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N Engl J Med. 2018 Aug 16;379(7):611-622. doi: 10.1056/NEJMoa1804355. Epub 2018 May 16.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

Collaborators (369)

Krützelmann A, Beck C, Choe C, Voget D, Hoppe J, Schröder J, Rozanski M, Nave A, Wollboldt C, van Sloten I, Göhler J, Herm J, Jungehülsing J, Lückl J, Kröber JM, Schurig J, Koehler L, Schlemm L, Knops M, Roennefarth M, Ipsen N, Harmel P, Bathe-Peters R, Fleischmann R, Ganeshan R, Geran R, Hellwig S, Schmidt S, Tütüncü S, Krause T, Gramse V, Röther J, Michels P, Michalski D, Pelz J, Schulz A, Hobohm C, Weise C, Weise G, Orthgieß J, Pomrehn K, Wegscheid M, Mueller AK, Griebe M, Alonso A, Filipov A, Marzina A, Anders B, Bähr C, Hoyer C, Schwarzbach C, Weber C, Hornberger E, Pledl HW, Klockziem M, Stuermlinger M, Wittayer M, Wolf M, Meyer N, Eisele P, Steinert S, Sauer T, Held V, Nagel S, Veltkamp R, Schwarting S, Schwarz A, Gumbinger C, Hametner C, Amiri H, Purrucker J, Ciatipis M, Menn O, Mundiyanapurath S, Schieber S, Kessler T, Reiff T, Panitz V, Singer O, Foerch C, Lauer A, Männer A, Seiler A, Guerzoglu D, Schäfer JH, Filipski K, Lorenz M, Kurka N, Zeiner P, Pfeilschifter W, Dziewas R, Minnerup J, Albiker C, Ritter M, Seidel M, Dittrich R, Kallmünzer B, Bobinger T, Madzar D, Stark D, Sembill J, Macha K, Winder K, Breuer L, Koehrmann M, Spruegel M, Gerner S, Moeller S, Kraft P, Mackenrodt D, Kleinschnitz C, Elhfnawy A, Heinen F, Gunreben I, Poli S, Ziemann U, Gaenslen A, Schlak D, Haertig F, Russo F, Richter H, Ebner M, Ribitsch M, Weimar C, Zegarac V, Chen HC, Althaus K, Neugebauer H, Jüttler E, Meier J, Stösser S, Puetz V, Bodechtel U, Ostergaard L, Møller A, Damgaard D, Hougaard Dupont K, Poulsen M, Hjort N, Ruiz de Morales N, von Weitzel P, Harbo T, Hansen A, Christensen H, Aegidius K, Jeppesen L, Meden P, Rosenbaum S, Iversen H, Back C, Hansen J, Michelsen L, Truelsen T, Kristensen B, Vestergaard K, Oppel L, Swinnen B, Smets I, Demeestere J, Dobbels L, Brouns R, De Smedt A, DeKeyser J, Yperzeele L, Van Hooff RJ, Peeters A, Dusart A, Etexberria A, Hanseeuw B, London F, Leempoel J, Hohenbichler K, Younan N, Maqueda V, Laloux P, De Coene B, De Maeseneire C, Turine G, Vandermeeren Y, De Klippel N, Willems C, de Hollander I, Soors P, Hermans S, Hemelsoet D, Desfontaines P, Vanacker P, Rutgers M, Druart C, Paindeville P, Peeters D, Bruneel B, Vancaester E, Vanhee F, Meersman G, Bourgeois P, Vanderdonckt P, Benoit A, Derex L, Mechthouff L, Berhoune N, Ritzenthaler T, Amarenco P, Hobeanu C, Meseguer Gancedo E, Calvet D, Ladoux A, Machet A, Lamy C, Mellerio C, Oppenheim C, Rodriguez-Regent C, Bodiguel E, Turc G, Birchenall J, Legrand L, Morin L, Edjali-Goujon M, Naggara O, Raphaelle S, Godon-Hardy S, Domigo V, Guiraud V, Samson Y, Leger A, Rosso C, Baronnet-Chauvet F, Yger M, Crozier S, Deltour S, Sibon I, Renou P, Sagnier S, Zuber M, Tamazyan R, Rodier G, Morel N, Felix S, Vadot W, Wolff V, Aniculaesei A, Yalo B, Bindila D, Quenardelle V, Balnc-Lasserre K, Landrault E, Breynaert L, Cakmak S, Peysson S, Viguier A, Lebely C, Raposo N, Vallet AE, Vallet P, Brugirard S, Kalladka D, Moreton F, Dani K, El Tawil S, Ramachandran S, Huang X, Warburton E, Evans N, Perry R, Patel B, Cloud G, Pereira A, Moynihan B, Lovelock C, Choy L, Khan U, Roffe C, Tyrell P, Smith C, Dixit A, Louw S, Broughton D, Shetty A, Appleton J, Sprigg N, Pedraza Gutierrez S, Raul Acosta B, van Eendenburg C, Puig Alcántara J, Serena Leal J, del Mar Castellanos Rodrigo M, Terceno Izaga M, Belchí Guillamon O, Arenillas J, Calleja A, Cortijo E, Mulero P, Garrido A, Martinez A, García Esperón C, Guerrero C, Carrera D, Vilas D, Lopez-cancio E, Palomeras E, Lucente G, Gomis M, Isern I, Becerra JL, Hervas Vicente J, Sánchez J, Dorado L, Grau L, Ispierto L, Prats L, Almendrote M, Hernández M, Jimenez M, Lozano Sánchez M, Millán Torne M, Presas S, Muñoz-Narbona L, Ustrell X, Pellisé A, Navalpotro I, Luna A, Nederkoorn P, Majoie C, van den Berg L, van den Berg S, Zonneveld T, Remmers M, Pichler A, Fandler S, Gattringer T, Mutzenbach J, Weber J, Höfner E, Kohlfürst H, Weinstich K, Kellert L, Bayer-Karpinska A, Opherk C, Wollenweber F, Klein M, Neumann-Haefelin T, Pierskalla A, Harloff A, Bardutzky J, Buggle F, von Schrader J, Kollmar R, Schill J, Löbbe AM, Moulin T, Bouamra B, Bonnet L, Touzé E, Bonnet AL, Touze E, Cogez J, Li L, Guettier S, Kar A, Sivagnanaratham A, Geraghty O, Bojaryn U, Nallasivan A, Blanco Gonzales M, Rodríguez-Yáñez M, Tembl J, Gorriz D, Oberndorfer S, Prohaska E.

Author information

1
From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).

Abstract

BACKGROUND:

Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.

METHODS:

In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).

RESULTS:

The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).

CONCLUSIONS:

In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

PMID:
29766770
DOI:
10.1056/NEJMoa1804355
[Indexed for MEDLINE]
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