Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants
Authors: Meinel Thomas R. , Wilson Duncan , Gensicke Henrik , Scheitz Jan F. , Ringleb Peter , Goganau Ioana , Kaesmacher Johannes , Bae Hee-Joon , Kim Do Yeon , Kermer Pawel , Suzuki Kentaro , Kimura Kazumi , Macha Kosmas , Koga Masatoshi , Wada Shinichi , Altersberger Valerian , Salerno Alexander , Palanikumar Logesh , Zini Andrea , Forlivesi Stefano , Kellert Lars , Wischmann Johannes , Kristoffersen Espen S. , Beharry James , Barber P. Alan , Hong Jae Beom , Cereda Carlo , Schlemm Eckhard , Yakushiji Yusuke , Poli Sven , Leker Ronen , Romoli Michele , Zedde Marialuisa , Curtze Sami , Ikenberg Benno , Uphaus Timo , Giannandrea David , Portela Pere Cardona , Veltkamp Roland , Ranta Annemarei , Arnold Marcel , Fischer Urs , Cha Jae-Kwan , Wu Teddy Y. , Purrucker Jan C. , Seiffge David J. ,   International DOAC-IVT, TRISP, and CRCS-K-NIH Collaboration,   DOAC-IVT Writing Group, Goeldlin Martina , Siepen Bernhard , Mueller Madlaine , Beyeler Morin , Scutelnic Adrian , Jung Simon , Mujanovic Adnan , Kurmann Christoph , Dobrocky Tomas , Piechoviak Eike , Wiest Roland , Hakim Arsany , Bücke Philipp , Jana Zarzitzky , Carmen Lichti , Diana Isabella Dmytrow , Ramos João Nuno , Strambo Davide , Buehrer Menuela , Simaan Naaem , Honig Asaf , Filioglo Andrei , Grisendi Ilaria , Ferri Laura , Trapasso Maria Claudia , Benini Matteo , Pascarella Rosario , Moratti Claudio , Napoli Manuela , Sumaria Sheetal , Gröschel Klaus , Hahn Marianne , Polymeris Alexandros , Traenka Christopher , Zietz Annaelle , Lyrer Philippe , DeMarchis Gian Marco , Thilemann Sebastian , Piot Ines , Enz Lukas , Peters Nils , Katan Mira , Brehm Alexander , Psychogios Marios , Prange Ulrike , Spratt Neil , Roten Laurent , Chew BL Alvin , Stefela Jakub , von Rennenberg Regina , Litmeier Simon , Riegler Christoph , Klammer Markus , Erdur Hebun , Simon Hellwig , Mauro Magoni , Marco Longoni , Francesco Cordici , Sara Biguzzi , Tan Peter , Ercegovac Marko , Berisavac Ivana , Haupenthal David , Gassmann Luise , Marsch Armin , Siedler Gabriela , Weir Louise , Pesavento Lauren , Yassi Nawaf , Davis Stephen , Ip Bonaventure , Leung Thomas , Gomez-Exposito Alexandra , Mbroh Joshua , Tünnerhoff Johannes , Barbu Gabriel , Wang Yi , Mengel Annerose , Katharina Feil , Kowarik Markus , Ziemann Ulf , Kim Jun Yup , Kang Jihoon , Han Moon-Ku , Kim Beom Joon , Choi Kang-Ho , Park Man-Seok , Cho Ki-Hyun , Kim Joon-Tae , Shin Dong-Ick , Yum Kyu Sun , Kim Dae-Hyun , Cha Jae-Kwan , Park Jong-Moo , Kang Kyusik , Kim Yong Soo , Kim Jae Guk , Lee Soo Joo , Oh Mi-Sun , Lee Byung-Chul , Lee Minwoo , Yu Kyung-Ho , Park Hong-Kyun , Hong Keun-Sik , Cho Yong-Jin , Choi Jay Chol , Kim Joong-Goo , Kang Chul-Hoo , Sohn Sung Il , Hong Jeong-Ho , Jang Seong Hwa , Park Hyungjong , Park Tai Hwan , Park Sang-Soon , Lee Kyung Bok , Kwon Jee-Hyun , Kim Wook-Joo , Lee Jun , Kwon Doo Hyuk , Gwak Dong-Seok , Kim Dong-Eog , Lee Keon-Joo , Lee Sang-Hwa , Kim Chulho , Jeong Hae-Bong , Park Kwang Yeol , Lee Ji Sung , Lee Juneyoung , Martinez-Majander Nicolas , Sibolt Gerli , Tiainen Marjaana , Gentile Mauro , Migliaccio Ludovica , Simonetti Luigi , Paolucci Matteo , Flores Alan , Seró Laia , Turc Guillaume , Oppenheim Catherine , Naggara Olivier , Ben Hassen Wagih , Benzakoun Joseph , Yakushiji Yusuke , Kunieda Takenobu , Kägi Georg , Engelter Stefan , Nolte Christian H. , Kallmünzer Bernd , Michel Patrik , Kleinig Timothy J. , Fink John , Rønning Ole Morten , Campbell Bruce , Nederkoorn Paul J. , Thomalla Götz , Kunieda Takenobu , Poli Khouloud , Béjot Yannick , Soo Yannie , Garcia-Esperon Carlos , Ntaios Georges , Cordonnier Charlotte , Marto João Pedro , Bigliardi Guido , Lun François , Choi Philip M. C. , Steiner Thorsten , Ustrell Xavier , Werring David , Wegener Susanne , Pezzini Alessandro , Du Houwei , Martí-Fàbregas Joan , Cánovas-Vergé David , Strbian Daniel , Padjen Visnja , Yaghi Shadi , Stretz Christoph , Kim Joon-Tae 
Published: January 2023

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 32 375 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 33 207 included patients, 14 458 (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.