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MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset
Götz Thomalla1, Claus Z Simonsen1, Florent Boutitie1
1From 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.).
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 .).
Insights
Intravenous alteplase benefits acute stroke patients with unknown onset times if recent infarction is confirmed by MRI. This treatment improved functional outcomes at 90 days compared to placebo.
Area of Science:
- Neurology
- Radiology
- Emergency Medicine
Background:
- Current acute stroke treatment guidelines restrict intravenous thrombolysis to cases within 4.5 hours of symptom onset.
- Identifying eligible patients with unknown stroke onset times remains a clinical challenge.
- Advanced neuroimaging, specifically MRI, may help identify recent ischemic events.
Purpose of the Study:
- To evaluate the efficacy and safety of intravenous alteplase in acute stroke patients with unknown onset times.
- To determine if MRI findings suggestive of recent infarction can guide thrombolysis treatment.
- To assess functional outcomes at 90 days using the modified Rankin Scale.
Main Methods:
- A multicenter, randomized, placebo-controlled trial involving 503 patients with acute stroke and unknown onset time.
- Patients received either intravenous alteplase or placebo, selected based on MRI diffusion-weighted imaging (DWI) and FLAIR criteria indicating recent ischemia.
- Exclusion criteria included planned thrombectomy; primary endpoint was a favorable outcome (modified Rankin Scale score 0-1) at 90 days.
Main Results:
- A favorable outcome at 90 days was achieved in 53.3% of patients treated with alteplase versus 41.8% in the placebo group (adjusted odds ratio, 1.61; P=0.02).
- The median modified Rankin Scale score at 90 days was significantly lower in the alteplase group (1 vs. 2; P=0.003).
- While numerically higher, symptomatic intracranial hemorrhage rates (2.0% vs. 0.4%) and deaths (4.1% vs. 1.2%) did not reach statistical significance between groups.
Conclusions:
- Intravenous alteplase, guided by MRI DWI/FLAIR mismatch in acute stroke patients with unknown onset, significantly improves functional outcomes.
- The treatment demonstrated a trend towards increased intracranial hemorrhages and deaths, necessitating careful patient selection.
- This approach expands treatment eligibility for acute ischemic stroke beyond the standard 4.5-hour window when recent infarction is confirmed.
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