A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

doi:10.1056/NEJMoa2107727

Randomized Controlled Trial

. 2021 Nov 11;385(20):1833-1844.

doi: 10.1056/NEJMoa2107727.

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

Natalie E LeCouffe¹, Manon Kappelhof¹, Kilian M Treurniet¹, Leon A Rinkel¹, Agnetha E Bruggeman¹, Olvert A Berkhemer¹, Lennard Wolff¹, Henk van Voorst¹, Manon L Tolhuisen¹, Diederik W J Dippel¹, Aad van der Lugt¹, Adriaan C G M van Es¹, Jelis Boiten¹, Geert J Lycklama À Nijeholt¹, Koos Keizer¹, Rob A R Gons¹, Lonneke S F Yo¹, Robert J van Oostenbrugge¹, Wim H van Zwam¹, Bob Roozenbeek¹, H Bart van der Worp¹, Rob T H Lo¹, Ido R van den Wijngaard¹, Inger R de Ridder¹, Vincent Costalat¹, Caroline Arquizan¹, Robin Lemmens¹, Jelle Demeestere¹, Jeannette Hofmeijer¹, Jasper M Martens¹, Wouter J Schonewille¹, Jan-Albert Vos¹, Maarten Uyttenboogaart¹, Reinoud P H Bokkers¹, Julia H van Tuijl¹, Hans Kortman¹, Floris H B M Schreuder¹, Hieronymus D Boogaarts¹, Karlijn F de Laat¹, Lukas C van Dijk¹, Heleen M den Hertog¹, Boudewijn A A M van Hasselt¹, Paul J A M Brouwers¹, Tomas Bulut¹, Michel J M Remmers¹, Anouk van Norden¹, Farshad Imani¹, Anouk D Rozeman¹, Otto E H Elgersma¹, Philippe Desfontaines¹, Denis Brisbois¹, Yves Samson¹, Frédéric Clarençon¹, G Menno Krietemeijer¹, Alida A Postma¹, Pieter-Jan van Doormaal¹, René van den Berg¹, Anouk van der Hoorn¹, Ludo F M Beenen¹, Daan Nieboer¹, Hester F Lingsma¹, Bart J Emmer¹, Jonathan M Coutinho¹, Charles B L M Majoie¹, Yvo B W E M Roos¹; MR CLEAN–NO IV Investigators

Collaborators, Affiliations

Collaborators

MR CLEAN–NO IV Investigators:
Yvo Roos, Charles Majoie, Kilian Treurniet, Jonathan Coutinho, Bart Emmer, Natalie LeCouffe, Manon Kappelhof, Leon Rinkel, Agnetha Bruggeman, Bob Roozenbeek, Adriaan van Es, Inger de Ridder, Wim van Zwam, Bart van der Worp, Rob Lo, Koos Keizer, Rob Gons, Lonneke Yo, Jelis Boiten, Ido van den Wijngaard, Geert Lycklama À Nijeholt, Jeannette Hofmeijer, Jasper Martens, Wouter Schonewille, Jan Albert Vos, Anil Tuladhar, Floris Schreuder, Jeroen Boogaarts, Sjoerd Jenniskens, Karlijm de Laat, Lukas van Dijk, Hellen den Hertog, Boudewijn van Hasselt, Paul Brouwers, Emiel Sturm, Tomas Bulut, Michel Remmers, Anouk van Norden, Thijs de Jong, Anouk Rozeman, Otto Elgersma, Maarten Uyttenboogaart, Reinoud Bokkers, Julia van Tuijl, Issam Boukrab, Hans Kortman, Vincent Costalat, Caroline Arquizan, Robin Lemmens, Jelle Demeestere, Philippe Desfontaines, Denis Brisbois, Frédéric Clarençon, Yves Samson, Diederik Dippel, Aad van der Lugt, Kilian Treurniet, Martin Brown, Phil White, John Gregson, Daan Nieboer, Rick van Nuland, Alida Postma, René van den Berg, Ludo Beenen, Pieter Jan van Doormaal, Geert Lycklama, Albert Yoo, Bas Hammer, Stefan Roosendaal, Anton Meijer, Menno Krietemeijer, Anouk van der Hoorn, Dick Gerrits, Robert van Oosternbrugge, Ben Jansen, Sanne Manschot, Henk Kerkhof, Peter Koudstaal, Hester Lingsma, Vicky Chalos, Olvert Berkhemer, Adriaan Versteeg, Lennard Wolff, Jiahang Su, Manon Tolhuisen, Henk van Voorst, Hugo Ten Cate, Moniek de Maat, Samantha Donse-Donkel, Heleen van Beusekom, Aladdin Taha, Sophie van den Berg, Rob van de Graaf, Robert-Jan Goldhoorn, Wouter Hinsenveld, Anne Pirson, Lotte Sondag, Rik Reinink, Josje Brouwer, Matthijs van der Sluijs, Sabine Collette, Wouter van der Steen, Miou Koopman, Rita Sprengers, Martin Sterrenberg, Naziha El Ghannouti, Sabrina Verheesen, Wilma Pellikaan, Kitty Blauwendraat, Yvonne Drabbe, Joke de Meris, Michelle Simons, Hester Bongenaar, Anja van Loon, Eva Ponjee, Rieke Eilander, Jasmijn Lodico, Hanneke Droste, Suze Kooij, Marieke de Jong, Esther Santegoets, Suze Roodenburg, Ayla van Ahee, Marinette Moynier, Annemie Devroye, Evelyn Marcelis, Ingrid Iezzi, Annie David, Atika Talbi, Leontien Heiligers, Yvonne Martens, N E LeCouffe, M Kappelhof, K M Treurniet

Affiliation

¹ From the Departments of Neurology (N.E.L., L.A.R., J.M.C., Y.B.W.E.M.R.), Radiology and Nuclear Medicine (M.K., K.M.T., A.E.B., O.A.B., H.V., M.L.T., R.B., L.F.M.B., B.J.E., C.B.L.M.M.), and Biomedical Engineering and Physics (O.A.B., H.V., M.L.T.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Departments of Radiology (K.M.T., G.J.L.N., I.R.W.) and Neurology (J.B., I.R.W.), The Hague Medical Center, and the Departments of Neurology (K.F.L.) and Radiology (L.C.D.), Haga Hospital, The Hague, the Departments of Radiology and Nuclear Medicine (O.A.B., L.W., A.L., P.-J.D.), Neurology (D.W.J.D., B.R.), and Public Health (D.N., H.F.L.), Erasmus MC University Medical Center, Rotterdam, the Department of Radiology, Leiden University Medical Center, Leiden (A.C.G.M.E.), the Departments of Neurology (K.K., R.A.R.G.) and Radiology (L.S.F.Y., G.M.K.), Catharina Hospital, Eindhoven, the Department of Neurology, Cardiovascular Research Institute Maastricht (R.J.O., I.R.R.), and the Department of Radiology and Nuclear Medicine (W.H.Z., A.A.P.), Maastricht University Medical Center, and the School for Mental Health and Sciences, Maastricht University (A.A.P.), Maastricht, the Department of Neurology and Neurosurgery, Brain Center (H.B.W.), and the Department of Radiology (R.T.H.L.), University Medical Center Utrecht, Utrecht, the Departments of Neurology (J.H.) and Radiology (J.M.M.), Rijnstate Hospital, Arnhem, the Departments of Neurology (W.J.S.) and Radiology (J.-A.V.), Sint Antonius Hospital, Nieuwegein, the Departments of Neurology (M.U.) and Radiology, Medical Imaging Center (R.P.H.B., A.H.), University Medical Center Groningen, Groningen, the Departments of Neurology (J.H.T.) and Radiology (H.K.), Elisabeth-TweeSteden Hospital, Tilburg, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Department of Neurology (F.H.B.M.S.), and the Department of Neurosurgery, Radboud University Medical Center (H.D.B.), Nijmegen, the Departments of Neurology (H.M.H.) and Radiology and Nuclear Medicine (B.A.A.M.H.), Isala Hospital, Zwolle, the Departments of Neurology (P.J.A.M.B.) and Radiology (T.B.), Medisch Spectrum Twente, Enschede, the Departments of Neurology (M.J.M.R., A.N.) and Radiology (F.I.), Amphia Hospital, Breda, and the Departments of Neurology (A.D.R.) and Radiology (O.E.H.E.), Albert Schweitzer Hospital, Dordrecht - all in the Netherlands; the Departments of Neuroradiology (V.C.) and Neurology (C.A.), Centre Hospitalier Universitaire de Montpellier, Montpellier, and the Departments of Neurology (Y.S.) and Neuroradiology (F.C.), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris Sorbonne Université, Paris - both in France; and the Department of Neurosciences, KU Leuven-University of Leuven, Experimental Neurology (R.L., J.D.), Vlaams Instituut voor Biotechnologie Center for Brain and Disease Research (R.L., J.D.), and University Hospitals Leuven, Department of Neurology (R.L., J.D.), Leuven, and the Departments of Neurology (P.D.) and Radiology (D.B.), Centre Hospitalier Chrétien, Liege - all in Belgium.

PMID: 34758251
DOI: 10.1056/NEJMoa2107727

Randomized Controlled Trial

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

Natalie E LeCouffe et al. N Engl J Med. 2021.

. 2021 Nov 11;385(20):1833-1844.

doi: 10.1056/NEJMoa2107727.

Authors

Collaborators

MR CLEAN–NO IV Investigators:
Yvo Roos, Charles Majoie, Kilian Treurniet, Jonathan Coutinho, Bart Emmer, Natalie LeCouffe, Manon Kappelhof, Leon Rinkel, Agnetha Bruggeman, Bob Roozenbeek, Adriaan van Es, Inger de Ridder, Wim van Zwam, Bart van der Worp, Rob Lo, Koos Keizer, Rob Gons, Lonneke Yo, Jelis Boiten, Ido van den Wijngaard, Geert Lycklama À Nijeholt, Jeannette Hofmeijer, Jasper Martens, Wouter Schonewille, Jan Albert Vos, Anil Tuladhar, Floris Schreuder, Jeroen Boogaarts, Sjoerd Jenniskens, Karlijm de Laat, Lukas van Dijk, Hellen den Hertog, Boudewijn van Hasselt, Paul Brouwers, Emiel Sturm, Tomas Bulut, Michel Remmers, Anouk van Norden, Thijs de Jong, Anouk Rozeman, Otto Elgersma, Maarten Uyttenboogaart, Reinoud Bokkers, Julia van Tuijl, Issam Boukrab, Hans Kortman, Vincent Costalat, Caroline Arquizan, Robin Lemmens, Jelle Demeestere, Philippe Desfontaines, Denis Brisbois, Frédéric Clarençon, Yves Samson, Diederik Dippel, Aad van der Lugt, Kilian Treurniet, Martin Brown, Phil White, John Gregson, Daan Nieboer, Rick van Nuland, Alida Postma, René van den Berg, Ludo Beenen, Pieter Jan van Doormaal, Geert Lycklama, Albert Yoo, Bas Hammer, Stefan Roosendaal, Anton Meijer, Menno Krietemeijer, Anouk van der Hoorn, Dick Gerrits, Robert van Oosternbrugge, Ben Jansen, Sanne Manschot, Henk Kerkhof, Peter Koudstaal, Hester Lingsma, Vicky Chalos, Olvert Berkhemer, Adriaan Versteeg, Lennard Wolff, Jiahang Su, Manon Tolhuisen, Henk van Voorst, Hugo Ten Cate, Moniek de Maat, Samantha Donse-Donkel, Heleen van Beusekom, Aladdin Taha, Sophie van den Berg, Rob van de Graaf, Robert-Jan Goldhoorn, Wouter Hinsenveld, Anne Pirson, Lotte Sondag, Rik Reinink, Josje Brouwer, Matthijs van der Sluijs, Sabine Collette, Wouter van der Steen, Miou Koopman, Rita Sprengers, Martin Sterrenberg, Naziha El Ghannouti, Sabrina Verheesen, Wilma Pellikaan, Kitty Blauwendraat, Yvonne Drabbe, Joke de Meris, Michelle Simons, Hester Bongenaar, Anja van Loon, Eva Ponjee, Rieke Eilander, Jasmijn Lodico, Hanneke Droste, Suze Kooij, Marieke de Jong, Esther Santegoets, Suze Roodenburg, Ayla van Ahee, Marinette Moynier, Annemie Devroye, Evelyn Marcelis, Ingrid Iezzi, Annie David, Atika Talbi, Leontien Heiligers, Yvonne Martens, N E LeCouffe, M Kappelhof, K M Treurniet

Affiliation

¹ From the Departments of Neurology (N.E.L., L.A.R., J.M.C., Y.B.W.E.M.R.), Radiology and Nuclear Medicine (M.K., K.M.T., A.E.B., O.A.B., H.V., M.L.T., R.B., L.F.M.B., B.J.E., C.B.L.M.M.), and Biomedical Engineering and Physics (O.A.B., H.V., M.L.T.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Departments of Radiology (K.M.T., G.J.L.N., I.R.W.) and Neurology (J.B., I.R.W.), The Hague Medical Center, and the Departments of Neurology (K.F.L.) and Radiology (L.C.D.), Haga Hospital, The Hague, the Departments of Radiology and Nuclear Medicine (O.A.B., L.W., A.L., P.-J.D.), Neurology (D.W.J.D., B.R.), and Public Health (D.N., H.F.L.), Erasmus MC University Medical Center, Rotterdam, the Department of Radiology, Leiden University Medical Center, Leiden (A.C.G.M.E.), the Departments of Neurology (K.K., R.A.R.G.) and Radiology (L.S.F.Y., G.M.K.), Catharina Hospital, Eindhoven, the Department of Neurology, Cardiovascular Research Institute Maastricht (R.J.O., I.R.R.), and the Department of Radiology and Nuclear Medicine (W.H.Z., A.A.P.), Maastricht University Medical Center, and the School for Mental Health and Sciences, Maastricht University (A.A.P.), Maastricht, the Department of Neurology and Neurosurgery, Brain Center (H.B.W.), and the Department of Radiology (R.T.H.L.), University Medical Center Utrecht, Utrecht, the Departments of Neurology (J.H.) and Radiology (J.M.M.), Rijnstate Hospital, Arnhem, the Departments of Neurology (W.J.S.) and Radiology (J.-A.V.), Sint Antonius Hospital, Nieuwegein, the Departments of Neurology (M.U.) and Radiology, Medical Imaging Center (R.P.H.B., A.H.), University Medical Center Groningen, Groningen, the Departments of Neurology (J.H.T.) and Radiology (H.K.), Elisabeth-TweeSteden Hospital, Tilburg, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Department of Neurology (F.H.B.M.S.), and the Department of Neurosurgery, Radboud University Medical Center (H.D.B.), Nijmegen, the Departments of Neurology (H.M.H.) and Radiology and Nuclear Medicine (B.A.A.M.H.), Isala Hospital, Zwolle, the Departments of Neurology (P.J.A.M.B.) and Radiology (T.B.), Medisch Spectrum Twente, Enschede, the Departments of Neurology (M.J.M.R., A.N.) and Radiology (F.I.), Amphia Hospital, Breda, and the Departments of Neurology (A.D.R.) and Radiology (O.E.H.E.), Albert Schweitzer Hospital, Dordrecht - all in the Netherlands; the Departments of Neuroradiology (V.C.) and Neurology (C.A.), Centre Hospitalier Universitaire de Montpellier, Montpellier, and the Departments of Neurology (Y.S.) and Neuroradiology (F.C.), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris Sorbonne Université, Paris - both in France; and the Department of Neurosciences, KU Leuven-University of Leuven, Experimental Neurology (R.L., J.D.), Vlaams Instituut voor Biotechnologie Center for Brain and Disease Research (R.L., J.D.), and University Hospitals Leuven, Department of Neurology (R.L., J.D.), Leuven, and the Departments of Neurology (P.D.) and Radiology (D.B.), Centre Hospitalier Chrétien, Liege - all in Belgium.

PMID: 34758251
DOI: 10.1056/NEJMoa2107727

Abstract

Background: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations.

Methods: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points.

Results: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81).

Conclusions: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.).

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Comment in

Trial of Intravenous Alteplase before Endovascular Treatment for Stroke.
Zheng H, Bu S. Zheng H, et al. N Engl J Med. 2022 Feb 3;386(5):496. doi: 10.1056/NEJMc2119227. N Engl J Med. 2022. PMID: 35108478 No abstract available.
In acute ischemic stroke, EVT alone vs. IV alteplase plus EVT did not differ for functional outcome at 90 d.
Eskin B. Eskin B. Ann Intern Med. 2022 Apr;175(4):JC42. doi: 10.7326/J22-0016. Epub 2022 Apr 5. Ann Intern Med. 2022. PMID: 35377718

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A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

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A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

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