TY - JOUR

T1 - MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

AU - Thomalla, Götz

AU - Simonsen, Claus Z

AU - Boutitie, Florent

AU - Andersen, Grethe

AU - Berthezene, Yves

AU - Cheng, Bastian

AU - Cheripelli, Bharath

AU - Cho, Tae-Hee

AU - Fazekas, Franz

AU - Fiehler, Jens

AU - Ford, Ian

AU - Galinovic, Ivana

AU - Gellissen, Susanne

AU - Golsari, Amir

AU - Gregori, Johannes

AU - Günther, Matthias

AU - Guibernau, Jorge

AU - Häusler, Karl Georg

AU - Hennerici, Michael

AU - Kemmling, André

AU - Marstrand, Jacob

AU - Modrau, Boris

AU - Neeb, Lars

AU - Perez de la Ossa, Natalia

AU - Puig, Josep

AU - Ringleb, Peter

AU - Roy, Pascal

AU - Scheel, Enno

AU - Schonewille, Wouter

AU - Serena, Joaquin

AU - Sunaert, Stefan

AU - Villringer, Kersten

AU - Wouters, Anke

AU - Thijs, Vincent

AU - Ebinger, Martin

AU - Endres, Matthias

AU - Fiebach, Jochen B

AU - Lemmens, Robin

AU - Muir, Keith W

AU - Nighoghossian, Norbert

AU - Pedraza, Salvador

AU - Gerloff, Christian

AU - WAKE-UP Investigators

PY - 2018

Y1 - 2018

N2 - 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 .).

AB - 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 .).

KW - Acute Disease

KW - Administration, Intravenous

KW - Aged

KW - Brain Ischemia/diagnostic imaging

KW - Diffusion Magnetic Resonance Imaging

KW - Female

KW - Fibrinolytic Agents/adverse effects

KW - Humans

KW - Intracranial Hemorrhages/chemically induced

KW - Magnetic Resonance Imaging, Interventional

KW - Male

KW - Middle Aged

KW - Stroke/diagnostic imaging

KW - Thrombectomy

KW - Thrombolytic Therapy/methods

KW - Time-to-Treatment

KW - Tissue Plasminogen Activator/adverse effects

KW - Treatment Outcome

U2 - 10.1056/NEJMoa1804355

DO - 10.1056/NEJMoa1804355

M3 - Journal article

C2 - 29766770

VL - 379

SP - 611

EP - 622

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 7

ER -