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Hamostaseologie 2021; 41(01): 031-034
DOI: 10.1055/a-1329-2523
Review Article

Direct Oral Anticoagulants after Ischemic Stroke: Which Patient? Which Drug? And How Early?

Gian Marco De Marchis 
1   Department of Neurology, University Hospital and University of Basel, Basel, Switzerland
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Abstract

Direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and ischemic stroke. The main advantage of DOAC over VKA is the lower rate of bleeding and mortality. This review covers challenges clinicians can encounter when treating patients with AF and ischemic stroke, including timing of DOAC start and ongoing randomized clinical trials, appropriate dosing, and available comparative evidence across DOACs. For patients without AF but with an ischemic stroke, the review outlines the role of DOACs. Finally, the risk of thrombotic events associated with specific DOAC reversal agents and DOAC pausing is reviewed.

Keywords

stroke - atrial fibrillation - anticoagulation - timing


Publication History

Received: 08 November 2020

Accepted: 03 December 2020

Article published online:
15 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22 (08) 983-988
    CrossrefPubMedGoogle Scholar
  • 2 Lin HJ, Wolf PA, Kelly-Hayes M. et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27 (10) 1760-1764
    CrossrefPubMedGoogle Scholar
  • 3 Klijn CJ, Paciaroni M, Berge E. et al. Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: a European Stroke Organisation guideline. Eur Stroke J 2019; 4 (03) 198-223
    CrossrefPubMedGoogle Scholar
  • 4 January CT, Wann LS, Calkins H. et al; Writing Group Members. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019; 16 (08) e66-e93
    CrossrefPubMedGoogle Scholar
  • 5 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
    CrossrefPubMedGoogle Scholar
  • 6 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedGoogle Scholar
  • 7 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 8 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 9 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
    CrossrefPubMedGoogle Scholar
  • 10 Paciaroni M, Agnelli G, Caso V. et al. Causes and risk factors of cerebral ischemic events in patients with atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants for stroke prevention. Stroke 2019; 50 (08) 2168-2174
    CrossrefPubMedGoogle Scholar
  • 11 Steinberg BA, Shrader P, Thomas L. et al; ORBIT-AF Investigators and Patients. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II Registry. J Am Coll Cardiol 2016; 68 (24) 2597-2604
    CrossrefPubMedGoogle Scholar
  • 12 Ntaios G, Papavasileiou V, Diener HC, Makaritsis K, Michel P. Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous stroke or transient ischemic attack: an updated systematic review and meta-analysis of randomized controlled trials. Int J Stroke 2017; 12 (06) 589-596
    CrossrefPubMedGoogle Scholar
  • 13 Yaghi S, Mistry E, Liberman AL. et al. Anticoagulation type and early recurrence in cardioembolic stroke: the IAC study. Stroke 2020; 51 (09) 2724-2732
    CrossrefPubMedGoogle Scholar
  • 14 Tsivgoulis G, Katsanos AH, Seiffge DJ. et al; RAF, RAF-DOAC, CROMIS-2, SAMURAI, NOACISP, Erlangen, Verona Registry Collaborators. Fatal intracranial haemorrhage occurring after oral anticoagulant treatment initiation for secondary stroke prevention in patients with atrial fibrillation. Eur J Neurol 2020; 27 (08) 1612-1617
    CrossrefPubMedGoogle Scholar
  • 15 Hankey GJ, Patel MR, Stevens SR. et al; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012; 11 (04) 315-322
    CrossrefPubMedGoogle Scholar
  • 16 Diener HC, Connolly SJ, Ezekowitz MD. et al; RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 2010; 9 (12) 1157-1163
    CrossrefPubMedGoogle Scholar
  • 17 Steffel J, Verhamme P, Potpara TS. et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
    CrossrefPubMedGoogle Scholar
  • 18 Seiffge DJ, Traenka C, Polymeris A. et al. Early start of DOAC after ischemic stroke: risk of intracranial hemorrhage and recurrent events. Neurology 2016; 87 (18) 1856-1862
    CrossrefPubMedGoogle Scholar
  • 19 Mizoguchi T, Tanaka K, Toyoda K. et al; SAMURAI Study Investigators. Early initiation of direct oral anticoagulants after onset of stroke and short- and long-term outcomes of patients with nonvalvular atrial fibrillation. Stroke 2020; 51 (03) 883-891
    CrossrefPubMedGoogle Scholar
  • 20 Paciaroni M, Agnelli G, Falocci N. et al. Early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with non-vitamin-K oral anticoagulants (RAF-NOACs) study. J Am Heart Assoc 2017; 6 (12) e007034
    CrossrefPubMedGoogle Scholar
  • 21 Wilson D, Ambler G, Banerjee G. et al; Clinical relevance of Microbleeds in Stroke (CROMIS-2) collaborators. Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study. J Neurol Neurosurg Psychiatry 2019; 90 (03) 320-325
    CrossrefPubMedGoogle Scholar
  • 22 Seiffge DJ, Werring DJ, Paciaroni M. et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol 2019; 18 (01) 117-126
    CrossrefPubMedGoogle Scholar
  • 23 Rutherford OW, Jonasson C, Ghanima W, Söderdahl F, Halvorsen S. Comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in atrial fibrillation: a nationwide cohort study. Eur Heart J Cardiovasc Pharmacother 2020; 6 (02) 75-85
    CrossrefPubMedGoogle Scholar
  • 24 Lip GYH, Keshishian A, Li X. et al. Effectiveness and safety of oral anticoagulants among nonvalvular atrial fibrillation patients. Stroke 2018; 49 (12) 2933-2944
    CrossrefPubMedGoogle Scholar
  • 25 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
    CrossrefPubMedGoogle Scholar
  • 26 Sharma M, Hart RG, Connolly SJ. et al. Stroke outcomes in the COMPASS trial. Circulation 2019; 139 (09) 1134-1145
    CrossrefPubMedGoogle Scholar
  • 27 Perera KS, Ng KKH, Nayar S. et al. Association between low-dose rivaroxaban with or without aspirin and ischemic stroke subtypes: a secondary analysis of the COMPASS trial. JAMA Neurol 2020; 77 (01) 43-48
    CrossrefPubMedGoogle Scholar
  • 28 Hart RG, Sharma M, Mundl H. et al; NAVIGATE ESUS Investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378 (23) 2191-2201
    CrossrefPubMedGoogle Scholar
  • 29 Diener HC, Sacco RL, Easton JD. et al; RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019; 380 (20) 1906-1917
    CrossrefPubMedGoogle Scholar
  • 30 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
    CrossrefPubMedGoogle Scholar
  • 31 Connolly SJ, Crowther M, Eikelboom JW. et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 (14) 1326-1335
    CrossrefPubMedGoogle Scholar
  • 32 Rodrigues AO, David C, Ferreira JJ, Pinto FJ, Costa J, Caldeira D. The incidence of thrombotic events with idarucizumab and andexanet alfa: a systematic review and meta-analysis. Thromb Res 2020; 196: 291-296
    CrossrefPubMedGoogle Scholar