Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants

Thomas R. Meinel; Duncan Wilson; Henrik Gensicke; Jan F. Scheitz; Peter Ringleb; Ioana Goganau; Johannes Kaesmacher; Hee-Joon Bae; Do Yeon Kim; Pawel Kermer; Kentaro Suzuki; Kazumi Kimura; Kosmas Macha; Masatoshi Koga; Shinichi Wada; Valerian Altersberger; Alexander Salerno; Logesh Palanikumar; Andrea Zini; Stefano Forlivesi; Lars Kellert; Johannes Wischmann; Espen S. Kristoffersen; James Beharry; P. Alan Barber; Jae Beom Hong; Carlo Cereda; Eckhard Schlemm; Yusuke Yakushiji; Sven Poli; Ronen Leker; Michele Romoli; Marialuisa Zedde; Sami Curtze; Benno Ikenberg; Timo Uphaus; David Giannandrea; Pere Cardona Portela; Roland Veltkamp; Annemarei Ranta; Marcel Arnold; Urs Fischer; Jae-Kwan Cha; Teddy Y. Wu; Jan C. Purrucker; David J. Seiffge; Georg Kägi; Stefan Engelter; Christian H. Nolte; Bernd Kallmünzer; Patrik Michel; Timothy J. Kleinig; John Fink; Ole Morten Rønning; Bruce Campbell; Paul J. Nederkoorn; G. tz Thomalla; Takenobu Kunieda; Khouloud Poli; Yannick Béjot; Yannie Soo; Carlos Garcia-Esperon; Georges Ntaios; Charlotte Cordonnier; João Pedro Marto; Guido Bigliardi; François Lun; Philip M. C. Choi; Thorsten Steiner; Xavier Ustrell; David Werring; Susanne Wegener; Alessandro Pezzini; Houwei du; Joan Martí-Fàbregas; David Cánovas-Vergé; Daniel Strbian; Visnja Padjen; Shadi Yaghi; Christoph Stretz; Joon-Tae Kim

doi:https://doi.org/10.1001/jamaneurol.2022.4782

Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants

Thomas R. Meinel, Duncan Wilson, Henrik Gensicke, Jan F. Scheitz, Peter Ringleb, Ioana Goganau, Johannes Kaesmacher, Hee-Joon Bae, Do Yeon Kim, Pawel Kermer, Kentaro Suzuki, Kazumi Kimura, Kosmas Macha, Masatoshi Koga, Shinichi Wada, Valerian Altersberger, Alexander Salerno, Logesh Palanikumar, Andrea Zini, Stefano ForlivesiLars Kellert, Johannes Wischmann, Espen S. Kristoffersen, James Beharry, P. Alan Barber, Jae Beom Hong, Carlo Cereda, Eckhard Schlemm, Yusuke Yakushiji, Sven Poli, Ronen Leker, Michele Romoli, Marialuisa Zedde, Sami Curtze, Benno Ikenberg, Timo Uphaus, David Giannandrea, Pere Cardona Portela, Roland Veltkamp, Annemarei Ranta, Marcel Arnold, Urs Fischer, Jae-Kwan Cha, Teddy Y. Wu, Jan C. Purrucker, David J. Seiffge, Georg Kägi, Stefan Engelter, Christian H. Nolte, Bernd Kallmünzer, Patrik Michel, Timothy J. Kleinig, John Fink, Ole Morten Rønning, Bruce Campbell, Paul J. Nederkoorn, G. tz Thomalla, Takenobu Kunieda, Khouloud Poli, Yannick Béjot, Yannie Soo, Carlos Garcia-Esperon, Georges Ntaios, Charlotte Cordonnier, João Pedro Marto, Guido Bigliardi, François Lun, Philip M. C. Choi, Thorsten Steiner, Xavier Ustrell, David Werring, Susanne Wegener, Alessandro Pezzini, Houwei du, Joan Martí-Fàbregas, David Cánovas-Vergé, Daniel Strbian, Visnja Padjen, Shadi Yaghi, Christoph Stretz, Joon-Tae Kim

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. Results: Of 33207 included patients, 14458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion..

Original language	English
Pages (from-to)	233-243
Number of pages	11
Journal	JAMA Neurology
Volume	80
Issue number	3
DOIs	https://doi.org/10.1001/jamaneurol.2022.4782
Publication status	Published - 13 Mar 2023

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Meinel, T. R., Wilson, D., Gensicke, H., Scheitz, J. F., Ringleb, P., Goganau, I., Kaesmacher, J., Bae, H.-J., Kim, D. Y., Kermer, P., Suzuki, K., Kimura, K., Macha, K., Koga, M., Wada, S., Altersberger, V., Salerno, A., Palanikumar, L., Zini, A., ... Kim, J.-T. (2023). Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants. JAMA Neurology, 80(3), 233-243. https://doi.org/10.1001/jamaneurol.2022.4782

@article{43e73454e81547ebb529198f789074ee,

title = "Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants",

abstract = "Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. Results: Of 33207 included patients, 14458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion..",

author = "Meinel, {Thomas R.} and Duncan Wilson and Henrik Gensicke and Scheitz, {Jan F.} and Peter Ringleb and Ioana Goganau and Johannes Kaesmacher and Hee-Joon Bae and Kim, {Do Yeon} and Pawel Kermer and Kentaro Suzuki and Kazumi Kimura and Kosmas Macha and Masatoshi Koga and Shinichi Wada and Valerian Altersberger and Alexander Salerno and Logesh Palanikumar and Andrea Zini and Stefano Forlivesi and Lars Kellert and Johannes Wischmann and Kristoffersen, {Espen S.} and James Beharry and Barber, {P. Alan} and Hong, {Jae Beom} and Carlo Cereda and Eckhard Schlemm and Yusuke Yakushiji and Sven Poli and Ronen Leker and Michele Romoli and Marialuisa Zedde and Sami Curtze and Benno Ikenberg and Timo Uphaus and David Giannandrea and Portela, {Pere Cardona} and Roland Veltkamp and Annemarei Ranta and Marcel Arnold and Urs Fischer and Jae-Kwan Cha and Wu, {Teddy Y.} and Purrucker, {Jan C.} and Seiffge, {David J.} and Georg K{\"a}gi and Stefan Engelter and Nolte, {Christian H.} and Bernd Kallm{\"u}nzer and Patrik Michel and Kleinig, {Timothy J.} and John Fink and R{\o}nning, {Ole Morten} and Bruce Campbell and Nederkoorn, {Paul J.} and Thomalla, {G. tz} and Takenobu Kunieda and Khouloud Poli and Yannick B{\'e}jot and Yannie Soo and Carlos Garcia-Esperon and Georges Ntaios and Charlotte Cordonnier and Marto, {Jo{\~a}o Pedro} and Guido Bigliardi and Fran{\c c}ois Lun and Choi, {Philip M. C.} and Thorsten Steiner and Xavier Ustrell and David Werring and Susanne Wegener and Alessandro Pezzini and Houwei du and Joan Mart{\'i}-F{\`a}bregas and David C{\'a}novas-Verg{\'e} and Daniel Strbian and Visnja Padjen and Shadi Yaghi and Christoph Stretz and Joon-Tae Kim",

note = "Funding Information: Funding/Support: The study was supported by a grant from the Bangerter-Rhyner Foundation. Publisher Copyright: {\textcopyright} 2023 American Medical Association. All rights reserved.",

year = "2023",

month = mar,

day = "13",

doi = "https://doi.org/10.1001/jamaneurol.2022.4782",

language = "English",

volume = "80",

pages = "233--243",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "3",

}

Meinel, TR, Wilson, D, Gensicke, H, Scheitz, JF, Ringleb, P, Goganau, I, Kaesmacher, J, Bae, H-J, Kim, DY, Kermer, P, Suzuki, K, Kimura, K, Macha, K, Koga, M, Wada, S, Altersberger, V, Salerno, A, Palanikumar, L, Zini, A, Forlivesi, S, Kellert, L, Wischmann, J, Kristoffersen, ES, Beharry, J, Barber, PA, Hong, JB, Cereda, C, Schlemm, E, Yakushiji, Y, Poli, S, Leker, R, Romoli, M, Zedde, M, Curtze, S, Ikenberg, B, Uphaus, T, Giannandrea, D, Portela, PC, Veltkamp, R, Ranta, A, Arnold, M, Fischer, U, Cha, J-K, Wu, TY, Purrucker, JC, Seiffge, DJ, Kägi, G, Engelter, S, Nolte, CH, Kallmünzer, B, Michel, P, Kleinig, TJ, Fink, J, Rønning, OM, Campbell, B, Nederkoorn, PJ, Thomalla, GT, Kunieda, T, Poli, K, Béjot, Y, Soo, Y, Garcia-Esperon, C, Ntaios, G, Cordonnier, C, Marto, JP, Bigliardi, G, Lun, F, Choi, PMC, Steiner, T, Ustrell, X, Werring, D, Wegener, S, Pezzini, A, du, H, Martí-Fàbregas, J, Cánovas-Vergé, D, Strbian, D, Padjen, V, Yaghi, S, Stretz, C & Kim, J-T 2023, 'Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants', JAMA Neurology, vol. 80, no. 3, pp. 233-243. https://doi.org/10.1001/jamaneurol.2022.4782

TY - JOUR

T1 - Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants

AU - Meinel, Thomas R.

AU - Wilson, Duncan

AU - Gensicke, Henrik

AU - Scheitz, Jan F.

AU - Ringleb, Peter

AU - Goganau, Ioana

AU - Kaesmacher, Johannes

AU - Bae, Hee-Joon

AU - Kim, Do Yeon

AU - Kermer, Pawel

AU - Suzuki, Kentaro

AU - Kimura, Kazumi

AU - Macha, Kosmas

AU - Koga, Masatoshi

AU - Wada, Shinichi

AU - Altersberger, Valerian

AU - Salerno, Alexander

AU - Palanikumar, Logesh

AU - Zini, Andrea

AU - Forlivesi, Stefano

AU - Kellert, Lars

AU - Wischmann, Johannes

AU - Kristoffersen, Espen S.

AU - Beharry, James

AU - Barber, P. Alan

AU - Hong, Jae Beom

AU - Cereda, Carlo

AU - Schlemm, Eckhard

AU - Yakushiji, Yusuke

AU - Poli, Sven

AU - Leker, Ronen

AU - Romoli, Michele

AU - Zedde, Marialuisa

AU - Curtze, Sami

AU - Ikenberg, Benno

AU - Uphaus, Timo

AU - Giannandrea, David

AU - Portela, Pere Cardona

AU - Veltkamp, Roland

AU - Ranta, Annemarei

AU - Arnold, Marcel

AU - Fischer, Urs

AU - Cha, Jae-Kwan

AU - Wu, Teddy Y.

AU - Purrucker, Jan C.

AU - Seiffge, David J.

AU - Kägi, Georg

AU - Engelter, Stefan

AU - Nolte, Christian H.

AU - Kallmünzer, Bernd

AU - Michel, Patrik

AU - Kleinig, Timothy J.

AU - Fink, John

AU - Rønning, Ole Morten

AU - Campbell, Bruce

AU - Nederkoorn, Paul J.

AU - Thomalla, G. tz

AU - Kunieda, Takenobu

AU - Poli, Khouloud

AU - Béjot, Yannick

AU - Soo, Yannie

AU - Garcia-Esperon, Carlos

AU - Ntaios, Georges

AU - Cordonnier, Charlotte

AU - Marto, João Pedro

AU - Bigliardi, Guido

AU - Lun, François

AU - Choi, Philip M. C.

AU - Steiner, Thorsten

AU - Ustrell, Xavier

AU - Werring, David

AU - Wegener, Susanne

AU - Pezzini, Alessandro

AU - du, Houwei

AU - Martí-Fàbregas, Joan

AU - Cánovas-Vergé, David

AU - Strbian, Daniel

AU - Padjen, Visnja

AU - Yaghi, Shadi

AU - Stretz, Christoph

AU - Kim, Joon-Tae

PY - 2023/3/13

Y1 - 2023/3/13

N2 - Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. Results: Of 33207 included patients, 14458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion..

AB - Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. Results: Of 33207 included patients, 14458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion..

UR - http://www.scopus.com/inward/record.url?scp=85150018160&partnerID=8YFLogxK

U2 - https://doi.org/10.1001/jamaneurol.2022.4782

DO - https://doi.org/10.1001/jamaneurol.2022.4782

M3 - Article

C2 - 36807495

SN - 2168-6149

VL - 80

SP - 233

EP - 243

JO - JAMA Neurology

JF - JAMA Neurology

IS - 3

ER -

Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants

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