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N Engl J Med. 2008 Sep 25;359(13):1317-29. doi: 10.1056/NEJMoa0804656.

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.

Collaborators (154)

Hacke W, Dávalos A, Kaste M, von Kummer R, Larrue V, Toni D, Wahlgren N, Lees KR, Heiss WD, Lesaffre E, Orgogozo JM, von Kummer R, Bastianello S, Wardlaw JM, Peyrieux JC, Sauce C, Medeghri Z, Mazenc R, Sauce C, Machnig T, Bluhmki E, Aichner F, Alf C, Baumhackl U, Brainin M, Eggers C, Gruber F, Ladurner G, Niederkorn K, Noistering G, Willeit J, Vanhooren G, Blecic S, Bruneel B, Caekebeke J, Laloux P, Simons PJ, Thijs V, Bar M, Dvorakova H, Vaclavik D, Boysen G, Andersen G, Iversen HK, Traberg-Kristensen B, Kaste M, Marttila R, Sivenius J, Trouillas P, Amarenco P, Bouillat J, Ducrocq X, Giroud M, Jaillard A, Larrieu JM, Larrue V, Leys D, Magne C, Mahagne MH, Milhaud D, Sablot D, Saudeau D, Busse O, Berrouschot J, Faiss JH, Glahn J, Görtler M, Grau A, Grond M, Haberl R, Hamann G, Hennerici M, Koch H, Krauseneck P, Marx J, Meves S, Meyding-Lamadé U, Ringleb P, Schneider D, Schwarz A, Sobesky J, Urban P, Karageorgiou K, Komnos A, Csányi A, Csiba L, Valikovics A, Toni D, Agnelli G, Billo G, Bovi P, Comi G, Gigli G, Guidetti D, Inzitari D, Marcello N, Marini C, Orlandi G, Pratesi M, Rasura M, Semplicini A, Serrati C, Tassinari T, Brouwers PJ, Stam J, Naess H, Indredavik B, Kloster R, Czlonkowska A, Kuczyńska-Zardzewialy A, Nyka W, Opala G, Romanowicz S, Cunha L, Correia C, Cruz V, Pinho e Melo T, Brozman M, Dvorak M, Garay R, Krastev G, Kurca E, Alvarez-Sabin J, Chamorro A, del Mar Freijo Guerrero M, Herrero JA, Gil-Peralta A, Leira R, Martí-Vilalta JL, Masjuan Vallejo J, Millán M, Molina C, Mostacero E, Segura T, Serena J, Vivancos Mora J, Danielsson E, Cederin B, von Zweigberg, Wahlgren NG, Welin L, Lyrer P, Bogousslavsky J, Hungerbühler HJ, Weder B, Ford GA, Jenkinson D, MacLeod MJ, MacWalter RS, Markus HS, Muir KW, Sharma AK, Walters MR, Warburton EA.

Author information

  • 1Department of Neurology, Universität Heidelberg, Heidelberg, Germany. werner.hacke@med.uni-heidelberg.de

Abstract

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.)

2008 Massachusetts Medical Society

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