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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]
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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.
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