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Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis
  1. Gian Marco De Marchis1,
  2. David J. Seiffge1,2,
  3. Sabine Schaedelin3,
  4. Duncan Wilson4,
  5. Valeria Caso5,
  6. Monica Acciarresi6,
  7. Georgios Tsivgoulis7,8,
  8. Masatoshi Koga9,
  9. Sohei Yoshimura9,
  10. Kazunori Toyoda9,
  11. Manuel Cappellari10,
  12. Bruno Bonetti10,
  13. Kosmas Macha11,
  14. Bernd Kallmünzer11,
  15. Carlo W. Cereda12,
  16. Philippe Lyrer1,
  17. Leo H. Bonati1,
  18. Maurizio Paciaroni13,
  19. Stefan T. Engelter1,14,
  20. David J. Werring4
  1. 1 Neurology and Stroke Center, University Hospital Basel & University of Basel, Basel, Switzerland
  2. 2 Neurology and Stroke Center, Inselspital, University Hospital Bern, Bern, Switzerland
  3. 3 Clinical Trial Unit, University Hospital of Basel & University of Basel, Basel, Switzerland
  4. 4 Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
  5. 5 Stroke Unit, Santa Maria Misericordia Hospital, Perugia, Italy
  6. 6 Department of Neurology, San Giovanni Battista Hospital of Foligno, Foligno, Umbria, Italy
  7. 7 Second Department of Neurology, 'Attikon' Hospital, University of Athens, School of Medicine, Athens, Greece
  8. 8 Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
  9. 9 Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
  10. 10 Department of Neuroscience, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
  11. 11 Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany
  12. 12 Neurocenter of Southern Switzerland, Ospedale Regionale di Lugano, Lugano, Switzerland
  13. 13 Department of Neurology & Stroke Unit, San Giuseppe Hospital IRCSS Multimedica, Milano, Italy
  14. 14 Department of Neurology & Neurorehabilitation, University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, Basel, Switzerland
  1. Correspondence to Dr Gian Marco De Marchis, Neurology and Stroke Center, University Hospital Basel, Basel, BS, Switzerland; gian.demarchis{at}


Objective The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start.

Methods This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH.

Results A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke.

Conclusions Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.

  • stroke
  • cerebrovascular disease

Data availability statement

Data are available upon reasonable request.

Statistics from

Data availability statement

Data are available upon reasonable request.

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  • Presented at The work as been presented as a poster at the European Stroke Organisation Conference 2019, Milano, Italy.

  • Contributors GMDM, DJS, MP amd DJW conceived and designed the study. GMDM, DJS, SS, DW, VC, MA, GT, MK, SY, KT, MC, BB, KM, BK, CWC, PL, LHB, MP, SE and DJW acquired and analysed the data. GMDM, DJS, SS, DW, VC, MA, GT, MK, SY, KT, MC, BB, KM, BK, CWC, PL, LHB, MP, SE and DJW drafted a significant portion of the manuscript or figures.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests The following companies manufacture drugs involved in this study: Bayer (BY, rivaroxaban), Boehringer Ingelheim (BI, dabigatran), Pfizer/Bristol Meyer Squibb (PB, apixaban) and Daiichi Sankyo (DS, edoxaban). GMDM: scientific advisory boards and travel honoraria: BY; speaker honoraria: PB. DJS: scientific advisory boards: BY and PB. GT: scientific advisory boards: BY, DS and BI. MK: speaker honoraria from DS, BY and PB. KT: speaker honoraria from DS, BY, BI and PB. KM: speaker honoraria from BY, travel grant from PB. PL: scientific advisory boards: BY, DS and BI; funding for travel or speaker honoraria: BY and BI; research funding: BI. LHB: consultancy or advisory board fees or speaker’s honoraria from BY and PB. MP: honoraria as a member of the speaker bureau of BI, BY and PB. SE: funding for travel or speaker honoraria: BY, BI, PB and DS; scientific advisory boards: BY, BI and PB; educational grant from PB; research grant from DS. DJW: speaking honoraria: BY.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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