Skip to main content

Advertisement

SpringerLink
Log in

Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal

  • Stroke (H Diener, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

An 80-year-old man presents with an acute right hemiparesis and National Institutes of Health Stroke Scale (NIHSS) of 25, 14 h after taking dabigatran. Activated partial thromboplastin time (aPTT) is 42.8 s. Arteriogram demonstrates left internal carotid artery thrombosis. What is the appropriate management of this patient with acute ischemic stroke while on a NOAC?

Recent Findings

Idarucizumab is a reversal agent approved for dabigatran, and two more reversal agents, andexanet alfa and aripazine, are currently in development for NOACs.

Summary

In this article, we review currently available NOACs, their laboratory monitoring, and reversal agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ (Clinical Research ed). 2012;345:e7498. doi:10.1136/bmj.e7498.

    Google Scholar 

  2. Urooj F, Kulkarni A, Stapleton D, Kaluski E. New oral anticoagulants in nonvalvular atrial fibrillation. Clin Cardiol. 2016;39(12):739–46. doi:10.1002/clc.22582.

    Article  PubMed  Google Scholar 

  3. Xian Y, Hernandez AF, Harding T, Fonarow GC, Bhatt DL, Suter RE, et al. Acute management of stroke patients taking non-vitamin K antagonist oral anticoagulants addressing real-world anticoagulant management issues in stroke (ARAMIS) registry: design and rationale. Am Heart J. 2016;182:28–35. doi:10.1016/j.ahj.2016.07.023.

    Article  CAS  PubMed  Google Scholar 

  4. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol. 2011;154(3):311–24. doi:10.1111/j.1365-2141.2011.08753.x.

    Article  PubMed  Google Scholar 

  5. Trikha R, Kowey PR. Practical considerations for the nonvitamin K antagonist oral anticoagulants. Cardiology. 2017;136(2):115–24. doi:10.1159/000447530.

    Article  CAS  PubMed  Google Scholar 

  6. van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968–75. doi:10.1182/blood-2014-04-571232.

    Article  PubMed  Google Scholar 

  7. Hinojar R, Jimenez-Natcher JJ, Fernandez-Golfin C, Zamorano JL. New oral anticoagulants: a practical guide for physicians. Eur Heart J Cardiovasc Pharmacother. 2015;1(2):134–45. doi:10.1093/ehjcvp/pvv002.

    Article  PubMed  Google Scholar 

  8. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2):527–39. doi:10.1161/01.CIR.84.2.527.

  9. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. doi:10.1056/NEJMoa0905561.

    Article  CAS  PubMed  Google Scholar 

  10. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. doi:10.1056/NEJMoa1009638.

    Article  CAS  PubMed  Google Scholar 

  11. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. doi:10.1056/NEJMoa1107039.

    Article  CAS  PubMed  Google Scholar 

  12. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104. doi:10.1056/NEJMoa1310907.

    Article  CAS  PubMed  Google Scholar 

  13. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S–88S. doi:10.1378/chest.11-2292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc. 2013;88(5):495–511. doi:10.1016/j.mayocp.2013.03.006.

    Article  PubMed  Google Scholar 

  15. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52. doi:10.1056/NEJMoa0906598.

    Article  CAS  PubMed  Google Scholar 

  16. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet (London, England). 2007;370(9591):949–56. doi:10.1016/s0140-6736(07)61445-7.

    Article  CAS  Google Scholar 

  17. Verdecchia P, Angeli F, Aita A, Bartolini C, Reboldi G. Why switch from warfarin to NOACs? Intern Emerg Med. 2016;11(3):289–93. doi:10.1007/s11739-016-1411-0.

    Article  PubMed  Google Scholar 

  18. Bowry R, Fraser S, Archeval-Lao JM, Parker SA, Cai C, Rahbar MH, et al. Thrombelastography detects the anticoagulant effect of rivaroxaban in patients with stroke. Stroke. 2014;45(3):880–3. doi:10.1161/strokeaha.113.004016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Samama MM, Contant G, Spiro TE, Perzborn E, Le Flem L, Guinet C, et al. Laboratory assessment of rivaroxaban: a review. Thromb J. 2013;11(1):11. doi:10.1186/1477-9560-11-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Douxfils J, Chatelain C, Chatelain B, Dogne JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost. 2013;110(2):283–94. doi:10.1160/th12-12-0898.

    Article  CAS  PubMed  Google Scholar 

  21. Steinberg BA. How I use anticoagulation in atrial fibrillation. Blood. 2016;128(25):2891–8. doi:10.1182/blood-2016-07-693614.

    Article  CAS  PubMed  Google Scholar 

  22. Altman R, Gonzalez CD. Simple and rapid assay for effect of the new oral anticoagulant (NOAC) rivaroxaban: preliminary results support further tests with all NOACs. Thromb J. 2014;12(1):7. doi:10.1186/1477-9560-12-7.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014;35(28):1844–55. doi:10.1093/eurheartj/ehu181.

    Article  CAS  PubMed  Google Scholar 

  24. Parasrampuria DA, Marbury T, Matsushima N, Chen S, Wickremasingha PK, He L, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost. 2015;113(4):719–27. doi:10.1160/th14-06-0547.

    Article  PubMed  Google Scholar 

  25. Bounameaux H, Camm AJ. Edoxaban: an update on the new oral direct factor Xa inhibitor. Drugs. 2014;74(11):1209–31. doi:10.1007/s40265-014-0261-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Desai NR, Krumme AA, Schneeweiss S, Shrank WH, Brill G, Pezalla EJ, et al. Patterns of initiation of oral anticoagulants in patients with atrial fibrillation—quality and cost implications. Am J Med. 2014;127(11):1075–82.e1. doi:10.1016/j.amjmed.2014.05.013.

    Article  PubMed  Google Scholar 

  27. Wilke T, Bauer S, Mueller S, Kohlmann T, Bauersachs R. Patient preferences for oral anticoagulation therapy in atrial fibrillation: a systematic literature review. The patient. 2016; doi:10.1007/s40271-016-0185-9.

  28. Simons LA, Ortiz M, Freedman SB, Waterhouse BJ, Colquhoun D, Thomas G. Improved persistence with non-vitamin-K oral anticoagulants compared with warfarin in patients with atrial fibrillation: recent Australian experience. Curr Med Res Opin. 2016;32(11):1857–61. doi:10.1080/03007995.2016.1218325.

    Article  CAS  PubMed  Google Scholar 

  29. Scridon A, Serban RC. Laboratory monitoring: a turning point in the use of new oral anticoagulants. Ther Drug Monit. 2016;38(1):12–21. doi:10.1097/ftd.0000000000000247.

    Article  CAS  PubMed  Google Scholar 

  30. Cowper PA, Sheng S, Lopes RD, Anstrom KJ, Stafford JA, Davidson-Ray L, et al. Economic analysis of apixaban therapy for patients with atrial fibrillation from a US perspective: results from the ARISTOTLE randomized clinical trial. JAMA cardiology. 2017;2(5):525–34. doi:10.1001/jamacardio.2017.0065.

    Article  PubMed  Google Scholar 

  31. Vargas M, Marra A, Perrone A, Servillo G. Bleeding management in patients with new oral anticoagulants. Minerva Anestesiol. 2016;82(8):884–94.

    PubMed  Google Scholar 

  32. Kakkar AK, Mueller I, Bassand JP, Fitzmaurice DA, Goldhaber SZ, Goto S, et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS One. 2013;8(5):e63479. doi:10.1371/journal.pone.0063479.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, et al. 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):2597–604. doi:10.1016/j.jacc.2016.09.966.

    Article  CAS  PubMed  Google Scholar 

  34. Purrucker JC, Haas K, Rizos T, Khan S, Poli S, Kraft P, et al. Coagulation testing in acute ischemic stroke patients taking non-vitamin K antagonist oral anticoagulants. Stroke. 2017;48(1):152–8. doi:10.1161/strokeaha.116.014963.

    Article  CAS  PubMed  Google Scholar 

  35. Wassef A, Butcher K. Novel oral anticoagulant management issues for the stroke clinician. Int J Stroke : Of J Int Stroke Soc. 2016;11(7):759–67. doi:10.1177/1747493016660100.

    Article  Google Scholar 

  36. Steiner T, Poli S, Griebe M, Husing J, Hajda J, Freiberger A, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15(6):566–73. doi:10.1016/s1474-4422(16)00110-1.

    Article  CAS  PubMed  Google Scholar 

  37. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9. doi:10.1161/circulationaha.111.029017.

    Article  CAS  PubMed  Google Scholar 

  38. Ruff CT, Giugliano RP, Antman EM. Management of bleeding with non-vitamin K antagonist oral anticoagulants in the era of specific reversal agents. Circulation. 2016;134(3):248–61. doi:10.1161/circulationaha.116.021831.

    Article  CAS  PubMed  Google Scholar 

  39. Tummala R, Kavtaradze A, Gupta A, Ghosh RK. Specific antidotes against direct oral anticoagulants: a comprehensive review of clinical trials data. Int J Cardiol. 2016;214:292–8. doi:10.1016/j.ijcard.2016.03.056.

    Article  PubMed  Google Scholar 

  40. Morotti A, Goldstein JN. New oral anticoagulants and their reversal agents. Curr Treat Options Neurol. 2016;18(11):47. doi:10.1007/s11940-016-0430-5.

    Article  PubMed  Google Scholar 

  41. • Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–20. doi:10.1056/NEJMoa1502000. This article is a prospective study that showed Idarucizumab competely reversed the anticoagulant effect of dabigatran within minutes.

    Article  CAS  PubMed  Google Scholar 

  42. Rogers KC, Shelton MP, Finks SW. Reversal agents for direct oral anticoagulants: understanding new and upcoming options. Cardiol Rev. 2016;24(6):310–5. doi:10.1097/crd.0000000000000118.

    Article  PubMed  Google Scholar 

  43. • Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131–41. doi:10.1056/NEJMoa1607887. This article is a preliminary analysis that showed andexanet reduced anti-factor-Xa activity in patients with acute major bleeding due to factor Xa inhibitors, achieving 79% effective hemostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vene N, Mavri A, Gubensek M, Tratar G, Vizintin Cuderman T, Pohar Perme M, et al. Risk of thromboembolic events in patients with non-valvular atrial fibrillation after dabigatran or rivaroxaban discontinuation—data from the Ljubljana registry. PLoS One. 2016;11(6):e0156943. doi:10.1371/journal.pone.0156943.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardio-Thorac Surg: Off J Eur Assoc Cardio-Thorac Surg. 2016;50(5):e1–e88. doi:10.1093/ejcts/ezw313.

    Article  Google Scholar 

  46. Purrucker JC, Steiner T. Management of acute stroke in patients on oral anticoagulants. Curr Opin Neurol. 2017;30(1):1–7. doi:10.1097/wco.0000000000000406.

    Article  CAS  PubMed  Google Scholar 

  47. Paciaroni M, Agnelli G, Caso V, Tsivgoulis G, Furie KL, Tadi P, et al. Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study. Stroke. 2017;48(3):726–32. doi:10.1161/strokeaha.116.015770.

    Article  PubMed  Google Scholar 

  48. Saji N, Kimura K, Tateishi Y, Fujimoto S, Kaneko N, Urabe T, et al. Safety and efficacy of non-vitamin K oral anticoagulant treatment compared with warfarin in patients with non-valvular atrial fibrillation who develop acute ischemic stroke or transient ischemic attack: a multicenter prospective cohort study (daVinci study). J Thromb Thrombolysis. 2016;42(4):453–62. doi:10.1007/s11239-016-1376-x.

    Article  CAS  PubMed  Google Scholar 

  49. Takahashi H, Jimbo Y, Takano H, Abe H, Sato M, Fujii Y, et al. Intracerebral hematoma occurring during warfarin versus non-vitamin K antagonist oral anticoagulant therapy. Am J Cardiol. 2016;118(2):222–5. doi:10.1016/j.amjcard.2016.04.034.

    Article  CAS  PubMed  Google Scholar 

  50. Staerk L, Fosbol EL, Lip GY, Lamberts M, Bonde AN, Torp-Pedersen C, et al. Ischaemic and haemorrhagic stroke associated with non-vitamin K antagonist oral anticoagulants and warfarin use in patients with atrial fibrillation: a nationwide cohort study. Eur Heart J. 2016; doi:10.1093/eurheartj/ehw496.

  51. Tempaku A. Intracranial hemorrhage during administration of a novel oral anticoagulant. J Rural Med: JRM. 2016;11(2):69–72. doi:10.2185/jrm.2901.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lopes RD, Guimaraes PO, Kolls BJ, Wojdyla DM, Bushnell CD, Hanna M, et al. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. Blood. 2017; doi:10.1182/blood-2016-08-731638.

  53. Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43(6):1511–7. doi:10.1161/strokeaha.112.650614.

    Article  CAS  PubMed  Google Scholar 

  54. von der Brelie C, Doukas A, Naumann R, Dempfle A, Larsen N, Synowitz M, et al. Clinical and radiological course of intracerebral haemorrhage associated with the new non-vitamin K anticoagulants. Acta Neurochir. 2017;159(1):101–9. doi:10.1007/s00701-016-3026-7.

    Article  PubMed  Google Scholar 

  55. Wilson D, Charidimou A, Shakeshaft C, Ambler G, White M, Cohen H, et al. Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type. Neurology. 2016;86(4):360–6. doi:10.1212/wnl.0000000000002310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kermer P, Eschenfelder CC, Diener HC, Grond M, Abdalla Y, Althaus K, et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany—a national case collection. Int J Stroke : Off J Int Stroke Soc. 2017;12(4):383–91. doi:10.1177/1747493017701944.

    Article  Google Scholar 

  57. Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, et al. The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke. 2012;43(3):770–5. doi:10.1161/strokeaha.111.625574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rybinnik I, Mullen MT, Messe S, Kasner SE, Cucchiara B. Treatment of acute stroke in patients on dabigatran: a survey of US stroke specialists. J Stroke Cerebrovasc Dis: Off J Natl Stroke Assoc. 2013;22(8):1312–6. doi:10.1016/j.jstrokecerebrovasdis.2012.12.005.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Texas Health Science Center At Houston, 6431 Fannin, MSB 7.044, Houston, TX, 77030, USA

    Sujan T. Reddy, TC Cossey & Sean I. Savitz

  2. Memorial Hermann Hospital, Houston, TX, USA

    James C. Grotta

Authors
  1. Sujan T. Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. TC Cossey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sean I. Savitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James C. Grotta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Sujan Reddy: Drafting.

TC Cossey: Drafting.

Sean Savitz: Conceptualization and editing.

James Grotta: Conceptualization and editing.

Corresponding author

Correspondence to Sujan T. Reddy.

Ethics declarations

Conflict of Interest

Sujan T. Reddy, TC Cossey, Sean I. Savitz, and James C. Grotta declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Stroke

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reddy, S.T., Cossey, T., Savitz, S.I. et al. Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal. Curr Neurol Neurosci Rep 17, 67 (2017). https://doi.org/10.1007/s11910-017-0774-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-017-0774-6

Keywords

Search

Navigation