1. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data
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Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation
- Subjects
medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Ischemic Stroke/*diagnostic imaging/*drug therapy ,Tomography, X-Ray Computed/methods ,Fibrinolytic Agents/adverse effects/*therapeutic use ,030204 cardiovascular system & hematology ,Ischemic Stroke/diagnostic imaging ,surgery ,0302 clinical medicine ,Modified Rankin Scale ,030212 general & internal medicine ,10. No inequality ,Infusions, Intravenous ,Stroke ,Tomography ,Time-to-Treatment ,General Medicine ,Thrombolysis ,X-Ray Computed/methods ,Tissue Plasminogen Activator/adverse effects ,3. Good health ,[SDV] Life Sciences [q-bio] ,Diffusion Magnetic Resonance Imaging/methods ,Treatment Outcome ,Meta-analysis ,Tissue Plasminogen Activator ,Intravenous ,medicine.medical_specialty ,Infusions ,Intravenous thrombolysis ,Neuroimaging ,Neuroscience(all) ,Placebo ,Tissue Plasminogen Activator/adverse effects/*therapeutic use ,03 medical and health sciences ,Fibrinolytic Agents ,Internal medicine ,medicine ,Humans ,ddc:610 ,Ischemic Stroke ,business.industry ,neurology ,Fibrinolytic Agents/adverse effects ,Odds ratio ,Recovery of Function ,medicine.disease ,Clinical research ,Diffusion Magnetic Resonance Imaging ,Human medicine ,business ,Tomography, X-Ray Computed ,Fibrinolytic agent - Abstract
International audience; 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 (I(2)=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 [\textless1%], 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.
- Published
- 2020
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