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Research paper
Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study
  1. Duncan Wilson1,
  2. Gareth Ambler2,
  3. Gargi Banerjee1,
  4. Clare Shakeshaft1,
  5. Hannah Cohen3,
  6. Tarek A Yousry4,
  7. Rustam Al-Shahi Salman5,
  8. Gregory Y H Lip6,
  9. Henry Houlden7,
  10. Martin M Brown1,
  11. Keith W Muir8,
  12. Hans Rolf Jäger4,
  13. David J Werring1
  14. on behalf of the Clinical relevance of Microbleeds in Stroke (CROMIS-2) collaborators
    1. 1 Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery UCL Stroke Research Centre, London, UK
    2. 2 Department of Statistical Science, University College London, London, UK
    3. 3 Haemostasis Research Unit, Department of Haematology, University College London, London, UK
    4. 4 Lysholm Department of Neuroradiology and the Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, UK
    5. 5 Centre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Edinburgh, UK
    6. 6 Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
    7. 7 Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK
    8. 8 Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK
    1. Correspondence to Prof David J Werring, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, UCL Stroke Research Centre, London WC1B 5EH, UK; d.werring{at}


    Background and purpose The optimal time to start oral anticoagulant (OAC) in patients with ischaemic stroke due to non-valvular atrial fibrillation (AF) is unknown. We reviewed OAC timing in relation to 90-day clinical outcomes as a post hoc analysis from a prospective multicentre observational study.

    Methods We included patients with data on time to initiation of OAC from CROMIS-2 (Clinical Relevence Of Microbleeds In Stroke-2), a prospective observational inception cohort study of 1490 patients with ischaemic stroke or transient ischaemic attack (TIA) and AF treated with OAC. The primary outcome was the composite outcome of TIA, stroke (ischaemic stroke or intracranial haemorrhage) or death within 90 days of the qualifying stroke or TIA. We performed adjusted logistic regression analyses to compare early (0–4 days) and later (≥5 days or never started) OAC initiation.

    Results We included 1355 patients, mean age 76 (SD 10), 580 (43%) women. OAC was started early in 358 (26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997 (5%) in the late-OAC group (2 intracranial haemorrhages, 18 ischaemic strokes or TIAs and 31 deaths (three deaths were as a result of new ischaemic strokes)) versus 7/358 (2%) in the early-OAC group (5 ischaemic strokes or TIAs and 2 deaths). In adjusted analyses, late OAC was not associated with the composite outcome (adjusted OR 1.17, 95% CI 0.48 to 2.84, p=0.736).

    Conclusion In adjusted analyses, early OAC after acute ischaemic stroke or TIA associated with AF was not associated with a difference in the rate of the composite outcome of stroke, TIA or death at 90 days, compared with late OAC. However, despite adjustment for important baseline factors, patients selected for early OAC and late OAC might still have differed in important respects; evaluation of OAC timing in adequately powered randomised trials is required.

    Clinical trial registration NCT02513316.

    • ischaemic stroke
    • anticoagulation
    • warfarin
    • DOAC
    • atrial fibrillation

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    • Collaborators Kirsty Harkness, Louise Shaw, Jane Sword, Azlisham Mohd Nor, Pankaj Sharma, Roland Veltkamp, Deborah Kelly, Frances Harrington, Marc Randall, Matthew Smith, Karim Mahawish, Abduelbaset Elmarim, Bernard Esisi, Claire Cullen, Arumug Nallasivam, Christopher Price, Adrian Barry, Christine Roffe, John Coyle, Ahamad Hassan, Caroline Lovelock, Jonathan Birns, David Cohen, L Sekaran, Adrian Parry-Jones, Anthea Parry, David Hargroves, Harald Proschel, Prabel Datta, Khaled Darawil, Aravindakshan Manoj, Mathew Burn, Chris Patterson, Elio Giallombardo, Nigel Smyth, Syed Mansoor, Ijaz Anwar, Rachel Marsh, Sissi Ispoglou, Dinesh Chadha, Mathuri Prabhakaran, Sanjeevikumar Meenakishundaram, Janice O’Connell, Jon Scott, Vinodh Krishnamurthy, Prasanna Aghoram, Michael McCormick, Nikola Sprigg Paul O’Mahony, Martin Cooper, Lillian Choy, Peter Wilkinson, Simon Leach, Sarah Caine, Ilse Burger, Gunaratam Gunathilagan, Paul Guyler, Hedley Emsley, Michelle Davis, Dulka Manawadu, Kath Pasco, Maam Mamun, Robert Luder, Mahmud Sajid, Ijaz Anwar, James Okwera, Julie Staals, Elizabeth Warburton, Kari Saastamoinen, Timothy England, Janet Putterill, Enrico Flossman, Michael Power, Krishna Dani, David Mangion, Appu Suman, John Corrigan, Enas Lawrence, Djamil Vahidassr.

    • Contributors DW wrote the draft, undertook statistical analysis and undertook imaging ratings. GB undertook imaging ratings and critical revisions to the manuscript. DJW was involved in study concept, study governance and made critical revisions to the manuscript. GA undertook statistical analysis, study governance and made critical revisions to the manuscript. All other authors were involved in study governance and made critical revisions to the manuscript.

    • Funding The CROMIS-2 study is funded by the Stroke Association and British Heart Foundation. GB receives funding from the Rosetrees Trust. GA receives funding from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. RA-SS is funded by an MRC senior clinical fellowship. MMB’s Chair in Stroke Medicine is supported by the Reta Lila Weston Trust for Medical Research. DJW receives research support from the Stroke Association, the British Heart Foundation and the Rosetrees Trust. This work was undertaken at UCLH/UCL which receives a proportion of funding from the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme.

    • Competing interests HC has received institutional research support from Bayer; honoraria for lectures and an Advisory Board from Bayer, diverted to a local charity; and travel/accommodation expenses for participation in scientific meetings covered by Bayer and Boehringer Ingelheim. GYHL is consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-Sankyo; speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim and Daiichi-Sankyo. No fees are directly received personally. The remaining authors report no disclosures or conflicts of interest relevant to the manuscript.

    • Patient consent Obtained.

    • Ethics approval CROMIS-2 was approved by the Central London Research Ethics Committee, National Research Ethics Service.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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