Practical “1-2-3-4-Day” Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study
Authors: Kimura Shunsuke , Toyoda Kazunori , Yoshimura Sohei , Minematsu Kazuo , Yasaka Masahiro , Paciaroni Maurizio , Werring David J. , Yamagami Hiroshi , Nagao Takehiko , Yoshimura Shinichi , Polymeris Alexandros , Zietz Annaelle , Engelter Stefan T. , Kallmünzer Bernd , Cappellari Manuel , Chiba Tetsuya , Yoshimoto Takeshi , Shiozawa Masayuki , Kitazono Takanari , Koga Masatoshi , Todo Kenichi , Kimura Kazumi , Yagita Yoshiki , Furui Eisuke , Itabashi Ryo , Terasaki Tadashi , Shiokawa Yoshiaki , Hirano Teruyuki , Kamiyama Kenji , Nakagawara Jyoji , Takizawa Shunya , Homma Kazunari , Okuda Satoshi , Okada Yasushi , Tokunaga Keisuke , Kameda Tomoaki , Kario Kazuomi , Nagakane Yoshinari , Hasegawa Yasuhiro , Akiyama Hisanao , Shibuya Satoshi , Mochizuki Hiroshi , Ito Yasuhiro , Nakashima Takahiro , Matsuoka Hideki , Takamatsu Kazuhiro , Nishiyama Kazutoshi , Sato Shoichiro , Arihiro Shoji , Inoue Manabu , Takagi Masahito , Tanaka Kanta , Nagatsuka Kazuyuki , Yamaguchi Takenori , Hasegawa Yasuhiro , Hashimoto Yoichiro , Houkin Kiyohiro , Kimura Kazumi , Kitagawa Kazuo , Matsumoto Masayasu , Okada Yasushi , Okuda Satoshi , Tanahashi Norio , Terayama Yasuo , Uchiyama Shinichiro , Mori Etsuro , Furukawa Yutaka , Kimura Takeshi , Kumon Yoshiaki , Nagata Ken , Nogawa Shigeru , Sakamoto Tomohiro , Hirano Teruyuki , Hirai Toshinori , Kudo Kohsuke , Sasaki Makoto , Kobayashi Shotai , Hamasaki Toshimitsu , Giustozzi Michela , Acciarresi Monica , Agnelli Giancarlo , Caso Valeria , Bandini Fabio , Tsivgoulis Georgios , Yaghi Shadi , Furie Karen L. , Tadi Prasanna , Becattini Cecilia , Zedde Marialuisa , Abdul-Rahim Azmil H , Lees Kennedy R , Alberti Andrea , Venti Michele , D’Amore Cataldo , Giulia Mosconi Maria , Anna Cimini Ludovica , Bovi Paolo , Carletti Monica , Rigatelli Alberto , Putaala Jukka , Tomppo Liisa , Tatlisumak Turgut , Marcheselli Simona , Pezzini Alessandro , Poli Loris , Padovani Alessandro , Vannucchi Vieri , Sohn Sung-Il , Lorenzini Gianni , Tassi Rossana , Guideri Francesca , Acampa Maurizio , Martini Giuseppe , Ntaios George , Athanasakis George , Makaritsis Konstantinos , Karagkiozi Efstathia , Vadikolias Konstantinos , Liantinioti Chrissoula , Chondrogianni Maria , Mumoli Nicola , Galati Franco , Sacco Simona , Tiseo Cindy , Corea Francesco , Ageno Walter , Bellesini Marta , Colombo Giovanna , Silvestrelli Giorgio , Ciccone Alfonso , Lanari Alessia , Scoditti Umberto , Denti Licia , Mancuso Michelangelo , Maccarrone Miriam , Ulivi Leonardo , Orlandi Giovanni , Giannini Nicola , Tassinari Tiziana , De Lodovici Maria Luisa , Rueckert Christina , Baldi Antonio , Toni Danilo , Letteri Federica , Giuntini Martina , Lotti Enrico Maria , Flomin Yuriy , Pieroni Alessio , Kargiotis Odysseas , Karapanayiotides Theodore , Monaco Serena , Baronello Mario Maimone , Csiba Laszló , Szabó Lilla , Chiti Alberto , Giorli Elisa , Del Sette Massimo , Imberti Davide , Zabzuni Dorjan , Doronin Boris , Volodina Vera , Michel Patrik , Vanacker Peter , Barlinn Kristian , Pallesen Lars-Peder , Barlinn Jessica , Deleu Dirk , Melikyan Gayane , Ibrahim Faisal , Akhtar Naveed , Gourbali Vanessa , Masotti Luca , Parry-Jones Adrian , Patterson Chris , Price Christopher , Elmarimi Abduelbaset , Parry Anthea , Nallasivam Arumug , Mohd Nor Azlisham , Esis Bernard , Bruce David , Roffe Christine , Holmes Clare , Cohen David , Hargroves David , Mangion David , Chadha Dinesh , Vahidassr Djamil , Manawadu Dulka , Giallombardo Elio , Warburton Elizabeth , Flossman Enrico , Gunathilagan Gunaratam , Proschel Harald , Emsley Hedley , Anwar Ijaz , Okwera James , Putterill Janet , O’Connell Janice , Bamford John , Corrigan John , Scott Jon , Birns Jonathan , Kee Karen , Saastamoinen Kari , Pasco Kath , Dani Krishna , Sekaran Lakshmanan , Choy Lillian , Iveson Liz , Mamun Maam , Sajid Mahmud , Cooper Martin , Burn Matthew , Smith Matthew , Power Michael , Davis Michelle , Smyth Nigel , Veltkamp Roland , Sharma Pankaj , Guyler Paul , O’Mahony Paul , Wilkinson Peter , Datta Prabel , Aghoram Prasanna , Marsh Rachel , Luder Robert , Meenakishundaram Sanjeevikumar , Subramonian Santhosh , Leach Simon , Ispoglou Sissi , Andole Sreeman , England Timothy , Manoj Aravindakshan , Harrington Frances , Rehman Habib , Sword Jane , Staals Julie , Mahawish Karim , Harkness Kirsty , Shaw Louise , McCormich Michael , Sprigg Nikola , Mansoor Syed , Krishnamurthy Vinodh , Lyrer Philippe A , Bonati Leo H , Seiffge David J , Traenka Christopher , Peters Nils , De Marchis Gian Marco , Thilemann Sebastian , Avramiotis Nikolaos S , Gensicke Henrik , Hert Lisa , Wagner Benjamin , Schaub Fabian , Meya Louisa , Fladt Joachim , Dittrich Tolga , Fisch Urs , Bonetti Bruno , Bovi Paolo , Tomelleri Giampaolo , Micheletti Nicola , Zivelonghi Cecilia , Emiliani Andrea , Macha Kosmas , Siedler Gabriela , Stoll Svenja , Wang Ruihao , Volbers Bastian , Schwab Stefan , Haupenthal David , Gaßmann Luise 
Published: February 2022

Background:
The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity.

Methods:
The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation.

Results:
In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data.

Conclusions:
In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.