 placebo) were randomized. In addition, the trial planned to evaluate the potential safety and efficacy of 600 subjects who could be enrolled in the companion group. At the time at the end of the trial, this group included 319 subjects (160 abciximab and 159 placebo) who could be treated in the interval of 5 to 6 hours after stroke onset and a group of 43 subjects (22 abciximab and 21 placebo) who had symptoms of stroke present on awakening. Subjects with stroke on awakening, but who were eligible for entry into one of the other 2 study cohorts (could be treated within 6 hours of last being normal), were enrolled in the cohort for which they were qualified and not in the wake-up group. Enrollment in the wake-up group was stopped in May 2005 after only 43 subjects (22 abciximab and 21 placebo) had been enrolled, because the rate of symptomatic intracranial hemorrhages among the subjects receiving abciximab exceeded anticipated safety margins. Although the trial stopped early, those subjects already enrolled completed regularly scheduled assessments and outcome evaluations before the database was finalized and the analyses were performed. The overall results of the trial are published. 8 For the purpose of this article, baseline and outcome data among those subjects in the wake-up group of the trial are compared with the remaining subjects (subsequently referred as the nonwake-up cohort). The goal was to look at any baseline or other variable that could affect responses to early administration of reperfusion therapy among persons with wake-up stroke. Another aim was to share this trial s experience so that other researchers and clinicians can gain knowledge about the issues related to treatment of persons who have symptoms of stroke present on awakening. Statistical Analyses The analysis combined the data from the primary cohort subjects and the companion cohort subjects treated within 5 to 6 hours of known onset of stroke and compared the safety and efficacy outcomes (as described previously) outcomes with those subjects in the wake-up group. Comparisons of groups were done using Mantel-Haenszel 2 and analysis of variance methods. Efficacy analyses, based on the adjusted dichotomous scoring of the modified Rankin Scale at 3 months, were performed on all randomized subjects. Safety analyses were performed on all subjects who received at least some study treatment according to the actual study treatment received. For the adjusted dichotomous modified Rankin scale responder analyses, data were imputed for subjects with missing observations on the 3-month modified Rankin scale by carrying forward the last available postrandomization value. If no postbaseline values were available for a subject of if a subject died before the 3-month assessment, the subject was considered to be a nonresponder for the 3-month modified Rankin scale responder end point. Mortality was calculated based on those deaths that occurred within 120 days of randomization. In the analysis of the dichotomous end points for each treatment group, Fisher exact test was used to compare the event rates between the wake-up group and the nonwake-up group. Results The trial enrolled 43 subjects into the wake-up group, whereas 758 subjects were enrolled into the nonwake-up group. Enrollment of subjects in the wake-up group was less than anticipated. Overall, the wake-up group accounted for only 5% of the persons enrolled in AbESTT-II. The baseline characteristics of the enrolled subjects are described in Table 1. As expected, the interval from last being known to be normal was significantly longer among the subjects in the wake-up group. The median NIHSS score for the subjects in the nonwake-up group was 8 and it was 10 in the wake-up group. There were more current smokers in

3 Adams et al Treating Patients With Wake-Up Stroke 3279 Table 1. Baseline Clinical and Imaging Characteristics Wake-Up Nonwake-Up Abciximab (N 22) Placebo (N 21) Abciximab (N 381) Placebo (N 377) Mean age, years Age range, years Men 13 (59%) 16 (76%) 218 (57%) 194 (51%) Mean interval from stroke onset, minutes* Hypertension 15 (68%) 12 (57%) 257 (67%) 271 (72%) Mean systolic blood pressure, mm Hg Mean diastolic blood pressure, mm Hg Diabetes 6 (27%) 3 (14%) 77 (20%) 87 (23%) Mean glucose, mg/dl Current smoking* 13 (59%) 13 (62%) 172 (45%) 159 (42%) Heart disease 6 (27%) 3 (14%) 92 (24%) 81 (21%) Atrial fibrillation 3 (14%) 5 (24%) 78 (20%) 78 (21%) Prior stroke* 8 (36%) 3 (14%) 55 (14%) 52 (14%) Prior transient ischemic attack 3 (14%) 0 38 (10%) 32 (8%) Aspirin use ( 7 days) 18 (82%) 16 (76%) 296 (78%) 300 (80%) NIHSS score Mean Median Range Score (32%) 9 (43%) 175 (46%) 175 (46%) Score (50%) 8 (38%) 126 (33%) 130 (34%) Score (18%) 4 (19%) 80 (21%) 72 (19%) Baseline CT Normal to treating physician* 3 (14%) 6 (29%) 156 (41%) 175 (46%) Old stroke* 13 (59%) 8 (38%) 134 (35%) 118 (31%) New stroke 9 (41%) 8 (38%) 109 (29%) 104 (28%) *All findings were not statistically different except for (1) mean interval from stroke onset (last normal), P 0.00; (2) history of prior stroke, P 0.04; (3) baseline CT being normal, P 0.01; (4) old stroke on CT, P 0.05; and (5) current smoking, P The median NIHSS score for the subjects in the wake-up group was 10 and the median score in the nonwake-up group was 8. those with wake-up stroke. The prevalence of old stroke detected by CT was higher in the group of patients with wake-up stroke. The detection of new stroke on CT as interpreted by the enrolling physician was approximately double among the subjects in the wake-up group than in the subjects in the nonwake-up cohort. Another difference was a clinical history of previously recognized stroke among the wake-up subjects administered abciximab. Otherwise, the initial findings among subjects in the wake-up group were similar to those of the subjects in the nonwake-up cohort. The safety outcome data are included in Table 2 and Figures 1 and 2. The rates of symptomatic intracranial hemorrhage within 5 days or at discharge (including fatal bleeding) tended to be higher among the subjects treated with abciximab in the wake-up group (13.6%) than the nonwake group of abciximab-treated subjects (4%; P 0.07). At 3 months, it was significantly higher among subjects treated with abciximab in the wake-up group (18.4%) than the nonwake-up group (4.8%; P 0.03). Among the group of subjects treated with placebo, the bleeding rate through 3 months for the wake-up group was 5% and it was not Table 2. Symptomatic or Asymptomatic Intracranial Hemorrhage Abciximab Placebo Outcome Wake-Up (N 22) Nonwake-Up (N 375) P Wake-Up (N 20) Nonwake-Up (N 377) P SICH 5 day 3 (13.6%) 15 (4.0%) (5%) 2 (0.5%) 0.14 SICH 3 month 4 (18.2%) 18 (4.8%) (5%) 4 (1.1%) 0.23 AICH 2 (9.1%) 40 (10.7%) (0%) 35 (9.3%) 0.24 SICH 5 day indicates symptomatic intracranial hemorrhage, events within 5 days or discharge; SICH 3 monnth, symptomatic intracranial hemorrhage, events within 3 months; AICH, asymptomatic intracranial hemorrhage found on brain imaging.

4 3280 Stroke December 2008 % of subjects wake-up other Figure 1. Comparison of safety and efficacy outcomes between wake-up (safety, n 22; efficacy, n 22) and nonwake-up (safety, n 375; efficacy, n 381) subjects treated with abciximab. See the definition of modified Rankin Scale responder at the bottom of Table 3. SICH, 5 days, symptomatic intracranial hemorrhage, events within 5 days or discharge; SICH, 3 months, symptomatic intracranial hemorrhage, events within 3 months; AICH, asymptomatic intracranial hemorrhage found on brain imaging; Barth, Barthel Index. 0 SICH 5 Day SICH 3 Mo AICH death at 90 days mrs responders Barth significantly different from 1.1% found among the subjects in the nonwake-up group (P 0.23; see Table 2). The bleeding rate of among the wake-up group assigned treatment with abciximab was above our anticipated safety margins. Because there was no interaction of treatment arm assignment in efficacy, the treatment arms were combined in the wake-up and nonwake-up groups (Tables 3 and 4). Although the numbers are small, the rate of favorable outcomes was significantly lower among the wake-up cohort (9.3%) administered abciximab than in the nonwake-up group treated with abciximab (29.2%; P 0.005; Figures 1 and 2). In addition, the rate of favorable outcomes among the placebo-treated subjects in the wake-up cohort was lower than the placebotreated patients in the nonwake-up group (Figures 1 and 2). Similar responses were noted in the scores in the Barthel Index. Discussion AbESTT-II prospectively enrolled subjects with wake-up stroke to test the possible safety and efficacy of an acutely % of subjects wake-up other administered medication, in this case abciximab, aimed at restoring perfusion to the brain. The trial found that enrollment of this group of subjects was difficult despite an anticipation of enrolling more of these patients into the study. The methodology such as categorizing subjects with symptoms on awakening but who could still be treated within 6 hours of last being normal as belonging to either the primary or companion groups may have reduced the size of the wake-up group. In addition, the short time window ( 3 hours from awakening until treatment) may have limited the number of persons who could be treated. Logistical reasons may have played a role. For example, delays in recognition and transport may have occurred. The attitude that the time of stroke must be known for early treatment may have lessened the sense of urgency by both patients and healthcare services. Although it is possible that some sites might have selected some patients with wake-up stroke to be treated with thrombolysis or mechanical interventions, we do not have evidence that this scenario occurred. Overall, the general baseline characteristics of the subjects in the wake-up group were similar to the other subjects in the trial. Overall, the Figure 2. Comparison of safety and efficacy outcomes between wake-up (safety, n 20; efficacy, n 21) and nonwake-up (safety, n 377; efficacy, n 377) subjects treated with placebo. Please see the definition of modified Rankin Scale responders at the bottom of Table 3. SICH, 5 day, symptomatic intracranial hemorrhage, events within 5 days or discharge; SICH, 3 months, symptomatic intracranial hemorrhage, events within 3 months; AICH, asymptomatic intracranial hemorrhage found on brain imaging; Barth, Barthel Index. 0 SICH 5 Day SICH 3 Mo AICH death at 90 days mrs responders Barth

5 Adams et al Treating Patients With Wake-Up Stroke 3281 Table 3. Efficacy Outcomes Wake-Up Nonwake-Up Abciximab (N 22) Placebo (N 21) Abciximab (N 381) Placebo (N 377) Favorable outcome 3 months Primary efficacy* 1 (5%) 3 (14%) 112 (29%) 109 (29%) Distribution of modified Rankin Scale scores 0 1 (5%) 2 (10%) 81 (21%) 71 (19%) 1 1 (5%) 4 (19%) 72 (19%) 90 (24%) 2 5 (23%) 5 (24%) 61 (16%) 53 (14%) 3 2 (9%) 5 (24%) 47 (12%) 55 (15%) (59%) 5 (24%) 121 (32%) 108 (29%) Barthel 95/100 7 (32%) 10 (48%) 217 (57%) 206 (55%) The primary efficacy was the score on the responder analysis judged by the modified Rankin Scale (mrs) score at 3 months. To be rated as having a favorable outcome among subjects with a baseline NIHSS score of 4 to 7, the mrs was 0; for subjects with a baseline NIHSS score of 8 to 14, the mrs score could be 1 or 2; and for those subjects with a baseline NIHSS score of 15 to 22, the mrs score could be 0 to 2. experience with recruitment of persons with wake-up stroke was disappointing. The baseline characteristics, including epidemiological factors such as age, among the subjects in the wake-up group were comparable to those persons in the other groups. The mean and median NIHSS scores were similar in both the wake-up and nonwake-up group. These findings are akin to those reported by other investigators. 2,3 However, the frequency of detecting the qualifying stroke on baseline CT was approximately 10% higher among the subjects in the wake-up group. The findings differ from those reported by other groups. 2,6 A higher rate of detection of brain abnormalities by CT should be expected because the time period from onset of stroke until the performance of the test may be several hours. Because the CT findings of acute cerebral infarction may take hours to appear, this finding suggests that some strokes among the wake-up group in AbESTT-II may have been older than 5 to 6 hours at the time of the brain imaging study. Although the baseline CT findings were not of sufficient severity to exclude the patients from the trial, the early detection of a stroke may mean that the ischemic lesion Table 4. Comparisons of Outcomes at 3 Months Wake-Up Versus Nonwake-Up Subjects Efficacy Variable Wake-Up Subjects (N 43) Nonwake-Up Subjects (N 758) P Modified Rankin 4 (9.3%) 221 (29.2%) Scale responder Barthel Index 95 or 17 (39.5%) 423 (55.8%) Mortality 9 (20.9%) 95 (12.5%) 0.11 Comparison of the aggregate data from the placebo- and abciximab-treated patients in the wake-up group in comparison to the data from the placebo- and abciximab-treated patients in the nonwake-up group. The modified Rankin scale (mrs) responders were judged on the mrs scores at 3 months; to be rated as a favorable outcome among subjects with a baseline NIHSS score of 4 to 7, the mrs was 0; for subjects with a baseline NIHSS score of 8 to 14, the mrs score could be 0 or 1; for those subjects with a baseline NIHSS score of 15 to 22, the mrs score could be 0 to 2. already is relatively mature and an intervention aimed at restoring or improving perfusion may not be successful. Further evaluation of the brain imaging findings among patients with stroke on awakening is needed. Although the numbers in the wake-up group are small, the rate of serious intracranial hemorrhage among subjects treated with abciximab was unacceptably high. This finding prompted premature halting of enrollment in this group of subjects. The high rate of bleeding was found, although the baseline characteristics of the subjects in the wake-up group generally were similar to those subjects enrolled in the other groups of the trial. Our experience suggests that a high number of patients with wake-up stroke may not tolerate reperfusion therapies even when started within a short period after awakening. Additional research is needed to identify clinical or imaging features that may select those patients with wake-up stroke who could benefit from therapies aimed at restoring perfusion. It is possible that the use of imaging techniques such as diffusion or gradient echo MRI would help in detection of patients with wake-up of stroke for whom measures to restore or improve perfusion may be dangerous. There was a lower rate of favorable outcomes among the subjects in the wake-up group independently of whether they were treated with either abciximab or placebo. The results of this prospectively recruited group of subjects enrolled in a clinical trial are particularly sobering. The rate of favorable outcomes was particularly low among the subjects treated with abciximab, which may in part be explained by the high rate of symptomatic hemorrhage. Although the group of subjects was relatively small, the rate of favorable outcomes was considerably less than among patients receiving the medication in the other study cohorts. In addition, the rate of favorable outcomes among the placebo-treated subjects in the wake-up cohort was approximately half of that found among the placebo-treated subjects in the remainder of the trial. Therefore, the low rate of favorable outcomes among the placebo-treated subjects cannot be solely attributed to the acute intervention. Rather, it implies there may be factors among persons with wake-up stroke that are associated with

6 3282 Stroke December 2008 a poor prognosis, perhaps including longer time to receive medical attention, which may, in turn, predispose to medical complications. The baseline characteristics among patients with stroke on awakening are generally the same as those found among persons with strokes with defined times of onset. Some other factor, which has yet to be identified, may be contributing to the poor prognosis of patients with wake-up stroke. Additional research about patients whose strokes are recognized on awakening is needed. Clarification of those clinical or imaging findings that might identify those persons who might be good candidates for aggressive treatment to lessen the acute effects of the stroke is needed. At present, data to help identify those patients with stroke on awakening who might benefit from interventions to restore or improve perfusion are needed. There are no data about the potential usefulness of neuroprotective agents in treatment of patients with wake-up strokes. Additional research on the baseline characteristics and natural history of persons whose strokes are recognized on awakening as a prelude to further clinical trials testing interventions in this cohort is strongly encouraged. Clearly, there is a need for interventions that may lessen the neurological consequences of acute brain ischemia in these patients. Source of Funding This study was sponsored by Eli Lilly & Company and Centocor Research. This study was partially supported by a AbESTT-II clinical trial grant. Disclosures E.S.B. and M.E. are employees of the sponsor, and L.P. is an employee of Centocor. The remaining authors have nothing to disclose. References 1. California Actue Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64: Fink JN, Kumar S, Horkan C, Linfante I, Selim MH, Caplan LR, Schlaug G. The stroke patient who woke up: clinical and radiological features, including diffusion and perfusion MRI. Stroke. 2002;33: Serena J, Davalos A, Segura T, Mostacero E, Castillo J. Stroke on awakening: looking for a more rational management. Cerebrovasc Dis. 2003;16: Nadeau JO, Fang J, Kapral MK, Silver FL, Hill MD, Registry of the Canadian Stroke Network. Outcome after stroke upon awakening. Can J Neurol Sci. 2005;32: Boode BS, Welzen V, van Oostenbrugge RJ. Estimating the number of stroke patients eligible for thrombolytic treatment if delay could be avoided. Cerebrovasc Dis. 2006;23: Todo K, Moriwaki H, Saito K, Tanaka M, Oe H, Naritomi H. Early CT findings in unknown-onset and wake-up strokes. Cerebrovasc Dis. 2006; 21: The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, doseescalation study. Stroke. 2000;31: Adams HP Jr, Effron MB, Torner J, Dávalos A, Frayne J, Teal P, Leclerc J, Oemar B, Padgett L, Barnathan E, Hacke W for the AbESTT II investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke results of an international phase III trial. Stroke. 2007;39: Adams HP Jr, Leclerc JR, Bluhmki E, Clarke W, Hansen MD, Hacke W. Measuring outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis. 2004;18: Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke. Results of a randomized phase 2 trial. Stroke. 2005;36: