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1. Practical '1-2-3-4-Day' Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study

Author

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

Subjects
Advanced and Specialized Nursing, acute ischemic stroke, Time Factors, Administration, Oral, Anticoagulants, Hemorrhage, cardioembolism, Hospitals, United States, Brain Ischemia, anticoagulation, atrial fibrillation, stroke prevention, Cohort Studies, Stroke, Treatment Outcome, Ischemic Attack, Transient, Atrial Fibrillation, Humans, Prospective Studies, Neurology (clinical), Cardiology and Cardiovascular Medicine, Ischemic Stroke
Abstract

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.

Published
2022
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2. Small Vessel Disease and Ischemic Stroke Risk During Anticoagulation for Atrial Fibrillation After Cerebral Ischemia

Author

Houwei Du, Duncan Wilson, Gareth Ambler, Gargi Banerjee, Clare Shakeshaft, Hannah Cohen, Tarek Yousry, Rustam Al-Shahi Salman, Gregory Y.H. Lip, Henry Houlden, Martin M. Brown, Keith W. Muir, Hans Rolf Jäger, David J. Werring, Adrian Parry-Jones, Chris Patterson, Christopher Price, Abduelbaset Elmarimi, Anthea Parry, Arumug Nallasivam, Azlisham Mohd Nor, Bernard Esisi, David Bruce, Biju Bhaskaran, Christine Roffe, Claire Cullen, Clare Holmes, David Cohen, David Hargroves, David Mangion, Dinesh Chadha, Djamil Vahidassr, Dulka Manawadu, Elio Giallombardo, Elizabeth Warburton, Enrico Flossman, Gunaratam Gunathilagan, Harald Proschel, Hedley Emsley, Ijaz Anwar, Ilse Burger, James Okwera, Janet Putterill, Janice O’Connell, John Bamford, John Corrigan, Jon Scott, Jonathan Birns, Karen Kee, Kari Saastamoinen, Kath Pasco, Krishna Dani, Lakshmanan Sekaran, Lillian Choy, Liz Iveson, Maam Mamun, Mahmud Sajid, Martin Cooper, Mathew Burn, Matthew Smith, Michael Power, Michelle Davis, Nigel Smyth, Roland Veltkamp, Pankaj Sharma, Paul Guyler, Paul O’Mahony, Peter Wilkinson, Prabel Datta, Prasanna Aghoram, Rachel Marsh, Robert Luder, Sanjeevikumar Meenakishundaram, Santhosh Subramonian, Simon Leach, Sissi Ispoglou, Sreeman Andole, Timothy England, Aravindakshan Manoj, Harrington Frances, Habib Rehman, Jane Sword, Julie Staals, Karim Mahawish, Kirsty Harkness, Louise Shaw, Michael McCormick, Nikola Sprigg, Syed Mansoor, and Vinodh Krishnamurthy

Subjects
Male, medicine.medical_specialty, brain, Small vessel occlusion, Ischemia, Disease, Brain Ischemia, White matter, Recurrence, Internal medicine, Atrial Fibrillation, medicine, Humans, ischemic attack, transient, atrial fibrillation, anticoagulation, Aged, Ischemic Stroke, Aged, 80 and over, Advanced and Specialized Nursing, business.industry, Atrial fibrillation, Middle Aged, medicine.disease, medicine.anatomical_structure, Cerebral Small Vessel Diseases, Ischemic stroke, Cardiology, Female, Neurology (clinical), Small vessel, Cardiology and Cardiovascular Medicine, business, white matter
Abstract

Background and Purpose: The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack. Methods: We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65–74, female score. Results: We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60–3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59–1.62) in those without SVD ( P =0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65–74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01–3.53]; P =0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04–1.70]; P =0.023). Conclusions: In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02513316.

Published
2021
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3. Observer Agreement on Computed Tomography Perfusion Imaging in Acute Ischemic Stroke

Author

Salwa El-Tawil, Grant Mair, Xuya Huang, Eleni Sakka, Jeb Palmer, Ian Ford, Lalit Kalra, Joanna Wardlaw, Keith W. Muir, Alessandro Adami, Alfonso Cerase, Ana Garcia, Anders von Heijne, Andre Peeters, Andrea Zini, Angelo Carneiro, Chris Patterson, Christine Roffe, Daniel Freedman, Daniel Scoffings, Derk W Krieger, Dipayan Mitra, Eivind Berge, Elena Adela Cora, Eoin O’Brien, Eric Bertholds, Ethem Murat, Fiona Moreton, Garryck Tan, Gillian Potter, Giuseppe Rinaldi, Jeremy Madigan, Joe Leyon, Johann Du Plessis, Jonathan Hewitt, José Eduardo Alves, Jose Egido, Laszlo Sztriha, Magnus Esbjoernsson, Manuel Correia, Martin Griebe, Michelle Dharmasiri, Olga Kirmi, Olivia Geraghty, Pablo García-Bermejo, Patrick Sutton, Pervinder Bhogal, Philip White, Phillip Ferdinand, Qazi Anjum, Robin Sellar, Rüdiger von Kummer, Sreeman Andole, Sriram Vundavalli, Thomas Webb, Tilak Das, Tomasz Matys, Tony Goddard, Vamsi Gontu, Vijay Sawlani, Volker Puetz, and Will Whiteley

Subjects
Perfusion Imaging, medicine.medical_treatment, Original Contributions, brain, Clinical Sciences, cerebral blood flow, Perfusion scanning, 030204 cardiovascular system & hematology, perfusion, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, Cerebral Blood Volume, Humans, Medicine, Computed Tomography Perfusion Imaging, Stroke, Aged, Aged, 80 and over, Advanced and Specialized Nursing, medicine.diagnostic_test, business.industry, Penumbra, computed tomography, Thrombolysis, Middle Aged, medicine.disease, Cerebral Angiography, 3. Good health, Cerebral blood flow, Cerebrovascular Circulation, Tissue Plasminogen Activator, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Neurology (clinical), Tomography, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business, Nuclear medicine, 030217 neurology & neurosurgery, Cerebral angiography, patient selection
Abstract

Supplemental Digital Content is available in the text., Background and Purpose— Computed tomography (CT) perfusion (CTP) provides potentially valuable information to guide treatment decisions in acute stroke. Assessment of interobserver reliability of CTP has, however, been limited to small, mostly single center studies. We performed a large, internet-based study to assess observer reliability of CTP interpretation in acute stroke. Methods— We selected 24 cases from the IST-3 (Third International Stroke Trial), ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke), and POSH (Post Stroke Hyperglycaemia) studies to illustrate various perfusion abnormalities. For each case, observers were presented with noncontrast CT, maps of cerebral blood volume, cerebral blood flow, mean transit time, delay time, and thresholded penumbra maps (dichotomized into penumbra and core), together with a short clinical vignette. Observers used a structured questionnaire to record presence of perfusion deficit, its extent compared with ischemic changes on noncontrast CT, and an Alberta Stroke Program Early CT Score for noncontrast CT and CTP. All images were viewed, and responses were collected online. We assessed observer agreement with Krippendorff-α. Intraobserver agreement was assessed by inviting observers who reviewed all scans for a repeat review of 6 scans. Results— Fifty seven observers contributed to the study, with 27 observers reviewing all 24 scans and 17 observers contributing repeat readings. Interobserver agreement was good to excellent for all CTP. Agreement was higher for perfusion maps compared with noncontrast CT and was higher for mean transit time, delay time, and penumbra map (Krippendorff-α =0.77, 0.79, and 0.81, respectively) compared with cerebral blood volume and cerebral blood flow (Krippendorff-α =0.69 and 0.62, respectively). Intraobserver agreement was fair to substantial in the majority of readers (Krippendorff-α ranged from 0.29 to 0.80). Conclusions— There are high levels of interobserver and intraobserver agreement for the interpretation of CTP in acute stroke, particularly of mean transit time, delay time, and penumbra maps.

Published
2019
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