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Background Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
Methods After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
Results We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
Conclusions As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036
[ClinicalTrials.gov]
.)
A subsequent analysis of the NINDS study4 and the combined analysis5 of data from six randomized trials,1,2,3,6,7 which investigated thrombolysis treatment for ischemic stroke in a total of 2775 patients, showed a clear association between treatment efficacy and the interval between the onset of symptoms and administration of the thrombolytic agent. In the pooled analysis, a favorable outcome was observed even if treatment was given between 3 and 4.5 hours, with an odds ratio of 1.4 for a favorable outcome with alteplase treatment as compared with placebo. This analysis also suggested that the longer time window, as compared with the shorter window, was not associated with higher rates of symptomatic intracranial hemorrhage or death.5 International guidelines recommend alteplase as a first-line treatment for eligible patients when administered within 3 hours after the onset of stroke.8,9,10 Despite this recommendation, alteplase is underused; it is estimated that fewer than 2% of patients receive this treatment in most countries, primarily because of delayed admission to a stroke center.11
Thrombolysis with alteplase has been approved in most countries. In Europe, the European Medicines Agency (EMEA) granted approval of alteplase in 2002 but included two requests. One request was that an observational safety study be initiated; subsequently, the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS–MOST) was undertaken. This study confirmed that alteplase is as safe and effective in routine clinical practice as it is in randomized trials.12 The second request was that a randomized trial be conducted in which the therapeutic time window was extended beyond 3 hours.
We describe the results of ECASS III, a randomized, placebo-controlled, phase 3 trial designed to test the hypothesis that the efficacy of alteplase administered in patients with acute ischemic stroke can be safely extended to a time window of 3 to 4.5 hours after the onset of stroke symptoms.
Methods
Patient Population and Study Design
ECASS III was a double-blind, parallel-group trial that enrolled patients from multiple centers across Europe (see the Appendix). Patients were eligible for inclusion in the study if they were 18 to 80 years of age, had received a clinical diagnosis of acute ischemic stroke, and were able to receive the study drug within 3 to 4 hours after the onset of symptoms. A cerebral computed tomographic (CT) scan was required before randomization to exclude patients who had an intracranial hemorrhage or major ischemic infarction. In some cases, magnetic resonance imaging (MRI) was performed instead of CT (Figure 1). The inclusion and exclusion criteria are summarized in Table 1. In May 2005, after 228 patients had been enrolled, the study protocol was amended, and the time window of 3 to 4 hours was extended by 0.5 hour (3 to 4.5 hours). There were two reasons for the extension of the time window: the publication of the pooled analysis, which suggested that patients may benefit from thrombolytic treatment administered up to 4.5 hours after the onset of symptoms,5 and a slow rate of patient recruitment. The trial protocol and the amendments were accepted by the EMEA and were approved by the institutional review boards of the participating centers. All patients or legally authorized representatives gave written informed consent before enrollment.
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Eligible patients were randomly assigned, in a 1:1 ratio, to receive 0.9 mg of alteplase (Actilyse, Boehringer Ingelheim) per kilogram, administered intravenously (with an upper limit of 90 mg), or placebo. An interactive voice-randomization system was used, with randomization at centers performed in blocks of four to ensure a balanced distribution of group assignments at any time. The size of the blocks was withheld from the investigators to make sure that they were unaware of the treatment assignments. Alteplase and matched placebo were reconstituted from a lyophilized powder in sterile water for injection. Of the total dose, 10% was administered as a bolus, and the remainder was given by continuous intravenous infusion over a period of 60 minutes. With the exception of the extended time window, alteplase was to be used in accordance with current European labeling.
Study Management
The steering committee designed and oversaw the trial. An independent data and safety monitoring board regularly monitored the safety of the trial. The data and safety monitoring board did not have access to functional outcome data but received a group assignment of A or B for death and C or D for monitoring of symptomatic intracranial hemorrhage to ensure unbiased review of each of the two main safety outcomes. The chair of the data and safety monitoring board, who contributed to the design of the trial but had no role in the conduct of the study, was invited to be part of the writing committee after completion of the trial. Monitoring and data management were undertaken by the sponsor of the trial. Statistical analyses were performed simultaneously by an independent external statistician and the statistician of the sponsor. The steering committee had complete access to the trial data after the database had been locked and assumed complete responsibility for the final statistical analysis and interpretation of the results. All study committees are listed in the Appendix. All the authors vouch for the accuracy and completeness of the data and analyses.
Concomitant Therapies
Treatment with intravenous heparin, oral anticoagulants, aspirin, or volume expanders such as hetastarch or dextrans during the first 24 hours after administration of the study drug had been completed was prohibited. However, the use of subcutaneous heparin (
10,000 IU), or of equivalent doses of low-molecular-weight heparin, was permitted for prophylaxis against deep-vein thrombosis.
Clinical Assessment
Patients were assessed by an examiner who was unaware of the treatment assignment. Assessments were made at the time of enrollment, at 1, 2, and 24 hours after administration of the study drug was begun, and on days 7, 30, and 90 after administration of the drug. In addition, the patients' clinical condition (e.g., blood pressure, oxygenation, and heart rate) was closely monitored for the first 24 hours. Initial assessments included a physical examination, CT or MRI, and the quantification of any neurologic deficit with the use of the National Institutes of Health Stroke Scale (NIHSS), a 15-item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe cerebral infarcts (<5, mild impairment; 
25, very severe neurologic impairment).13 Examiners were trained and certified in the use of the NIHSS examination. Patients were assessed with the NIHSS on days 1, 7, 30, and 90. The modified Rankin scale,14 a measure of disability, was used to assess patients on days 30 and 90. Scores on the modified Rankin scale range from 0 (no symptoms at all) to 6 (death); a score of 5 indicates severe disability (the patient is bedridden and incontinent and requires constant nursing care and attention). Investigators were instructed in the use of the modified Rankin scale by watching video clips from a training DVD.15 During the follow-up period, two other commonly used functional scales were also applied16: the Barthel Index17 and the Glasgow Outcome Scale.18 The Barthel Index, which assesses the ability to perform activities of daily living, on a scale that ranges from 0 (complete dependence on help with activities of daily living) to 100 (independence), was scored on days 30 and 90. We assigned a score of 0 to patients who died. The Glasgow Outcome Scale, a 5-point scale on which 1 indicates independence, 3 severe disability, and 5 death, was scored on day 90.
Assessment of Hemorrhages and Adjudication of Symptomatic Intracranial Hemorrhage
CT or MRI was performed before treatment and 22 to 36 hours after treatment. Additional CT studies were performed at the discretion of the investigators. Members of the safety outcome adjudication committee, who were unaware of the treatment assignments, reviewed all CT or MRI scans, classified the findings according to the ECASS morphologic definitions,2 and logged the results in a database. On the basis of these findings, the chairs of the safety outcome adjudication committee and the steering committee, who remained unaware of the treatment assignments, together adjudicated whether each death or score change indicating neurologic deterioration was likely to have been due to intracranial hemorrhage, other brain injury or disease, or neither of these causes.
Outcome Measures
The primary efficacy end point was disability at day 90 (3-month visit), as assessed by means of the modified Rankin scale, dichotomized as a favorable outcome (a score of 0 or 1) or an unfavorable outcome (a score of 2 to 6). The secondary efficacy end point was a global outcome measure that combined the outcomes at day 90 of a score of 0 or 1 on the modified Rankin scale, a score of 95 or higher on the Barthel Index, a score of 0 or 1 on the NIHSS, and a score of 1 on the Glasgow Outcome Scale.1 Further functional end points were based on predefined cutoff points for the NIHSS score (a score of 0 or 1, or more than an 8-point improvement in the score), the score on the modified Rankin scale (dichotomized as 0 to 2 or 3 to 6), and the Barthel Index (95 points), assessed on day 90 and also on day 30. Because of recent interest in the scientific community in a stratified analysis of the outcome distribution of the modified Rankin scale at day 90, this type of evaluation was undertaken according to the methods described previously.19
Safety end points included overall mortality at day 90, any intracranial hemorrhage, symptomatic intracranial hemorrhage, symptomatic edema (defined as brain edema with mass effect as the predominant cause of clinical deterioration), and other serious adverse events. In the ECASS III protocol, symptomatic intracranial hemorrhage was defined as any apparently extravascular blood in the brain or within the cranium that was associated with clinical deterioration, as defined by an increase of 4 points or more in the score on the NIHSS, or that led to death and that was identified as the predominant cause of the neurologic deterioration. To allow comparison with published data, a post hoc analysis of rates of symptomatic intracranial hemorrhage was also performed according to definitions used in other trials.1,3,12,20
Statistical Analysis
Efficacy end points were assessed in the intention-to-treat population, which included all randomly assigned patients, whether or not they were treated. In the case of missing data on outcome among patients known to be alive, the worst possible outcome score was assigned. For the primary end point, between-group differences were calculated with the use of the chi-square test of proportions (with a two-sided alpha level of 5%). Ninety-five percent confidence intervals were calculated for odds ratios and for relative risk. In keeping with the study protocol, all predefined analyses were performed without adjustment for confounding factors. A post hoc adjusted analysis (logistic regression) of the primary end point was undertaken in the intention-to-treat population. This analysis was performed by including all baseline variables in the model and retaining those that were significant at P<0.10. For the secondary end point — the probability of a favorable outcome with alteplase as compared with placebo — a global odds-ratio test based on a linear logistic-regression model (a method that uses generalized estimation equations to perform a Wald-type test)21,22 was used. For the per-protocol population (Figure 1), the same statistical tests were applied. The post hoc stratified analysis of scores on the modified Rankin scale was adjusted for the two most strongly prognostic baseline variables: the NIHSS score and the time to the start of treatment.19
The calculation of the sample size was based on the analysis of pooled data from the cohorts that received thrombolysis or placebo between 3 and 4.5 hours after the onset of symptoms5 (with data from the first ECASS trial3 excluded because of the higher dose of alteplase used in that trial). On the basis of these data, we calculated that 400 patients per group were required in order to have 90% power to detect an odds ratio of 1.4 for the primary end point.
Results
Study Patients
Between July 29, 2003, and November 13, 2007, a total of 821 patients from 130 sites in 19 European countries were randomly assigned to a study group: 418 patients were assigned to receive alteplase and 403 patients were assigned to receive placebo (Figure 1). Grouped according to 0.5-hour intervals, 10.0% of the patients were treated between 3 and 3.5 hours, 46.8% between 3.5 and 4 hours, and 39.2% between 4 and 4.5 hours (Table 2). (The values do not add up to 100% because data on the exact time of treatment initiation were not available for 12 patients in the alteplase group and 15 patients in the placebo group; in addition, treatment was initiated after 4.5 hours in 1 patient in the alteplase group and 5 patients in the placebo group.) Baseline demographic and clinical characteristics of the two groups were similar (Table 2), except that there were significant differences between the groups (before adjustment for multiple comparisons) with respect to the initial severity of the stroke and the presence or absence of a history of stroke.
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For the primary end point, 219 of the 418 patients in the alteplase group (52.4%) had a favorable outcome (defined as a score of 0 or 1 on the modified Rankin scale), as compared with 182 of the 403 patients in the placebo group (45.2%), representing an absolute improvement of 7.2 percentage points (odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; relative risk, 1.16; 95% CI, 1.01 to 1.34; P=0.04). In the post hoc intention-to-treat analysis, adjusted for confounding baseline variables (logistic regression), study-group assignment, baseline NIHSS score, smoking status, time from the onset of stroke to treatment, and presence or absence of prior hypertension were identified as significant at P<0.10. In the adjusted analysis, treatment with alteplase remained significantly associated with a favorable outcome (odds ratio, 1.42; 95% CI, 1.02 to 1.98; P=0.04) (Table 3 and Fig. S1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org).
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The overall distribution of scores on the modified Rankin scale is shown in Figure 2. The post hoc stratified analysis of scores on the modified Rankin scale at day 90 (performed with the use of the Cochran–Mantel–Haenszel test, with adjustment for the baseline NIHSS score and time to the start of treatment) also showed a favorable outcome with alteplase as compared with placebo (P=0.02).
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A total of 66 patients died — 32 of the 418 patients in the alteplase group (7.7%) and 34 of the 403 in the placebo group (8.4%). Of these 66 patients, 25 died between days 1 and 7 (12 [2.9%] in the alteplase group and 13 [3.2%] in the placebo group), 18 between days 8 and 30 (10 [2.4%] and 8 [2.0%], respectively), and 16 between days 31 and 90 (6 [1.4%] and 10 [2.5%], respectively). Seven patients died after day 90 (four [1.0%] and three [0.7%], respectively).
There were more cases of intracranial hemorrhage in the alteplase group than in the placebo group (27.0% vs. 17.6%, P=0.001). The incidence of symptomatic intracranial hemorrhage with alteplase was less than 3 cases per 100 patients (10 of 418 patients [2.4%]), but that incidence was significantly higher than the incidence with placebo (1 of 403 [0.3%]; odds ratio, 9.85; 95% CI, 1.26 to 77.32; P=0.008). The incidence of symptomatic intracranial hemorrhage according to definitions used in other studies followed a similar pattern (Table 5 and Fig. S2 in the Supplementary Appendix). All symptomatic intracranial hemorrhages occurred within the first 22 to 36 hours after initiation of treatment.
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Discussion
In this randomized, placebo-controlled study, patients with acute ischemic stroke benefited from treatment with intravenous alteplase administered 3 to 4.5 hours after the onset of stroke symptoms. ECASS III is the second randomized trial (after the NINDS trial of 19951) to show a significant treatment effect with intravenous alteplase in the unadjusted analysis of the primary end point. The treatment effect remained significant after adjustment for all prognostic baseline characteristics. The overall rate of symptomatic intracranial hemorrhage was increased with alteplase as compared with placebo, but mortality was not affected. Both of these findings are consistent with results from other randomized, controlled trials of thrombolysis in patients with acute ischemic stroke.1,5,23 The results of the analysis of secondary end points and of the post hoc stratified analysis mirrored the primary efficacy results in favor of alteplase.
The initial severity of a stroke is a strong predictor of the functional and neurologic outcome and of the risk of death. Patients with severe stroke were excluded from this trial in order to meet the protocol requirements requested by the EMEA and to conform with the European label of alteplase. It is likely that the milder initial severity of stroke overall among patients enrolled in this trial as compared with those in the NINDS trial1 explains, for the most part, the improved outcomes in the placebo group in our study as compared with the outcomes in the placebo group in the NINDS trial. Outcomes in the placebo group in our study were similar to those observed in ECASS II.3
In this context, it is interesting to note that there has been a gradual decline in the overall initial severity of stroke and in mortality rates among patients enrolled in major randomized studies of acute ischemic stroke over the past two decades.1,2,3 This observation may reflect the trend toward the use of thrombolytic agents in patients who have less severe acute ischemic stroke, as reflected in the results of SITS–MOST,12 as well as the increased number of stroke units in Europe and the improved care provided in such units.
Some of the previous trials of treatment with alteplase for acute ischemic stroke included patients who received treatment within 0 to 6 hours after the onset of symptoms. However, these trials failed to show a significant advantage of alteplase therapy.2,3,6,24 Potential explanations for the failure to show a significant difference in previous trials include the choice of end points, a time window of up to 6 hours, and a lack of statistical power. (In the ECASS II3 and in the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS] trial,6 the cohorts that were treated 3 to 4.5 hours after the onset of symptoms were much smaller, and these studies were therefore not powered to detect an effect size of 7 to 10%.)
Thrombolysis in patients with acute ischemic stroke is associated with an increased risk of symptomatic intracranial hemorrhage, which is the most feared complication. It is difficult, however, to compare the incidence of symptomatic intracranial hemorrhage across studies because of the varying definitions used. In our study, we modified the ECASS definition of symptomatic intracranial hemorrhage by specifying that the hemorrhage had to have been identified as the predominant cause of the neurologic deterioration. With the use of this definition, the difference in rates of symptomatic intracranial hemorrhage between the two study groups was significant (a difference of 2.14 percentage points), although the incidence of symptomatic intracranial hemorrhage among alteplase-treated patients was low. To allow for comparison across trials, we also analyzed rates of symptomatic intracranial hemorrhage according to definitions used in other trials.1,2,3,20 With these definitions, the rate of symptomatic intracranial hemorrhage in our trial was no higher than that reported in previous randomized trials or in SITS–MOST, despite the extended time window in our study.12
Although in our trial the incidence of symptomatic intracranial hemorrhage was higher in the alteplase group than in the placebo group, we did not observe a difference in mortality between the two groups. The overall mortality rate (approximately 8%) was lower than that in previous trials, probably also owing to the inclusion of patients with less severe strokes.
Early treatment remains essential. The effect size of thrombolysis is time-dependent. In the pooled analysis, treatment with alteplase is nearly twice as efficacious when administered within the first 1.5 hours after the onset of a stroke as it is when administered within 1.5 to 3 hours afterward (odds ratio for the global outcome, 2.81 for an interval of 0 to 90 minutes, 1.55 for 91 to 180 minutes, and 1.40 for 181 to 270 minutes).5 In comparison, in ECASS III, the odds ratio was 1.34 for an interval of 181 to 270 minutes. For 1 patient to have a favorable outcome (a score of 0 or 1 on the modified Rankin scale), the number needed to treat is 14 with the extended time window. This effect size is clinically meaningful and thus extends the treatment window for patients who do not arrive at the hospital early. It does not mean, however, that patients who can be treated within 3 hours should have their treatment delayed. The "door-to-needle" time remains paramount and must be kept as short as possible to increase the chance of a positive outcome.
In this study, intravenous alteplase given 3 to 4.5 hours (median, 3 hours 59 minutes) after the onset of stroke symptoms was associated with a modest but significant improvement in the clinical outcome, without a higher rate of symptomatic intracranial hemorrhage than that reported previously among patients treated within 3 hours. Although our findings suggest that treatment with alteplase may be effective in patients who present 3 to 4.5 hours after the onset of stroke symptoms, patients should be treated with alteplase as early as possible to maximize the benefit. Having more time does not mean we should be allowed to take more time.
Supported by Boehringer Ingelheim.
Dr. Hacke reports receiving consulting, advisory board, and lecture fees from Paion, Forest Laboratories, Lundbeck, and Boehringer Ingelheim and grant support from Lundbeck; Dr. Brozman, receiving consulting and lecture fees from Sanofi-Aventis and consulting fees and grant support from Boehringer Ingelheim; Dr. Davalos, receiving consulting fees from Boehringer Ingelheim, the Ferrer Group, Paion, and Lundbeck and lecture fees from Boehringer Ingelheim, Pfizer, Ferrer Group, Paion, and Bristol-Myers Squibb; Dr. Kaste, receiving consulting and lecture fees from Boehringer Ingelheim; Dr. Larrue, receiving consulting fees from Pierre Fabre; Dr. Lees, receiving consulting fees from Boehringer Ingelheim, Paion, Forest, and Lundbeck, lecture fees from the Ferrer Group, and grant support from Boehringer Ingelheim; Dr. Schneider, receiving consulting fees from the Ferrer Group, D-Pharm, BrainsGate, and Stroke Treatment Academic Industry Round Table (STAIR) and lecture fees from Boehringer Ingelheim and Trommsdorff Arzneimittel; Dr. von Kummer, receiving consulting fees from Boehringer Ingelheim and Paion and lecture fees from Boehringer Ingelheim and Bayer Schering Pharma; Dr. Wahlgren, receiving consulting fees from ThromboGenics, lecture fees from Ferrer and Boehringer Ingelheim, and grant support from Boehringer Ingelheim; Dr. Toni, receiving consulting fees from Boehringer Ingelheim and lecture fees from Boehringer Ingelheim, Sanofi-Aventis, and Novo Nordisk; and Drs. Bluhmki, Machnig, and Medeghri, being employees of Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Neurology, Universität Heidelberg, Heidelberg, Germany (W.H.); the Department of Neurology, Helsinki University Central Hospital, Helsinki (M.K.); the Department of Statistics, Boehringer Ingelheim, Biberach, Germany (E.B.); the Neurology Clinic, University Hospital Nitra, Nitra, Slovakia (M.B.); the Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (A.D.); the Department of Neurology, Hospital of Piacenza, Piacenza, Italy (D.G.); the Department of Neurology, University of Toulouse, Toulouse, France (V.L.); the Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom (K.R.L.); Boehringer Ingelheim, Reims, France (Z.M.); Boehringer Ingelheim, Ingelheim, Germany (T.M.); the Department of Neurology, Universität Leipzig, Leipzig, Germany (D.S.); the Department of Neuroradiology, Technische Universität Dresden, Dresden, Germany (R.K.); the Department of Neurology, Karolinska Institutet, Stockholm (N.W.); and the Department of Neurological Sciences, University La Sapienza, Rome (D.T.).
Address reprint requests to Dr. Hacke at the Department of Neurology, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany, or at werner.hacke{at}med.uni-heidelberg.de.
References
The European Cooperative Acute Stroke Study (ECASS) investigators are as follows: Steering Committee — W. Hacke (chair), A. Dávalos, M. Kaste, R. von Kummer, V. Larrue, D. Toni, N. Wahlgren; Data and Safety Monitoring Board — K.R. Lees (chair), W.D. Heiss, E. Lesaffre, J.M. Orgogozo; Safety Outcome Adjudication Committee — R. von Kummer (chair), S. Bastianello, J.M. Wardlaw; Statisticians — J.-C. Peyrieux (STATMED, Lyon, France), C. Sauce (Boehringer Ingelheim); Trial Management Team at Boehringer Ingelheim — Z. Medeghri, R. Mazenc, C. Sauce, T. Machnig, E. Bluhmki; principal investigators (with the number of patients enrolled given in parentheses) — Austria (53): F. Aichner, C. Alf, U. Baumhackl, M. Brainin, C. Eggers, F. Gruber, G. Ladurner, K. Niederkorn, G. Noistering, J. Willeit; Belgium (22): G. Vanhooren (national coordinator), S. Blecic, B. Bruneel, J. Caekebeke, P. Laloux, P.J. Simons, V. Thijs; Czech Republic (18): M. Bar, H. Dvorakova, D. Vaclavik; Denmark (44): G. Boysen (national coordinator), G. Andersen, H.K. Iversen, B. Traberg-Kristensen; Finland (15): M. Kaste (national coordinator), R. Marttila, J. Sivenius; France (104): P. Trouillas (national coordinator), P. Amarenco, J. Bouillat, X. Ducrocq, M. Giroud, A. Jaillard, J.-M. Larrieu, V. Larrue, D. Leys, C. Magne, M.-H. Mahagne, D. Milhaud, D. Sablot, D. Saudeau; Germany (130): O. Busse (national coordinator), J. Berrouschot, J.H. Faiss, J. Glahn, M. Görtler, A. Grau, M. Grond, R. Haberl, G. Hamann, M. Hennerici, H. Koch, P. Krauseneck, J. Marx, S. Meves, U. Meyding-Lamadé, P. Ringleb, D. Schneider, A. Schwarz, J. Sobesky, P. Urban; Greece (2): K. Karageorgiou (national coordinator), A. Komnos; Hungary (9): A. Csányi, L. Csiba, A. Valikovics; Italy (147): D. Toni (national coordinator), G. Agnelli, G. Billo, P. Bovi, G. Comi, G. Gigli, D. Guidetti, D. Inzitari, N. Marcello, C. Marini, G. Orlandi, M. Pratesi, M. Rasura, A. Semplicini, C. Serrati, T. Tassinari; the Netherlands (5): P.J.A.M. Brouwers (national coordinator), J. Stam (national coordinator); Norway (14): H. Naess (national coordinator), B. Indredavik, R. Kloster; Poland (16): A. Czlonkowska (national coordinator), A. Kuczy
ska-Zardzewialy, W. Nyka, G. Opala, S. Romanowicz; Portugal (13): L. Cunha (national coordinator), C. Correia, V. Cruz, T. Pinho e Melo; Slovakia (59): M. Brozman, M. Dvorak, R. Garay, G. Krastev, E. Kurca; Spain (111): J. Alvarez-Sabin (national coordinator), A. Chamorro, M. del Mar Freijo Guerrero, J.A.E. Herrero, A. Gil-Peralta, R. Leira, J.L. Martí-Vilalta, J. Masjuan Vallejo, M. Millán, C. Molina, E. Mostacero, T. Segura, J. Serena, J. Vivancos Mora; Sweden (14): E. Danielsson (national coordinator), B. Cederin, E. von Zweigberg, N.-G. Wahlgren, L. Welin; Switzerland (23): P. Lyrer (national coordinator), J. Bogousslavsky, H.-J. Hungerbühler, B. Weder; United Kingdom (22): G.A. Ford (national coordinator), D. Jenkinson, M.J. MacLeod, R.S. MacWalter, H.S. Markus, K.W. Muir, A.K. Sharma, M.R. Walters, E.A. Warburton.
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Related Letters:
Thrombolysis 3 to 4.5 Hours after Acute Ischemic Stroke
Torbey M. T., Jauch E., Liebeskind D. S., the Acute Stroke Advisory Board of the National Stroke Association , Fitzpatrick A. E., Noone I., O'Shea D. D., Schwamm L. H., Fonarow G. C., Morris D. C., Hacke W., Kaste M., Toni D.
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Full Text |
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N Engl J Med 2008;
359:2839-2841, Dec 25, 2008.
Correspondence
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