Götz Thomalla1, Florent Boutitie2, Henry Ma3, Masatoshi Koga4, Peter Ringleb5, Lee H Schwamm6, Ona Wu7, Martin Bendszus8, Christopher F Bladin9, Bruce C V Campbell10, Bastian Cheng11, Leonid Churilov10, Martin Ebinger12, Matthias Endres13, Jochen B Fiebach14, Mayumi Fukuda-Doi15, Manabu Inoue4, Timothy J Kleinig16, Lawrence L Latour17, Robin Lemmens18, Christopher R Levi19, Didier Leys20, Kaori Miwa4, Carlos A Molina21, Keith W Muir22, Norbert Nighoghossian23, Mark W Parsons10, Salvador Pedraza24, Peter D Schellinger25, Stefan Schwab26, Claus Z Simonsen27, Shlee S Song28, Vincent Thijs29, Danilo Toni30, Chung Y Hsu31, Nils Wahlgren32, Haruko Yamamoto33, Nawaf Yassi34, Sohei Yoshimura4, Steven Warach35, Werner Hacke5, Kazunori Toyoda4, Geoffrey A Donnan10, Stephen M Davis10, Christian Gerloff11. 1. Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. Electronic address: thomalla@uke.de. 2. Hospices Civils de Lyon, Service de Biostatistique, Lyon, France; Université Lyon 1, Villeurbanne, France; Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France. 3. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia. 4. Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan. 5. Department of Neurology, University of Heidelberg, Heidelberg, Germany. 6. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. 7. Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA. 8. Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany. 9. Department of Neurosciences, Eastern Health and Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia. 10. Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia. 11. Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. 12. Centrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Klinik für Neurologie Medical Park Berlin Humboldtmühle, Berlin, Germany. 13. Centrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; German Centre of Cardiovascular Research, Berlin, Germany; German Center of Neurodegenerative Diseases, Berlin, Germany. 14. Centrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany. 15. Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan. 16. Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia. 17. Acute Cerebrovascular Diagnostics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. 18. Department of Neurosciences, Experimental Neurology, KU Leuven, University of Leuven, Leuven, Belgium; VIB Center for Brain and Disease Research Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium. 19. The Department of Neurology, Priority Research Centre for Brain and Mental Health Research, John Hunter Hospital, University of Newcastle, Newcastle, NSW, Australia. 20. Université de Lille, Inserm U1171, Lille, France. 21. Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain. 22. Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK. 23. Department of Stroke Medicine, Université Claude Bernard Lyon 1, CarMeN Laboratory, INSERM U1060/INRA 1397, Lyon, France. 24. Department of Radiology, Institut de Diagnòstic per la Imatge, Hospital Dr Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona, Spain. 25. Universitätsklinik für Neurologie, Mühlenkreiskliniken, Johannes Wesling Klinikum Minden, Universitätsklinikum der Ruhr-Universität Bochum, Minden, Germany. 26. Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany. 27. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark. 28. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 29. Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia; Department of Neurology, Austin Health, Heidelberg, VIC, Australia. 30. Department of Human Neurosciences, University of Rome "La Sapienza", Rome, Italy. 31. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. 32. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 33. Center for Advancing Clinical and Translational Sciences, National Cerebral and Cardiovascular Center, Suita, Japan. 34. Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. 35. Dell Medical School, University of Texas at Austin, Austin, TX, USA.
Abstract
BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.
BACKGROUND:Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patientsdied in the alteplase group and 14 (3%) patientsdied among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.
Authors: Nils Wahlgren; Niaz Ahmed; Antoni Dávalos; Gary A Ford; Martin Grond; Werner Hacke; Michael G Hennerici; Markku Kaste; Sonja Kuelkens; Vincent Larrue; Kennedy R Lees; Risto O Roine; Lauri Soinne; Danilo Toni; Geert Vanhooren Journal: Lancet Date: 2007-01-27 Impact factor: 79.321
Authors: Peter Ringleb; Martin Bendszus; Erich Bluhmki; Geoffrey Donnan; Christoph Eschenfelder; Marc Fatar; Christof Kessler; Carlos Molina; Didier Leys; Girish Muddegowda; Sven Poli; Peter Schellinger; Stefan Schwab; Joaquin Serena; Danilo Toni; Nils Wahlgren; Werner Hacke Journal: Int J Stroke Date: 2019-04-04 Impact factor: 5.266
Authors: Gregory W Albers; Michael P Marks; Stephanie Kemp; Soren Christensen; Jenny P Tsai; Santiago Ortega-Gutierrez; Ryan A McTaggart; Michel T Torbey; May Kim-Tenser; Thabele Leslie-Mazwi; Amrou Sarraj; Scott E Kasner; Sameer A Ansari; Sharon D Yeatts; Scott Hamilton; Michael Mlynash; Jeremy J Heit; Greg Zaharchuk; Sun Kim; Janice Carrozzella; Yuko Y Palesch; Andrew M Demchuk; Roland Bammer; Philip W Lavori; Joseph P Broderick; Maarten G Lansberg Journal: N Engl J Med Date: 2018-01-24 Impact factor: 91.245
Authors: Urs Fischer; Johannes Kaesmacher; Vitor Mendes Pereira; René Chapot; Adnan H Siddiqui; Michael T Froehler; Christoph Cognard; Anthony J Furlan; Jeffrey L Saver; Jan Gralla Journal: Stroke Date: 2017-09-08 Impact factor: 7.914
Authors: Lee H Schwamm; Ona Wu; Shlee S Song; Lawrence L Latour; Andria L Ford; Amie W Hsia; Alona Muzikansky; Rebecca A Betensky; Albert J Yoo; Michael H Lev; Gregoire Boulouis; Arne Lauer; Pedro Cougo; William A Copen; Gordon J Harris; Steven Warach Journal: Ann Neurol Date: 2018-04-27 Impact factor: 10.422
Authors: Niaz Ahmed; Heinrich Audebert; Guillaume Turc; Charlotte Cordonnier; Hanne Christensen; Simona Sacco; Else Charlotte Sandset; George Ntaios; Andreas Charidimou; Danilo Toni; Christian Pristipino; Martin Köhrmann; Joji B Kuramatsu; Götz Thomalla; Robert Mikulik; Gary A Ford; Joan Martí-Fàbregas; Urs Fischer; Magnus Thoren; Erik Lundström; Gabriel Je Rinkel; H Bart van der Worp; Marius Matusevicius; Georgios Tsivgoulis; Haralampos Milionis; Marta Rubiera; Robert Hart; Tiago Moreira; Maria Lantz; Christina Sjöstrand; Grethe Andersen; Peter Schellinger; Konstantinos Kostulas; Katharina Stibrant Sunnerhagen; Boris Keselman; Eleni Korompoki; Jan Purrucker; Pooja Khatri; William Whiteley; Eivind Berge; Michael Mazya; Diederik Wj Dippel; Satu Mustanoja; Mads Rasmussen; Åsa Kuntze Söderqvist; Irene Escudero-Martínez; Thorsten Steiner Journal: Eur Stroke J Date: 2019-09-02
Authors: William J Powers; Alejandro A Rabinstein; Teri Ackerson; Opeolu M Adeoye; Nicholas C Bambakidis; Kyra Becker; José Biller; Michael Brown; Bart M Demaerschalk; Brian Hoh; Edward C Jauch; Chelsea S Kidwell; Thabele M Leslie-Mazwi; Bruce Ovbiagele; Phillip A Scott; Kevin N Sheth; Andrew M Southerland; Deborah V Summers; David L Tirschwell Journal: Stroke Date: 2019-10-30 Impact factor: 7.914
Authors: Rüdiger von Kummer; Joseph P Broderick; Bruce C V Campbell; Andrew Demchuk; Mayank Goyal; Michael D Hill; Kilian M Treurniet; Charles B L M Majoie; Henk A Marquering; Michael V Mazya; Luis San Román; Jeffrey L Saver; Daniel Strbian; William Whiteley; Werner Hacke Journal: Stroke Date: 2015-09-01 Impact factor: 7.914
Authors: Guillaume Turc; Georgios Tsivgoulis; Heinrich J Audebert; Hieronymus Boogaarts; Pervinder Bhogal; Gian Marco De Marchis; Ana Catarina Fonseca; Pooja Khatri; Mikaël Mazighi; Natalia Pérez de la Ossa; Peter D Schellinger; Daniel Strbian; Danilo Toni; Philip White; William Whiteley; Andrea Zini; Wim van Zwam; Jens Fiehler Journal: Eur Stroke J Date: 2022-02-17
Authors: Stefan Krebs; Alexandra Posekany; Alina Pilz; Julia Ferrari; Alexandra Bernegger; Christian Neumann; Siegfried Thurnher; Dominik Roth; Wilfried Lang; Marek Sykora Journal: J Stroke Date: 2022-09-30 Impact factor: 8.632
Authors: Eivind Berge; William Whiteley; Heinrich Audebert; Gian Marco De Marchis; Ana Catarina Fonseca; Chiara Padiglioni; Natalia Pérez de la Ossa; Daniel Strbian; Georgios Tsivgoulis; Guillaume Turc Journal: Eur Stroke J Date: 2021-02-19