(Stroke. 2000;31:811.)
© 2000 American Heart Association, Inc.
Original Contributions |
The rtPA (Alteplase) 0- to 6-Hour Acute Stroke Trial, Part A (A0276g)
Results of a Double-Blind, Placebo-Controlled, Multicenter Study
From the Oregon Stroke Center, Portland, Ore (W.M.C.); Stanford Stroke Center, Palo Alto, Calif (G.W.A.); Marshfield Clinic, Marshfield, Wis (K.P.M.); and Genentech, Inc, South San Francisco, Calif (S.H.).
Correspondence to Wayne M. Clark, MD, Oregon Stroke Center, UHS 44, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. E-mail clarkw{at}ohsu.edu
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Abstract |
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Background and Purpose—The Thrombolytic Therapy in Acute Ischemic Stroke Study, which started in August of 1991, was designed to assess the efficacy and safety of intravenous rtPA (alteplase) in patients with acute (0 to 6 hours) ischemic stroke. In October 1993 enrollment was halted because of Safety Committee (DMSB) concerns. In December 1993 the time window was changed to 0 to 5 hours, and it was decided to restart enrollment as a separate study (part B). We report here the results of the original study (part A), focusing on evaluating the safety and efficacy of rtPA given between 0 and 6 hours after stroke onset.
Methods—This investigation was a phase II, placebo-controlled, double-blind, randomized study utilizing 0.9 mg/kg IV rtPA or placebo over 1 hour, which was conducted at university and community sites in North America. Except for time to treatment, enrollment criteria were very similar to those of the NINDS rtPA stroke study. Primary efficacy end points were the number of patients with a decrease of 4 or more points on the National Institutes of Health Stroke Scale (NIHSS) at 24 hours and day 30, along with infarct volume at day 30. Secondary end points included mortality and functional recoveries on the Barthel Index and Modified Rankin scale at days 30 and 90.
Results—A total of 142 patients were enrolled at 42 sites in North America, including 22 <3 hours (15%) and 46 between 5 and 6 hours (32%). The groups were well matched on baseline characteristics, including NIHSS (mean of 13 for both). For the primary end points, a higher percentage of rtPA patients had a 4-point improvement at 24 hours (placebo 21%, rtPA 40%; P=0.02); however, this early effect was reversed by 30 days, with more placebo patients having a 4-point improvement (75%) than patients treated with rtPA (60%, P=0.05). Treatment with rtPA significantly increased the rate of symptomatic intracerebral hemorrhage within 10 days (11% versus 0%, P<0.01) and mortality at 90 days (23% versus 7%, P<0.01).
Conclusions—This study found no significant rtPA benefit on any of the planned efficacy end points at 30 and 90 days in patients treated between 0 and 6 hours after stroke onset. These negative results apply to patients treated after 3 hours, because only 15% of the patients were enrolled before 3 hours. The risk of symptomatic intracerebral hemorrhage was increased with rtPA treatment, particularly in patients treated between 5 and 6 hours after onset. These results do not support the use of intravenous rtPA for stroke treatment >3 hours after onset.
Key Words: stroke • therapy • thrombolysis • tissue plasminogen activator
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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Stroke, which afflicts more than 500 000 Americans per year, represents the third most common cause of death and hospitalization. In the early 1990s, 3 large randomized trials were started to test the hypothesis that thrombolysis with intravenous recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke could restore blood flow and improve patient outcome. In the National Institute of Neurological Disorders (NINDS) study, patients with ischemic strokes were treated within 3 hours after stroke onset with either 0.9 mg/kg rtPA (alteplase) or placebo.1 The European Cooperative Acute Stroke Study (ECASS 1) treated patients enrolled between 0 to 6 hours after onset with 1.1 mg/kg rtPA.2 Our study, the Thrombolytic Therapy in Acute Ischemic Stroke Study in the United States, evaluated patients treated with 0.9 mg/kg treated within 6 hours of onset. This Genentech-sponsored trial was planned to run concurrently with the NINDS study, with the goal of evaluating whether rtPA was beneficial when administered up to 6 hours after symptom onset. The significant 11% to 15% absolute benefit favoring rtPA in the NINDS trial led to FDA approval in June 1996 for patients with acute ischemic stroke who were treated within 3 hours of symptom onset. The question of whether a patient should be treated with rtPA >3 hours after onset has remained unanswered.
The objectives of this phase II trial were to assess the efficacy (as measured by improved clinical outcome and reduced infarct size) and relative safety of 0.9 mg/kg rtPA (alteplase; Genentech, Inc) versus placebo in acute ischemic stroke patients treated between 0 and 6 hours after stroke onset. This article reports the results of the 141 patients enrolled in part A of the study between August 1991 and October 1993.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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The Thrombolytic Therapy in Acute Ischemic Stroke Study first began in August 1991 and was initially designed to assess the efficacy and safety of intravenous rtPA (alteplase) administered between 0 and 6 hours after symptom onset in patients with acute ischemic stroke. In October 1993 enrollment was halted following an interim analysis due to Data Monitoring and Safety Board (DMSB) concerns in the 5- to 6-hour group. In December 1993 it was decided to restart the trial as a separate "part B," reflecting a new time window (0 to 5 hours) and new study end points. Patients enrolled in the original "part A" were considered to be in a separate trial for analysis and reporting purposes. The company and investigators remained blinded to results from patients in part A until February 1999, when part B of the trial was reported. The 142 patients enrolled in part A are presented in this article; the 617 part B patients are reported in a separate publication.3
This was a randomized, double-blind, multicenter, placebo-controlled clinical trial. Enrollment was based on clinical and CT criteria; angiography was not required. The study, sponsored by Genentech, Inc, was conducted at 42 centers in North America. Enrollment was originally planned to be 150 patients per treatment group, for a total of 300 patients. All investigators were required to be certified in the National Institutes of Health Stroke Scale (NIHSS),4 according to NIH guidelines, through use of a standard training videotape.5 Patients were randomized (1:1) and treated with either rtPA (0.9 mg/kg) or matched placebo. All patients or their legal representatives signed an informed consent approved by the Institutional Review Board of each study site.
Enrollment criteria included patients aged 18 to 79 years who
presented with a clinical diagnosis of stroke causing a
measurable neurological deficit and who could receive the study drug
within 6 hours of definite symptom onset. A CT scan that excluded
intracerebral hemorrhage (ICH) was required
before randomization. However, there was no exclusion for early infarct
signs in the middle cerebral artery territory. A full list of inclusion
and exclusion criteria is provided in Table 1
.
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The patients were randomized, following a central randomization code, by use of a blocked randomization stratified by clinical center. No one at the local site was aware of the patients’ group assignments. The study drug consisted of white lyophilized powder, indistinguishable between groups, that was reconstituted with sterile water. The reconstituted study drug 0.9 mg/kg (no more than 90 mg total) was given as a 10% intravenous bolus over 1 to 2 minutes through a dedicated line, followed immediately by a 60-minute infusion of the remaining dose. Administration of heparin, oral anticoagulants, antiplatelet agents, or other hemorheologic agents was prohibited during the initial 24 hours after completion of the study drug. After 24 hours the use of intravenous heparin or other antithrombotic agents was at the local investigators’ discretion.
The sample-size estimate for the NIHSS primary end point (a 4-point
improvement or complete recovery at day 30) was based on a 2-sample
test of proportions. The placebo group was assumed to have a 30%
improvement rate. On the basis of this assumption, 300 patients would
be required to detect a primary end point rate of 47% in the rtPA
group, with an 
level of 0.05 and power of 90%. There were 3
planned safety and futility analyses at approximately
75, 150, and 225 patients. The trial was stopped on the basis of an
interim safety analysis by the DMSB in October 1993 "due to
safety concerns in the 5 to 6 hours group."
Patients were monitored closely for the development of any neurological symptoms or bleeding complications. An NIHSS and general physical examination was completed by certified investigators at baseline, 120 minutes, 24 hours, and at 7, 30, and 90 days following initiation of study drug; Barthel Index, modified Rankin scale, and Glasgow outcome assessments were performed at days 30 and 90. Vital signs were obtained hourly for the first 24 hours. After initiation of study drug, the blood pressure was maintained at <185/110 mm Hg following a treatment algorithm that included aggressive measures if needed. A noncontrast cerebral CT scan was performed at baseline, 24±6 hours (or sooner if clinical deterioration), and 30±7 days after study drug infusion for assessment of ICH, infarct signs, and infarct size. To avoid potential unblinding, the clinical exams at 30 and 90 days were performed by an individual who was not present during study drug administration and did not see the patient in the first 24 hours.
Data management and analysis were conducted by the sponsor. All
personnel at each study site and at Genentech involved in conducting
and monitoring the trial were blinded to the study drug codes. The
primary efficacy outcome variables were the clinical improvement,
as measured by a decrease of 
4 points on the NIHSS, or complete
resolution of symptoms from baseline to 24 hours and from baseline to
30 days, and the volume of the cerebral infarction as measured by CT
scan at day 30. Secondary end points included mortality at day 90 and
functional recovery at days 30 and 90 measured with the Barthel
Index6 and the Modified Rankin scale median
scores.7 A full list of the outcome variables for the
trial is given in Table 2.
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Although they were not part of the original study analyses, 2 "complete recovery" post hoc tests have been added for this report. These include the percentage of patients at 90 days who achieved (1) a Barthel Index score of 95 and (2) an NIHSS score of 1. These results allow for direct comparison with the NINDS study results, since they were some of the efficacy end points used in that study.1
Safety parameters included overall mortality, asymptomatic ICH, symptomatic ICH, fatal ICH, and other serious adverse events (SAEs). Causes of death were assessed by the local investigator. All patients who died and had any type of ICH were reviewed by the blinded independent data safety monitoring board (DMSB) on an ongoing basis.
Statistics
Data were double entered and verified with the Informix database
management system. SAS (SAS, Inc)was used to perform the statistical
analysis. All tests of significance were two-sided conducted at
the 0.05 level of significance. Results are based on the "last
observation carried forward" method, with death given the worst
outcome score on all of the measures. Differences in baseline
characteristics were determined with t tests for continuous
variables and the 
2 test for categories.
Efficacy end points were tested by use of a 2-sample binomial test
adjusted for baseline differences if necessary. Difference in ICH and
SAEs between groups were compared with the Fischer exact test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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From August 1991 through October 1993, a total of 142 patients were enrolled into part A at 41 sites. Enrollment was slow because of the acute time window and the lack of established stroke teams in the early 1990s. All randomized patients were included in the intent-to-treat (ITT) analysis. The groups were well matched on baseline characteristics, including age, percent male, and baseline NIHSS (mean of 13 for both groups) (see Table 3
). The mean time to treatment was 4
hours 17 minutes in placebo and 4 hours 24 minutes for rtPA. Only 17%
of placebo patients and 14% of rtPA patients were treated in <3
hours, while 34% of placebo and 31% of rtPA patients were treated
between 5 and 6 hours. The groups were also well matched for history of
smoking, hypertension, cardiac disease, atrial fibrillation, and prior
stroke. A significantly higher percentage of patients in the placebo
group were diabetic.
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Efficacy Results
Results of the efficacy analysis for the ITT
population are shown in Table 4. For the
first primary end points (4-point NIHSS improvement), a higher
percentage of rtPA patients had a 4-point improvement at 24 hours
(placebo 21%, rtPA 40%; P=0.02); however, this early
effect was reversed by 30 days, with more placebo patients having a
4-point improvement (75%) compared with patients treated with rtPA
(60%, P=0.05). No difference was seen on CT lesion volume
at day 30, with both groups showing large variations: placebo 64±74
cm3 versus rtPA 45±54 cm3
(P=0.17). There were also no treatment benefits seen on any
of the planned secondary functional outcomes at 30 and 90 days with
placebo patients actually having a lower (better) median Rankin score
(see Table 4).
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In order to provide a direct comparison with the NINDS rtPA study results several "excellent recovery " (scores of 0 and 1) post hoc analyses were conducted.1 In these tests a higher percentage of rtPA patients had an excellent outcome on the NIHSS at day 30 (placebo 20%, rtPA 36%; P=0.04 by uncorrected post hoc test) but not day 90. This, along with the 24-hour 4-point NIHSS findings, suggests that rtPA treatment produces a higher number of cases with early, dramatic neurological recoveries. In contrast, no benefit was seen on the "excellent recovery" post hoc functional outcome assessments using the Barthel Index. However, because the trial was not powered to detect differences on these "excellent recovery" variables, these results may reflect a type II error.
SAE s for the ITT population are shown in Table 4
. The
occurrence of ICH was determined by a CT scan at 24±6 hours, although
any ICH detected by repeat CT within the first 10 days was also
included. Determination of whether the ICH was asymptomatic
or symptomatic was made by the local principal
investigator, who was blinded to treatment group. Treatment with
rtPA increased the rate of both asymptomatic and
symptomatic ICH: asymptomatic 4.3% versus
12.7, symptomatic 0.0% versus 11.3%. The mortality rate
at 30 and 90 days was significantly higher in the rtPA group: 30 days,
4.2% with placebo, 18.3% with rtPA (P=0.008); 90 days,
7.0% with placebo, 22.5% with rtPA (P=0.009; see Table 4).
The trial was stopped by the DMSB because of safety concerns in
the 5- to 6-hour group. Table 5 provides
the results for the 5- to 6-hour subgroup of patients. The rate of
symptomatic ICH and the 30- and 90-day mortality rates were
higher with rtPA treatment than with placebo, and the rates in the 5-
to 6-hour rtPA group were higher than the corresponding rtPA rates in
the study overall. However these increased SAE results in the 5- to
6-hour rtPA group may have been confounded by a baseline imbalance in
the number of patients with severe strokes. In the 5- to 6-hour group,
only 8% (2/24) of the placebo patients had an NIHSS >20 at baseline
compared with 23% (5/22) of the rtPA patients (P<0.05). In
the study overall, patients with an NIHSS of >20 had increased ICH
rates and very poor outcomes (see Table 6). In patients with an NIHSS >20, there
was a 38% rate of symptomatic ICH and a 100% 90-day
mortality rate with rtPA treatment. If the 5- to 6-hour patients are
excluded, the symptomatic ICH rate in the remaining 0- to
5-hour patients is 8.2%.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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This trial did not find a benefit of intravenous rtPA therapy for patients with ischemic stroke when treatment was initiated between 0 and 6 hours after symptom onset. On the planned primary or secondary neurological and functional outcomes at 30 and 90 days, there were either no differences between the groups, or the placebo group had a better recovery. Because the trial was stopped before the planned number of patients were enrolled, these efficacy results may be confounded by the small numbers of patients producing a type II error. Treatment with rtPA was associated with a marked increase in the rate of symptomatic ICH and mortality. However, because <15% of patients were treated with rtPA within 3 hours in this study, these results apply only to patients treated beyond the FDA-approved 3-hour window. There is some evidence that a higher number of patients experienced a major early improvement with rtPA, in that the percentage of patients with an excellent recovery on the NIHSS (score of 0 or 1) was significantly higher at day 30 with rtPA treatment. However, this beneficial effect was outweighed by the increased symptomatic ICH and mortality rates in the overall population with rtPA treatment (see Figure 1
).
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Comparing the results of this study with the NINDS under 3 hour rtPA trial reveals that patients in our trial had milder strokes, with a median NIHSS score of 11 compared with 14 in the NINDS study. This likely explains the lower death rate in the placebo group seen in our study (7%, versus 21% in the NINDS trial). The spontaneous recovery rates in the placebo groups were slightly higher in our trial compared with the NINDS trial; eg, Barthel Index >95 49% versus 38% at 3 months. Comparing the rtPA treated groups in the 2 trials reveals that the rate of symptomatic ICH was nearly double in our study (11%, compared with 6% in the NINDS trial), while the mortality was slightly higher in our study (23% versus 18%). The fact that our trial involved patients with milder stroke may be confounding these results: if we had had patients with more severe stroke, it is possible that our symptomatic ICH rate could have been even higher. The major difference between the studies was the time of treatment, with only 15% of patients in our trial receiving rtPA in <3 hours.
Our study was completed in 1993, and the results have remained unknown
until this year. As such, it provides an opportunity to see how stroke
trial methodology has changed during the past decade. In the early
1990s many stroke trials were using a 4-point change in the NIHSS as a
primary end point. In the power calculations for this study, it was
estimated that approximately 30% of placebo patients would achieve
this level of recovery. However, as our study illustrates, a much
higher percentage of patients spontaneously achieve this degree of
improvement, with 75% of our placebo group meeting this criteria at 30
days. This high spontaneous recovery rate is likely to produce a type
II error unless a prohibitively high number of patients are used in a
trial. Our trial also illustrates that the timing of the efficacy end
point is also important. Using the NIHSS 4-point improvement
criterion, we found a benefit in favor of rtPA at 24 hours; however, a
significant negative treatment effect for rtPA treatment was seen at 30
days with the same end point. Clearly, a successful therapy must
produce beneficial effects that are still present at later time
points. Our trial and others also tried to utilize infarct size
determination as a primary end point. As seen in this study, the high
variability in clinical stroke size again is likely to produce a type
II error unless large numbers of patients are used. To avoid these
problems, subsequent trials adopted a more stringent neurological
criterion end point: eg, an "excellent recovery" on the NIHSS (0 or
1). If this criterion at 30 days had been the primary end point in our
study, it would have been a positive trial, with 25% of placebo and
35% of rtPA patients having full recoveries (P=0.04). This
illustrates the danger in this approach, because using this end point
alone ignores the possibility that the treatment may concurrently be
increasing the percentage of patients with death or poor outcomes. To
avoid this error and to provide end points that are clinically
meaningful, most stroke trials have now adopted end points based on
categorized functional outcomes. Such analyses allow a
determination of whether the increase in excellent outcomes is
accompanied by an increase in severe disability or death. In our study,
such an analysis (see Figure 1) illustrates that overall
there is no net benefit for rtPA in this population.
This study confirms that patients with large strokes (NIHSS >20) have very poor outcomes. In our study there was a 70% 3-month mortality rate in placebo-treated patients and a 100% 3-month mortality rate in rtPA-treated patients. These patients also had a markedly increased rate of symptomatic ICH hemorrhage with rtPA therapy (38%). In the NINDS <3-hour study, patients with severe strokes also had poor outcomes and increased risk of ICH, although in that study this subgroup (NIHSS >20) still had a beneficial rtPA treatment effect (Rankin score of 0 or 1, 10% rtPA versus 4% placebo).8 In our study, patients treated >5 hours after onset had the worst outcomes and highest incidence of ICH. However, due to the imbalance of severe strokes in this group, it is impossible to tell whether the increased symptomatic ICH and mortality rates were caused by the time delay or the stroke severity.
Since our study was completed, 3 additional randomized trials have investigated rtPA therapy in patients primarily treated within 3 to 6 hours of onset. These trials include the initial ECASS I study2 ; a later, revised ECASS II trial9 ; and part B of our study, called the ATLANTIS trial, performed in North America.3 All 3 of these large, randomized trials have failed to find significant treatment benefit for rtPA on their primary end points in their ITT population and have reported symptomatic ICH rates associated with rtPA of 7% to 8%. In post hoc analyses the ECASS II trial but not the ATLANTIS trial found that a higher percentage of patients treated with rtPA had a "good" recovery on the Rankin scale (scores of 0, 1, or 2) at 90 days. In comparison to these studies, our trial had a higher incidence of symptomatic ICH despite having a similar baseline stroke severity. Taken together, these studies do not appear to support the use of rtPA beyond 3 hours. Because the vast majority (>80%) of patients in these trials were enrolled after 3 hours, these negative results do not apply to patients treated with rtPA as approved within 3 hours. This time limitation is particularly important in light of a recent phase IV trial involving rtPA in North America, which found that >15% of patients are actually being treated beyond 3 hours, even at experienced stroke centers.10
Conclusions
The results of our Thrombolytic Therapy in Acute
Ischemic Stroke Study Trial, Part A, failed to find a treatment
benefit for rtPA given within 0 to 6 hours after stroke onset. Although
rtPA treatment appears to increase the number of patients with early
dramatic recoveries, no net treatment benefits were seen on the planned
end points at 30 and 90 days. In the 0- to 6-hour population in this
study, the risk of death and symptomatic ICH may be higher
than that reported for patients treated in <3 hours. Although the
results of our study are based on a relatively small number of
patients, when taken together with the primary results of the ECASS I,
ECASS II, and ATLANTIS part B trials, the use of
intravenous rtPA in a general population of stroke patients
presenting >3 hours after onset is not supported. These negative
results apply only to patients treated with rtPA >3 hours after
symptom onset. Further investigations with new imaging
techniques to identify subgroups of patients that may still benefit
from intravenous thrombolysis after 3 hours
or those utilizing new thrombolytic delivery approaches
are needed.
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Appendix |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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The following sites successfully enrolled patients for the Thrombolytic Therapy in Acute Ischemic Stroke Study Trial, Part A.
Albany Medical Center, Albany, NY (2 patients): Steven Horowitz, MD, principal investigator; Midge Manning, RN. Buffalo General Hospital, Buffalo, NY (1): Frederick Munschauer III, MD, principal investigator; Margo Hens, RN, MS. Denver General Hospital, Denver, Colo (8): Richard Hughes, MD, principal investigator; Vivian Noonan, RN. Duke University Medical Center, Durham, NC (1): Mark Alberts, MD, principal investigator; Cheryl McClenny, RN. Evanston Hospital, Evanston, Ill (1): Daniel Homer, MD, principal investigator; Debbie Heldenreich, RN. The Graduate Hospital, Philadelphia, Pa (2): Howard Hurtig, MD, principal investigator; Brett Skolnick, PhD. Marshfield Clinic, Marshfield, Wis (15): Kenneth Madden, MD, principal investigator; Charmaine Matti, RN. Medical College of Georgia Research, August, Ga (20): David Hess, MD, principal investigator; Angela Touhey, RN. Noran Neurological Clinic, PA, Minneapolis, Minn (5): Richard Koller, MD, principal investigator; A. Benker, RN. Oregon Stroke Center, Portland, Ore (29): Wayne Clark, MD, principal investigator; Kathy Kearns, RN. Parkview Memorial Hospital, Fort Wayne, Ind (6): Stanley Wissman, MD, principal investigator; Mary Ann Wissman, RN, MSN. St. Joseph Hospital, Wichita, Kan (10): Mark Mandelbaum, MD, principal investigator; Le Sedlacek, RN. San Francisco General Hospital, San Francisco, Calif (3): Roger Simon, MD, principal investigator; Faith Allen, RN. San Francisco General Hospital, San Francisco, Calif (13): Wade Smith, MD, principal investigator; Faith Allen, RN. Stanford University Medical Center, Palo Alto, Calif (19): Gregory Albers, MD, principal investigator; Nanette Hock, RN, MS. University of Arizona Health Sciences Center, Tucson, Ariz (3): William Feinberg, MD, principal investigator; Karen MacKay, RN. Vanderbilt Medical Center, Nashville, Tenn (4): Howard Kirshner, MD, principal investigator; Ann Nelson, RN.
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Acknowledgments |
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This study was funded by Genentech, Inc. The authors wish to thank Valerie Roska for her assistance with this manuscript.
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Footnotes |
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This study was funded by Genentech, Inc.
Received August 30, 1999; revision received January 6, 2000; accepted January 6, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
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[Abstract/Free Full Text] - Hacke W, Kaste M, Fieshchi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnon G, Schneider D, Diez-Tejedor E, Trouillas P (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]
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D. M. Kent, L. L. Price, P. Ringleb, M. D. Hill, and H. P. Selker Sex-Based Differences in Response to Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke: A Pooled Analysis of Randomized Clinical Trials Stroke, January 1, 2005; 36(1): 62 - 65. [Abstract] [Full Text] [PDF]
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Y. Pierre Gobin, S. Starkman, G. R. Duckwiler, T. Grobelny, C. S. Kidwell, R. Jahan, J. Pile-Spellman, A. Segal, F. Vinuela, and J. L. Saver MERCI 1: A Phase 1 Study of Mechanical Embolus Removal in Cerebral Ischemia Stroke, December 1, 2004; 35(12): 2848 - 2854. [Abstract] [Full Text] [PDF]
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J. W. Simpkins, S.-H. Yang, R. Liu, E. Perez, Z. Y. Cai, D. F. Covey, and P. S. Green Estrogen-Like Compounds for Ischemic Neuroprotection Stroke, November 1, 2004; 35(11_suppl_1): 2648 - 2651. [Abstract] [Full Text] [PDF]
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 G. W. Albers, P. Amarenco, J. D. Easton, R. L. Sacco, and P. Teal Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 483S - 512S. [Abstract] [Full Text] [PDF]
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C. S. Weaver, J. Leonardi-Bee, F. J. Bath-Hextall, and P. M.W. Bath Sample Size Calculations in Acute Stroke Trials: A Systematic Review of Their Reporting, Characteristics, and Relationship With Outcome Stroke, May 1, 2004; 35(5): 1216 - 1224. [Abstract] [Full Text] [PDF]
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D. M. Kent, J. Hinchey, L. L. Price, S. R. Levine, and H. P. Selker In Acute Ischemic Stroke, Are Asymptomatic Intracranial Hemorrhages Clinically Innocuous? Stroke, May 1, 2004; 35(5): 1141 - 1146. [Abstract] [Full Text] [PDF]
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R. T. Higashida and A. J. Furlan Trial Design and Reporting Standards for Intra-Arterial Cerebral Thrombolysis for Acute Ischemic Stroke Stroke, August 1, 2003; 34(8): e109 - 137. [Abstract] [Full Text] [PDF]
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J.M. Wardlaw, P.A.G. Sandercock, and E. Berge Thrombolytic Therapy With Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke: Where Do We Go From Here? A Cumulative Meta-Analysis Stroke, June 1, 2003; 34(6): 1437 - 1442. [Abstract] [Full Text] [PDF]
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 D. Saur, T. Kucinski, U. Grzyska, B. Eckert, C. Eggers, W. Niesen, V. Schoder, H. Zeumer, C. Weiller, and J. Rother Sensitivity and Interrater Agreement of CT and Diffusion-Weighted MR Imaging in Hyperacute Stroke AJNR Am. J. Neuroradiol., May 1, 2003; 24(5): 878 - 885. [Abstract] [Full Text] [PDF]
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H. P. Adams Jr, R. J. Adams, T. Brott, G. J. del Zoppo, A. Furlan, L. B. Goldstein, R. L. Grubb, R. Higashida, C. Kidwell, T. G. Kwiatkowski, et al. Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association Stroke, April 1, 2003; 34(4): 1056 - 1083. [Full Text] [PDF]
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B. R. Mahon, G. M. Nesbit, S. L. Barnwell, W. Clark, T. R. Marotta, A. Weill, P. A. Teal, and A. I. Qureshi North American Clinical Experience with the EKOS MicroLysUS Infusion Catheter for the Treatment of Embolic Stroke AJNR Am. J. Neuroradiol., March 1, 2003; 24(3): 534 - 538. [Abstract] [Full Text] [PDF]
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 W. F. Baker Jr Thrombolytic Therapy Clinical and Applied Thrombosis/Hemostasis, October 1, 2002; 8(4): 291 - 314. [PDF]
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 J. P. Broderick and W. Hacke Treatment of Acute Ischemic Stroke: Part I: Recanalization Strategies Circulation, September 17, 2002; 106(12): 1563 - 1569. [Full Text] [PDF]
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C. A. Molina, J. Alvarez-Sabin, J. Montaner, S. Abilleira, J. F. Arenillas, P. Coscojuela, F. Romero, and A. Codina Thrombolysis-Related Hemorrhagic Infarction: A Marker of Early Reperfusion, Reduced Infarct Size, and Improved Outcome in Patients With Proximal Middle Cerebral Artery Occlusion Stroke, June 1, 2002; 33(6): 1551 - 1556. [Abstract] [Full Text] [PDF]
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 J. Lenzer, C. Warlow, J. L Saver, C. S Kidwell, and S. Starkman Alteplase for stroke: money and optimistic claims buttress the "brain attack" campaign * Commentary: Who pays the guideline writers? * Commentary: Thrombolysis in stroke: it works! BMJ, March 23, 2002; 324(7339): 723 - 729. [Full Text] [PDF]
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G. W. Albers, W. M. Clark, K. P. Madden, S. A. Hamilton, S. M. Davis, and G. A. Donnan ATLANTIS Trial: Results for Patients Treated Within 3 Hours of Stroke Onset * Editorial Comment: Results for Patients Treated Within 3 Hours of Stroke Onset Stroke, February 1, 2002; 33(2): 493 - 496. [Abstract] [Full Text] [PDF]
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J. R. Toomey, R. E. Valocik, P. F. Koster, M. A. Gabriel, M. McVey, T. K. Hart, E. H. Ohlstein, A. A. Parsons, and F. C. Barone Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke Stroke, February 1, 2002; 33(2): 578 - 585. [Abstract] [Full Text] [PDF]
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 S. Ishikawa, K. Yokoyama, T. Kuroiwa, and K. Makita Evolution of cerebral ischaemia induced by thromboembolism in rats detected by early sequential MR imaging Br. J. Anaesth., September 1, 2001; 87(3): 469 - 476. [Abstract] [Full Text] [PDF]
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C. A. Molina, J. Montaner, S. Abilleira, B. Ibarra, F. Romero, J. F. Arenillas, and J. Alvarez-Sabín Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke Stroke, May 1, 2001; 32(5): 1079 - 1084. [Abstract] [Full Text]
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