Journal of Neurology

, Volume 265, Issue 12, pp 3022–3033 | Cite as

Management of patients with stroke treated with direct oral anticoagulants

  • D. J. Seiffge
  • A. A. Polymeris
  • J. Fladt
  • P. A. Lyrer
  • S. T. Engelter
  • Gian Marco De MarchisEmail author
Neurological Update


Since their market approval, direct oral anticoagulants (DOACs) are being increasingly used for stroke prevention in patients with atrial fibrillation. However, the management of DOAC-treated patients with stroke poses several challenges for physicians in everyday clinical practice, both in the acute setting and in long-term care. This has spurred extensive research activity in the field over the past few years, which we review here.


Atrial fibrillation DOAC Stroke 


Compliance with ethical standards

Conflicts of interest

David J. Seiffge (MD): has received research support from the Swiss Heart Foundation, the Science Funds of the University Hospital Basel and the University of Basel and served on a scientific advisory board for Bayer and Pfizer. Alexandros Polymeris (MD): has received research support from the Swiss Academy of Medical Sciences/Bangerter Foundation. Joachim Fladt (MD): has received research support from the Swiss Heart Foundation. Philippe A. Lyrer (MD): has received honoraria from Bayer, Daiichi-Sankyo, Schering Pharma, Boehringer Ingelheim, and Shire plc; research support from AstraZeneca, Boehringer Ingelheim, Sanofi-aventis, PhotoThera, the Swiss National Science Foundation, and the Swiss Heart Foundation. Stefan T. Engelter (MD): has received honoraria from Bayer and Boehringer Ingelheim, has served on scientific advisory boards for Bayer, Boehringer Ingelheim, BMS/Pfizer, Covidien and on the editorial board of Stroke. He has received an educational grant from Pfizer and research support from the Science Funds (Wissenschaftsfonds) of the University Hospital Basel, the University Basel, the Swiss Heart Foundation, and the Swiss National Science Foundation. Gian Marco De Marchis (MD, M.Sc.): has received research support from the Swiss National Science Foundation, the Science Funds (Wissenschaftsfonds) of the University Hospital Basel and University of Basel, the Bangerter-Rhyner-Stiftung, the Swisslife Jubiläumsstiftung for Medical Research, the Swiss Neurological Society, the Fondazione Dr. Ettore Balli, as well as the De Quervain research grant and support from Thermo Fisher GmbH; moreover, he received travel honoraria by Bayer and speaker honoraria by Medtronic and BMS/Pfizer.


  1. 1.
    World Health Organization (2004) The global burden of disease: 2004 update. WHO, GenevaGoogle Scholar
  2. 2.
    Hayden DT, Hannon N, Callaly E, Nii Chroiiniin D, Horgan G, Kyne L, Duggan J, Dolan E, O’Rourke K, Williams D, Murphy S, Kelly PJ (2015) Rates and determinants of 5-year outcomes after atrial fibrillation-related stroke: a population study. Stroke. CrossRefPubMedGoogle Scholar
  3. 3.
    Perera KS, Vanassche T, Bosch J, Swaminathan B, Mundl H, Giruparajah M, Barboza MA, O’Donnell MJ, Gomez-Schneider M, Hankey GJ, Yoon BW, Roxas A Jr, Lavallee P, Sargento-Freitas J, Shamalov N, Brouns R, Gagliardi RJ, Kasner SE, Pieroni A, Vermehren P, Kitagawa K, Wang Y, Muir K, Coutinho JM, Connolly SJ, Hart RG (2016) Global survey of the frequency of atrial fibrillation-associated stroke: embolic stroke of undetermined source global registry. Stroke 47(9):2197–2202. CrossRefPubMedGoogle Scholar
  4. 4.
    The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators (1990) The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 323:1505–1511. CrossRefGoogle Scholar
  5. 5.
    EAFT (European Atrial Fibrillation Trial) Study Group (1993) Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 342(8882):1255–1262Google Scholar
  6. 6.
    Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, Del Zoppo GJ, Baigent C, Sandercock P, Hacke W (2014) Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millan M, Davis SM, Roy D, Thornton J, Roman LS, Ribo M, Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG (2016) Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387(10029):1723–1731. CrossRefPubMedGoogle Scholar
  8. 8.
    Hart RG, Coull BM, Hart D (1983) Early recurrent embolism associated with nonvalvular atrial fibrillation: a retrospective study. Stroke 14(5):688–693CrossRefGoogle Scholar
  9. 9.
    Merali Z, Huang K, Mikulis D, Silver F, Kassner A (2017) Evolution of blood–brain-barrier permeability after acute ischemic stroke. PLoS One 12:e0171558. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ (2010) Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 137(2):263–272. CrossRefPubMedGoogle Scholar
  11. 11.
    Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010) A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138(5):1093–1100. CrossRefPubMedGoogle Scholar
  12. 12.
    Béjot Y, Bailly H, Durier J, Giroud M (2016) Epidemiology of stroke in Europe and trends for the 21st century. La Presse Méd 45:e391–e398. CrossRefGoogle Scholar
  13. 13.
    Go AS, Hylek EM, Phillips KA et al (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA 285(18):2370–2375. CrossRefGoogle Scholar
  14. 14.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, R-LS Committee Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. CrossRefGoogle Scholar
  15. 15.
    Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S, AS Committee Investigators (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364(9):806–817. CrossRefPubMedGoogle Scholar
  16. 16.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104. CrossRefPubMedGoogle Scholar
  17. 17.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, RA Investigators (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. CrossRefPubMedGoogle Scholar
  18. 18.
    Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955–962. CrossRefPubMedGoogle Scholar
  19. 19.
    Bruins Slot KM, Berge E (2018) Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 3:Cd008980. CrossRefPubMedGoogle Scholar
  20. 20.
    Cuker A, Siegal DM, Crowther MA, Garcia DA (2014) Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 64(11):1128–1139. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Huisman MV, Rothman KJ, Paquette M, Teutsch C, Diener HC, Dubner SJ, Halperin JL, Ma CS, Zint K, Elsaesser A, Bartels DB, Lip GY (2017) The changing landscape for stroke prevention in AF: findings from the GLORIA-AF Registry Phase 2. J Am Coll Cardiol 69(7):777–785. CrossRefPubMedGoogle Scholar
  22. 22.
    Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 50(5):e1–e88. CrossRefGoogle Scholar
  23. 23.
    Wardlaw JM, Murray V, Berge E, del Zoppo GJ (2014) Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 7:CD000213. CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL (2018) 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 49(3):e46-e110. CrossRefPubMedGoogle Scholar
  25. 25.
    Drouet L, Bal Dit Sollier C, Steiner T, Purrucker J (2016) Measuring non-vitamin K antagonist oral anticoagulant levels: When is it appropriate and which methods should be used? Int J Stroke 11(7):748–758. CrossRefPubMedGoogle Scholar
  26. 26.
    Purrucker JC, Haas K, Rizos T, Khan S, Poli S, Kraft P, Kleinschnitz C, Dziewas R, Binder A, Palm F, Jander S, Soda H, Heuschmann PU, Veltkamp R (2017) Coagulation testing in acute ischemic stroke patients taking non-vitamin K antagonist oral anticoagulants. Stroke 48(1):152–158. CrossRefPubMedGoogle Scholar
  27. 27.
    Seiffge DJ, Traenka C, Polymeris A, Hert L, Fisch U, Peters N, De Marchis GM, Guzman R, Nickel CH, Lyrer PA, Bonati LH, Tsakiris D, Engelter S (2017) Feasibility of rapid measurement of rivaroxaban plasma levels in patients with acute stroke. J Thromb Thrombolysis 43(1):112–116. CrossRefPubMedGoogle Scholar
  28. 28.
    Steiner T, Bohm M, Dichgans M, Diener HC, Ell C, Endres M, Epple C, Grond M, Laufs U, Nickenig G, Riess H, Rother J, Schellinger PD, Spannagl M, Veltkamp R (2013) Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 102(6):399–412. CrossRefPubMedGoogle Scholar
  29. 29.
    Seiffge DJ, Kagi G, Michel P, Fischer U, Bejot Y, Wegener S, Zedde M, Turc G, Cordonnier C, Sandor PS, Rodier G, Zini A, Cappellari M, Schadelin S, Polymeris AA, Werring D, Thilemann S, Maestrini I, Berge E, Traenka C, Vehoff J, De Marchis GM (2018) Rivaroxaban plasma levels in acute ischemic stroke and intracerebral hemorrhage. 83(3):451–459. CrossRefGoogle Scholar
  30. 30.
    Seiffge DJ, Traenka C, Polymeris AA, Thilemann S, Wagner B, Hert L, Muller MD, Gensicke H, Peters N, Nickel CH, Stippich C, Sutter R, Marsch S, Fisch U, Guzman R, De Marchis GM, Lyrer PA, Bonati LH, Tsakiris DA, Engelter ST (2017) Intravenous thrombolysis in patients with stroke taking rivaroxaban using drug specific plasma levels: experience with a standard operation procedure in clinical practice. J Stroke 19(3):347–355. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Cappellari M, Bovi P (2015) Intravenous thrombolysis for stroke in patients taking non-VKA oral anticoagulants: an update. Thromb Haemost 114(2):440–444. CrossRefPubMedGoogle Scholar
  32. 32.
    Purrucker JC, Wolf M, Haas K, Rizos T, Khan S, Dziewas R, Kleinschnitz C, Binder A, Groschel K, Hennerici MG, Lobotesis K, Poli S, Seidel G, Neumann-Haefelin T, Ringleb PA, Heuschmann PU, Veltkamp R (2016) Safety of endovascular thrombectomy in patients receiving non-vitamin k antagonist oral anticoagulants. Stroke 47:1127–1130. CrossRefPubMedGoogle Scholar
  33. 33.
    Seiffge DJ, Hooff RJ, Nolte CH, Bejot Y, Turc G, Ikenberg B, Berge E, Persike M, Dequatre-Ponchelle N, Strbian D, Pfeilschifter W, Zini A, Tveiten A, Naess H, Michel P, Sztajzel R, Luft A, Gensicke H, Traenka C, Hert L, Scheitz JF, De Marchis GM, Bonati LH, Peters N, Charidimou A, Werring DJ, Palm F, Reinhard M, Niesen WD, Nagao T, Pezzini A, Caso V, Nederkoorn PJ, Kagi G, von Hessling A, Padjen V, Cordonnier C, Erdur H, Lyrer PA, Brouns R, Steiner T, Tatlisumak T, Engelter ST (2015) Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome. Circulation 132(13):1261–1269. CrossRefPubMedGoogle Scholar
  34. 34.
    Xian Y, Federspiel JJ, Hernandez AF, Laskowitz DT, Schwamm LH, Bhatt DL, Smith EE, Fonarow GC, Peterson ED (2017) Use of intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke who take non-vitamin K antagonist oral anticoagulants before stroke. Circulation 135(11):1024–1035. CrossRefPubMedGoogle Scholar
  35. 35.
    Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI (2017) Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med 377(5):431–441. CrossRefPubMedGoogle Scholar
  36. 36.
    Kermer P, Eschenfelder CC, Diener HC, Grond M, Abdalla Y, Althaus K, Berrouschot J, Cangur H, Daffertshofer M, Edelbusch S, Groschel K, Haase CG, Harloff A, Held V, Kauert A, Kraft P, Lenz A, Mullges W, Obermann M, Partowi S, Purrucker J, Ringleb PA, Rother J, Rossi R, Schafer N, Schneider A, Schuppner R, Seitz RJ, Szabo K, Wruck R (2017) Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany—a national case collection. Int J Stroke 12(4):383–391. CrossRefPubMedGoogle Scholar
  37. 37.
    Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M (2016) Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146(12):857–867CrossRefGoogle Scholar
  39. 39.
    Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J (2003) Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107(4):598–603CrossRefPubMedGoogle Scholar
  40. 40.
    Kassner A, Merali Z (2015) Assessment of blood–brain barrier disruption in stroke. Stroke 46(11):3310–3315. CrossRefPubMedGoogle Scholar
  41. 41.
    Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, Caso V, Micheli S, Bertolani L, Venti M, Palmerini F, Biagini S, Comi G, Previdi P, Silvestrelli G (2008) Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke 39(8):2249–2256. CrossRefPubMedGoogle Scholar
  42. 42.
    Yoon CH, Park YK, Kim SJ, Lee MJ, Ryoo S, Kim GM, Chung CS, Lee KH, Kim JS, Bang OY (2014) Eligibility and preference of new oral anticoagulants in patients with atrial fibrillation. Comparison between patients with versus without stroke. Stroke 45(10):2983–2988. CrossRefPubMedGoogle Scholar
  43. 43.
    Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W, For the RAFSCI (2012) Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 11(4):315–322. CrossRefPubMedGoogle Scholar
  44. 44.
    Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, Alings M, Goto S, Lewis BS, Rosenqvist M, Hanna M, Mohan P, Alexander JH, Diener HC, For the ACI (2012) Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 11(6):503–511. CrossRefPubMedGoogle Scholar
  45. 45.
    Macha K, Volbers B, Bobinger T, Kurka N, Breuer L, Huttner HB, Schwab S, Kohrmann M (2016) Early initiation of anticoagulation with direct oral anticoagulants in patients after transient ischemic attack or ischemic stroke. J Stroke Cerebrovasc Dis. CrossRefPubMedGoogle Scholar
  46. 46.
    Cappellari M, Carletti M, Danese A, Bovi P (2016) Early introduction of direct oral anticoagulants in cardioembolic stroke patients with non-valvular atrial fibrillation. J Thromb Thrombolysis. CrossRefPubMedGoogle Scholar
  47. 47.
    Toyoda K, Arihiro S, Todo K, Yamagami H, Kimura K, Furui E, Terasaki T, Shiokawa Y, Kamiyama K, Takizawa S, Okuda S, Okada Y, Kameda T, Nagakane Y, Hasegawa Y, Mochizuki H, Ito Y, Nakashima T, Takamatsu K, Nishiyama K, Kario K, Sato S, Koga M (2015) Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: the SAMURAI-NVAF study. Int J Stroke 10(6):836–842. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, Engelter ST, Bonati LH, De Marchis GM (2016) Early start of DOAC after ischemic stroke: risk of intracranial hemorrhage and recurrent events. Neurology 87(18):1856–1862. CrossRefPubMedGoogle Scholar
  49. 49.
    Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, Rueckert C, Pezzini A, Poli L, Padovani A, Csiba L, Szabo L, Sohn SI, Tassinari T, Abdul-Rahim AH, Michel P, Cordier M, Vanacker P, Remillard S, Alberti A, Venti M, Scoditti U, Denti L, Orlandi G, Chiti A, Gialdini G, Bovi P, Carletti M, Rigatelli A, Putaala J, Tatlisumak T, Masotti L, Lorenzini G, Tassi R, Guideri F, Martini G, Tsivgoulis G, Vadikolias K, Liantinioti C, Corea F, Del Sette M, Ageno W, De Lodovici ML, Bono G, Baldi A, D’Anna S, Sacco S, Carolei A, Tiseo C, Acciarresi M, D’Amore C, Imberti D, Zabzuni D, Doronin B, Volodina V, Consoli D, Galati F, Pieroni A, Toni D, Monaco S, Baronello MM, Barlinn K, Pallesen LP, Kepplinger J, Bodechtel U, Gerber J, Deleu D, Melikyan G, Ibrahim F, Akhtar N, Mosconi MG, Bubba V, Silvestri I, Lees KR (2015) Early recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: effect of anticoagulation and its timing: the RAF Study. Stroke 46(8):2175–2182. CrossRefPubMedGoogle Scholar
  50. 50.
    Paciaroni M, Agnelli G, Falocci N, Tsivgoulis G, Vadikolias K, Liantinioti C, Chondrogianni M, Bovi P, Carletti M, Cappellari M, Zedde M, Ntaios G, Karagkiozi E, Athanasakis G, Makaritsis K, Silvestrelli G, Lanari A, Ciccone A, Putaala J, Tomppo L, Tatlisumak T, Abdul-Rahim AH, Lees KR, Alberti A, Venti M, Acciarresi M, D’Amore C, Becattini C, Mosconi MG, Cimini LA, Soloperto R, Masotti L, Vannucchi V, Lorenzini G, Tassi R, Guideri F, Acampa M, Martini G, Sohn SI, Marcheselli S, Mumoli N, De Lodovici ML, Bono G, Furie KL, Tadi P, Yaghi S, Toni D, Letteri F, Tassinari T, Kargiotis O, Lotti EM, Flomin Y, Mancuso M, Maccarrone M, Giannini N, Bandini F, Pezzini A, Poli L, Padovani A, Scoditti U, Denti L, Consoli D, Galati F, Sacco S, Carolei A, Tiseo C, Gourbali V, Orlandi G, Giuntini M, Chiti A, Giorli E, Gialdini G, Corea F, Ageno W, Bellesini M, Colombo G, Monaco S, Maimone Baronello M, Karapanayiotides T, Caso V (2017) 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 6(12):e007034. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Gioia LC, Kate M, Sivakumar L, Hussain D, Kalashyan H, Buck B, Bussiere M, Jeerakathil T, Shuaib A, Emery D, Butcher K (2016) Early rivaroxaban use after cardioembolic stroke may not result in hemorrhagic transformation: a prospective magnetic resonance imaging study. Stroke 47(7):1917–1919. CrossRefPubMedGoogle Scholar
  52. 52.
    Shibazaki K, Kimura K, Aoki J, Saji N, Sakai K (2013) Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation. J Neurol Sci 331:90–93. CrossRefPubMedGoogle Scholar
  53. 53.
    Arihiro S, Todo K, Koga M, Furui E, Kinoshita N, Kimura K, Yamagami H, Terasaki T, Yoshimura S, Shiokawa Y, Kamiyama K, Takizawa S, Okuda S, Okada Y, Nagakane Y, Kameda T, Hasegawa Y, Shibuya S, Ito Y, Nakashima T, Takamatsu K, Nishiyama K, Matsuki T, Homma K, Takasugi J, Tokunaga K, Sato S, Kario K, Kitazono T, Toyoda K (2016) Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: The SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study. Int J Stroke 11(5):565–574. CrossRefPubMedGoogle Scholar
  54. 54.
    Ahmed N, Steiner T, Caso V, Wahlgren N (2017) Recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 13–15 November 2016. Eur Stroke J 2(2):95–102. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI (2015) Idarucizumab for dabigatran reversal. N Engl J Med 373(6):511–520. CrossRefPubMedGoogle Scholar
  56. 56.
    Tsivgoulis G, Lioutas VA, Varelas P, Katsanos AH, Goyal N, Mikulik R, Barlinn K, Krogias C, Sharma VK, Vadikolias K, Dardiotis E, Karapanayiotides T, Pappa A, Zompola C, Triantafyllou S, Kargiotis O, Ioakeimidis M, Giannopoulos S, Kerro A, Tsantes A, Mehta C, Jones M, Schroeder C, Norton C, Bonakis A, Chang J, Alexandrov AW, Mitsias P, Alexandrov AV (2017) Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage. Neurology. CrossRefPubMedGoogle Scholar
  57. 57.
    Hagii J, Tomita H, Metoki N, Saito S, Shiroto H, Hitomi H, Kamada T, Seino S, Takahashi K, Baba Y, Sasaki S, Uchizawa T, Iwata M, Matsumoto S, Osanai T, Yasujima M, Okumura K (2014) Characteristics of intracerebral hemorrhage during rivaroxaban treatment: comparison with those during warfarin. Stroke 45(9):2805–2807. CrossRefPubMedGoogle Scholar
  58. 58.
    Wilson D, Seiffge DJ, Traenka C, Basir G, Purrucker JC, Rizos T, Sobowale OA, Sallinen H, Yeh SJ, Wu TY, Ferrigno M, Houben R, Schreuder F, Perry LA, Tanaka J, Boulanger M, Al-Shahi Salman R, Jager HR, Ambler G, Shakeshaft C, Yakushiji Y, Choi PMC, Staals J, Cordonnier C, Jeng JS, Veltkamp R, Dowlatshahi D, Engelter ST, Parry-Jones AR, Meretoja A, Werring DJ (2017) Outcome of intracerebral hemorrhage associated with different oral anticoagulants. Neurology 88(18):1693–1700. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Boulouis G, Morotti A, Pasi M, Goldstein JN, Gurol ME, Charidimou A (2017) Outcome of intracerebral haemorrhage related to non-vitamin K antagonists oral anticoagulants versus vitamin K antagonists: a comprehensive systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 89:263–270. CrossRefPubMedGoogle Scholar
  60. 60.
    Sprigg N, Flaherty K, Appleton JP, Salman RA, Bereczki D, Beridze M, Christensen H, Ciccone A, Collins R, Czlonkowska A, Dineen RA, Duley L, Egea-Guerrero JJ, England TJ, Krishnan K, Laska AC, Law ZK, Ozturk S, Pocock SJ, Roberts I, Robinson TG, Roffe C, Seiffge D, Scutt P, Thanabalan J, Werring D, Whynes D, Bath PM (2018) Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, Xavier D, Di Pasquale G, Yusuf S, group R-Ls (2010) 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 9(12):1157–1163. CrossRefPubMedGoogle Scholar
  62. 62.
    Rost NS, Giugliano RP, Ruff CT, Murphy SA, Crompton AE, Norden AD, Silverman S, Singhal AB, Nicolau JC, SomaRaju B, Mercuri MF, Antman EM, Braunwald E (2016) Outcomes with edoxaban versus warfarin in patients with previous cerebrovascular events: findings from ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke 47(8):2075–2082. CrossRefGoogle Scholar
  63. 63.
    Kato ET, Giugliano RP, Ruff CT, Koretsune Y, Yamashita T, Kiss RG, Nordio F, Murphy SA, Kimura T, Jin J, Lanz H, Mercuri M, Braunwald E, Antman EM (2016) Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc 5(5):e003432. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Halperin JL, Hankey GJ, Wojdyla DM, Piccini JP, Lokhnygina Y, Patel MR, Breithardt G, Singer DE, Becker RC, Hacke W, Paolini JF, Nessel CC, Mahaffey KW, Califf RM, Fox KA (2014) Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 130(2):138–146. CrossRefPubMedGoogle Scholar
  65. 65.
    Lauw MN, Eikelboom JW, Coppens M, Wallentin L, Yusuf S, Ezekowitz M, Oldgren J, Nakamya J, Wang J, Connolly SJ (2017) Effects of dabigatran according to age in atrial fibrillation. Heart 103(13):1015–1023. CrossRefPubMedGoogle Scholar
  66. 66.
    Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L (2014) Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 35(28):1864–1872. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ntaios G, Papavasileiou V, Diener HC, Makaritsis K, Michel P (2017) 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 12(6):589–596. CrossRefPubMedGoogle Scholar
  68. 68.
    Sadlon AH, Tsakiris DA (2016) Direct oral anticoagulants in the elderly: systematic review and meta-analysis of evidence, current and future directions. Swiss Med Wkly 146:w14356. CrossRefPubMedGoogle Scholar
  69. 69.
    Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M (2015) Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation 132(3):194–204. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Cavallari I, Patti G (2018) Efficacy and safety of oral anticoagulation in elderly patients with atrial fibrillation. Anatol J Cardiol 19(1):67–71. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lindley RI (2018) Stroke prevention in the very elderly. Stroke. CrossRefPubMedGoogle Scholar
  72. 72.
    Ho P, Brooy BL, Hayes L, Lim WK (2015) Direct oral anticoagulants in frail older adults: a geriatric perspective. Semin Thromb Hemost 41(4):389–394. CrossRefPubMedGoogle Scholar
  73. 73.
    Wolff A, Shantsila E, Lip GYH, Lane DA (2015) Impact of advanced age on management and prognosis in atrial fibrillation: insights from a population-based study in general practice. Age Ageing 44(5):874–878. CrossRefPubMedGoogle Scholar
  74. 74.
    Chao TF, Liu CJ, Lin YJ, Chang SL, Lo LW, Hu YF, Tuan TC, Liao JN, Chung FP, Chen TJ, Lip GYH, Chen SA (2018) Oral anticoagulation in very elderly patients with atrial fibrillation—a nationwide cohort study. Circulation. CrossRefPubMedGoogle Scholar
  75. 75.
    McGrath ER, Go AS, Chang Y, Borowsky LH, Fang MC, Reynolds K, Singer DE (2017) Use of oral anticoagulant therapy in older adults with atrial fibrillation after acute ischemic stroke. J Am Geriatr Soc 65(2):241–248. CrossRefPubMedGoogle Scholar
  76. 76.
    Appelros P, Farahmand B, Terent A, Asberg S (2017) To treat or not to treat: anticoagulants as secondary preventives to the oldest old with atrial fibrillation. Stroke 48(6):1617–1623. 10.1111/jgs.14688CrossRefPubMedGoogle Scholar
  77. 77.
    Mant J, Hobbs FDR, Fletcher K, Roalfe A, Fitzmaurice D, Lip GYH, Murray E (2007) Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 370(9586):493–503. CrossRefPubMedGoogle Scholar
  78. 78.
    Lawrence J, Pogue J, Synhorst D, Adalet K, Atar D, Avezum A, Budaj A, Commerford PJ, Dans AL, De Caterina R, Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, O’Donnell M, Hohnloser SH, Hankey GJ, Shestakovska O, Yusuf S, AS Committee Investigators (2012) Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 11(3):225–231. CrossRefGoogle Scholar
  79. 79.
    Ng KH, Shestakovska O, Connolly SJ, Eikelboom JW, Avezum A, Diaz R, Lanas F, Yusuf S, Hart RG (2016) Efficacy and safety of apixaban compared with aspirin in the elderly: a subgroup analysis from the AVERROES trial. Age Ageing 45(1):77–83. CrossRefPubMedGoogle Scholar
  80. 80.
    Patti G, Lucerna M, Pecen L, Siller-Matula JM, Cavallari I, Kirchhof P, De Caterina R (2017) Thromboembolic risk, bleeding outcomes and effect of different antithrombotic strategies in very elderly patients with atrial fibrillation: a sub-analysis from the PREFER in AF (PREvention oF Thromboembolic Events-European Registry in Atrial Fibrillation). J Am Heart Assoc. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Siu CW, Tse HF (2014) Net clinical benefit of warfarin therapy in elderly Chinese patients with atrial fibrillation. Circ Arrhythm Electrophysiol 7(2):300–306. CrossRefPubMedGoogle Scholar
  82. 82.
    Stollberger C, Brooks R, Finsterer J, Pachofszky T (2016) Use of direct-acting oral anticoagulants in nonagenarians: a call for more data. Drugs Aging 33(5):315–320. CrossRefPubMedGoogle Scholar
  83. 83.
    Khan F, Huang H, Datta YH (2016) Direct oral anticoagulant use and the incidence of bleeding in the very elderly with atrial fibrillation. J Thromb thrombolysis 42(4):573–578. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Zou R, Tao J, Shi W, Yang M, Li H, Lin X, Yang S, Hua P (2017) Meta-analysis of safety and efficacy for direct oral anticoagulation treatment of non-valvular atrial fibrillation in relation to renal function. Thromb Res 160:41–50. CrossRefPubMedGoogle Scholar
  85. 85.
    Jia B, Lynn HS, Rong F, Zhang W (2014) Meta-analysis of efficacy and safety of the new anticoagulants versus warfarin in patients with atrial fibrillation. J Cardiovasc Pharmacol 64(4):368–374. CrossRefPubMedGoogle Scholar
  86. 86.
    Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, Cesari M, Chumlea WC, Doehner W, Evans J, Fried LP, Guralnik JM, Katz PR, Malmstrom TK, McCarter RJ, Gutierrez Robledo LM, Rockwood K, von Haehling S, Vandewoude MF, Walston J (2013) Frailty consensus: a call to action. J Am Med Dir Assoc 14(6):392–397. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Patti G, Mantione L, Bressi E, Bisignani A (2018) Efficacy and safety of oral anticoagulant therapy in frail patients with atrial fibrillation. Monaldi Arch Chest Dis 88(2):958. CrossRefPubMedGoogle Scholar
  88. 88.
    Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, Kowey PR, Mahaffey KW, Naccarelli G, Reiffel J, Singer DE, Peterson ED, Piccini JP (2016) Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II Registry. J Am Coll Cardiol 68(24):2597–2604. CrossRefPubMedGoogle Scholar
  89. 89.
    Emren SV, Senoz O, Bilgin M, Beton O, Aslan A, Taskin U, Aciksari G, Asarcikli LD, Cakir H, Bekar L, Bolat I, Yayla C, Celebi B, Dalgic O, Celik O, Safak O, Akyel S, Gungor H, Duzel B, Zoghi M (2018) Drug adherence in patients with nonvalvular atrial fibrillation taking non-vitamin K antagonist oral anticoagulants in Turkey: NOAC-TR. Clin Appl Thromb Hemost 24(3):525–531. CrossRefPubMedGoogle Scholar
  90. 90.
    Borne RT, O’Donnell C, Turakhia MP, Varosy PD, Jackevicius CA, Marzec LN, Masoudi FA, Hess PL, Maddox TM, Ho PM (2017) Adherence and outcomes to direct oral anticoagulants among patients with atrial fibrillation: findings from the veterans health administration. BMC Cardiovasc Disord 17(1):236. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P (1998) Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 352(9136):1245–1251CrossRefGoogle Scholar
  92. 92.
    The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333(24):1581–1587. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neurology and Stroke Center, Department of Clinical ResearchUniversity Hospital and University of BaselBaselSwitzerland
  2. 2.Stroke Research Center, Department of Brain Repair and RehabilitationUCL Institute of Neurology and The National Hospital for Neurology and NeurosurgeryLondonUK
  3. 3.Neurorehabilitation Unit, University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter HospitalUniversity of BaselBaselSwitzerland

Personalised recommendations