Skip to main content
SpringerLink
Log in

Reversal Strategies for NOACs: State of Development, Possible Clinical Applications and Future Perspectives

  • Current Opinion
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

The non-vitamin K antagonist oral anticoagulants (NOACs) are used for thromboembolic prophylaxis of patients with atrial fibrillation and in the treatment as well as secondary prophylaxis of patients with venous thromboembolism. Even though NOACs have a better safety profile than vitamin K antagonists (VKAs), there will still be bleeding complications on NOAC treatment. In some cases, stopping the NOAC and non-drug-related management such as manual compression and interventional endoscopy will be sufficient to stop the bleeding. In more serious bleeding events and before acute surgery, coagulation factor concentrates or NOAC-specific antidotes could be used. Coagulation factor concentrates can be used in patients with haemophilia and to reverse the effect of VKAs but, in NOAC-treated patients, results are inconsistent and these agents could potentially have pro-thrombotic effects. Specific antidotes for NOACs are expected to be on the market soon. Phase III clinical trials with a humanized antibody fragment directed against dabigatran (idarucizumab) and recombinant, modified factor Xa (andexanet alfa) are ongoing. A molecule (aripazine) with broad activity against various anticoagulants including NOACs is currently undergoing phase II trials. For use of these specific antidotes, it is desirable that measurements for coagulation activity with a short response delay are widely available for the different NOACs and further research in this field is needed. Furthermore, guidelines for antidote use, including general measures for the treatment of NOAC-related bleeding, should be available.

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

Similar content being viewed by others

References

  1. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, 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):955–62.

    Article  PubMed  CAS  Google Scholar 

  2. Blaich C, Muller C, Michels G, Wiesen MH. Multi-analyte analysis of non-vitamin K antagonist oral anticoagulants in human plasma using tandem mass spectrometry. Clin Chem Lab Med. 2015. http://www.degruyter.com/view/j/cclm.ahead-of-print/cclm-2014-1108/cclm-2014-1108.xml.

  3. Douxfils J, Mani H, Minet V, Devalet B, Chatelain B, Dogne JM, et al. Non-VKA oral anticoagulants: accurate measurement of plasma drug concentrations. Biomed Res Int. 2015;2015:345138.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385(9984):2288–95.

    Article  PubMed  CAS  Google Scholar 

  5. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321–8.

    Article  PubMed  CAS  Google Scholar 

  6. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–14.

    Article  PubMed  CAS  Google Scholar 

  7. Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clin Lab Med. 2014;34(3):503–17.

    Article  PubMed  Google Scholar 

  8. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128–39.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med. 2011;49(5):761–72.

    Article  PubMed  CAS  Google Scholar 

  10. Garcia D, Barrett YC, Ramacciotti E, Weitz JI. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost. 2013;11(2):245–52.

    Article  PubMed  CAS  Google Scholar 

  11. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ. 2014;23(349):g4670.

    Article  Google Scholar 

  12. Hyphen Biomed. Application sheet for dabigatran with hemoclot thrombin inhibitors v3. Available at: http://www.aniara.com/pdf/ADA-ACK002KLCS2000i-2100i.pdf. Accessed July 2015.

  13. Faaborg L, Comuth WJ, Bloch-Münster AM, Henriksen LØ, Husted S. Handling of the hemoclot thrombin inhibitor assay reagents on Sysmex CS-2100i when monitoring dabigatran in acute clinical situations. Poster, XXV International Society on Thrombosis and Haemostasis Congress, Toronto, Canada 2015, Abstract (June). http://www.postersessiononline.eu/pr/aula_poster.asp?congreso=740245997. Accessed 19 Oct 2015.

  14. Schmitz EM, Boonen K, van den Heuvel DJ, van Dongen JL, Schellings MW, Emmen JM, et al. Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost. 2014;12(10):1636–46.

    Article  PubMed  CAS  Google Scholar 

  15. Antovic JP, Skeppholm M, Eintrei J, Boija EE, Soderblom L, Norberg EM, et al. Evaluation of coagulation assays versus LC–MS/MS for determinations of dabigatran concentrations in plasma. Eur J Clin Pharmacol. 2013;69(11):1875–81.

    Article  PubMed  CAS  Google Scholar 

  16. Hawes EM, Deal AM, Funk-Adcock D, Gosselin R, Jeanneret C, Cook AM, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost. 2013;11(8):1493–502.

    Article  PubMed  CAS  Google Scholar 

  17. Bates SM, Weitz JI. Coagulation assays. Circulation. 2005;112(4):e53–60.

    Article  PubMed  Google Scholar 

  18. Lange U, Nowak G, Bucha E. Ecarin chromogenic assay—a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb. 2003–2004;33(4):184–191.

  19. Douxfils J, Chatelain B, Hjemdahl P, Devalet B, Sennesael AL, Wallemacq P, et al. Does the Russell Viper Venom time test provide a rapid estimation of the intensity of oral anticoagulation? A cohort study. Thromb Res. 2015;135(5):852–60.

    Article  PubMed  CAS  Google Scholar 

  20. Kluft C, Burggraaf J. Introduction to haemostasis from a pharmacodynamic perspective. Br J Clin Pharmacol. 2011;72(4):538–46.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Dinkelaar J, Patiwael S, Harenberg J, Leyte A, Brinkman HJ. Global coagulation tests: their applicability for measuring direct factor Xa- and thrombin inhibition and reversal of anticoagulation by prothrombin complex concentrate. Clin Chem Lab Med. 2014;52(11):1615–23.

    PubMed  CAS  Google Scholar 

  22. Gatt A, van Veen JJ, Woolley AM, Kitchen S, Cooper P, Makris M. Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost. 2008;100(2):350–5.

    PubMed  CAS  Google Scholar 

  23. Lance MD. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thromb J 2015;13:1. doi:10.1186/1477-9560-13-1.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Beyer-Westendorf J, Forster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014;124(6):955–62.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Beyer-Westendorf J, Ebertz F, Forster K, Gelbricht V, Michalski F, Kohler C, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost. 2015;113(6):1247–57.

    Article  PubMed  Google Scholar 

  26. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(5):625–51.

    Article  PubMed  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. Verheugt FW, Granger CB. Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet. 2015;386(9990):303–10.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. Levi M, Moore KT, Castillejos CF, Kubitza D, Berkowitz SD, Goldhaber SZ, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428–36.

    Article  PubMed  CAS  Google Scholar 

  31. Martin AC, Le Bonniec B, Fischer AM, Marchand-Leroux C, Gaussem P, Samama CM, et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168(4):4228–33.

    Article  PubMed  Google Scholar 

  32. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42(12):3594–9.

    Article  PubMed  Google Scholar 

  33. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116(1):94–102.

    Article  PubMed  CAS  Google Scholar 

  34. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554–62.

    Article  PubMed  CAS  Google Scholar 

  35. Glund S, Stangier J, Schmohl M. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Blood. 2014;124(344). http://www.bloodjournal.org/content/124/21/344. Accessed 19 Oct 2015.

  36. Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113(5):943–51.

    Article  PubMed  Google Scholar 

  37. Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386(9994):680–90.

    Article  PubMed  CAS  Google Scholar 

  38. Grottke O, Honickel M, van Ryn J, Ten Cate H, Rossaint R, Spronk HM. Idarucizumab, a specific dabigatran reversal agent, reduces blood loss in a porcine model of trauma with dabigatran anticoagulation. J Am Coll Cardiol. 2015;66(13):1518–9.

    Article  PubMed  Google Scholar 

  39. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–51.

    Article  PubMed  CAS  Google Scholar 

  40. Hollenbach S, Tan S, Deguzman F, Malinowski J, Hutchaleelaha A, Inagaki M, et al. PRT064445 reverses rivaroxaban induced anticoagulation in a rabbit liver laceration “treatment” model. Eur Heart J. 2013;241. http://eurheartj.oxfordjournals.org/content/34/suppl_1/P241. Accessed 19 Oct 2015.

  41. Lu G, Deguzman F, Hollenbach S, Luan P, Abe K, Siu G, et al. Reversal of low molecular weight heparin and fondaparinux by a recombinant antidote (r-Antidote, PRT064445). Abstract 12420. Circulation. 2010;122. http://circ.ahajournals.org/cgi/content/meeting_abstract/122/21_MeetingAbstracts/A12420. Accessed 19 Oct 2015.

  42. Hollenbach S, Lu G, Deguzman F, Curnutte J, Conley P, Sinha U. Bolus administration of PRT064445, a recombinant factor Xa inhibitor antidote, reverses blood loss and PD markers in a rat model following enoxaparin-induced anticoagulation. Abstract P1857. Eur Heart J. 2012;33 (abstract supplement):309. http://www.postersessiononline.eu/pr/aula_poster.asp?congreso=740245997&direccion_posters=Seleccion&pagina_posters=5&ordenacion=n_poster&cod_congreso_integracion=&pst_clave=&buscar=&swAcceso=&swAccesoAdmin=&cod_congreso_aula_rel=&busqueda_rapida=&tipo=autor&texto=&texto2=&grupo2_aula=&grupo=&texto_ident=. Accessed 19 Oct 2015.

  43. Crowther M, Levy G, Lu G. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet Alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors. Blood. 2014;124. http://www.bloodjournal.org/content/124/21/4269?sso-checked=true. Accessed 19 Oct 2015 (abstract).

  44. Crowther M, Lu G, Conley P. Sustained reversal of apixaban anticoagulation with andexanet alfa using a bolus plus infusion regimen in a phase 2 placebo controlled trial. Eur.Heart J. 2014;35(137). http://spo.escardio.org/SessionDetails.aspx?eevtid=69&sessId=14101&subSessId=3562#.VgqhNPntmko. Accessed 19 Oct 2015 (abstract).

  45. Crowther M, Mathur A, Kitt M. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors. Blood. 2013;122(A 3636). http://www.bloodjournal.org/content/122/21/3636. Accessed 19 Oct 2015 (abstract).

  46. Crowther M, Levy G, Lu G. ANNEXA (TM)–R: A phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of apixaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors. Circulation. 2014;130:2116–7. Accessed 19 Oct 2015 (abstract).

  47. Gold A, Crowther M, Levy G. ANNEXA (TM)–R: A phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors. J Am Coll Cardiol. 2015. http://content.onlinejacc.org/article.aspx?articleid=2196748 (abstract).

  48. Laulicht B, Bakhru S, Lee C. Small molecule antidote for anticoagulants. Circulation. 2012;126(A11395). http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11395 (abstract).

  49. Laulicht B, Bakhru S, Jiang X. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. J Thromb Haemost JTH. 2013;11:75. http://perosphere.com/content/media/documents/AntidoteforNewOralAnticoagulants-MechanismofActionandBindingSpecificityofPER977.pdf (abstract).

  50. Bakhru S, Laulicht B, Jiang X. PER977: a synthetic small molecule which reverses over-dosage and bleeding by new oral anticoagulants. Circulation. 2013;128. http://circ.ahajournals.org/cgi/content/meeting_abstract/128/22_MeetingAbstracts/A18809 (abstract).

  51. Ansell J, Laulicht B, Bakhru S. Aripazine reverses unfractionated and low molecular weight heparins, fondaparinux and new Xa and IIa oral anticoagulants: report of Phase I/II clinical trial with edoxaban. Eur Heart J. 2014;35:854–5.

    Google Scholar 

  52. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2.

    Article  PubMed  Google Scholar 

  53. Mueck W, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008;100(3):453–61.

    PubMed  CAS  Google Scholar 

  54. Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50(10):675–86.

    Article  PubMed  CAS  Google Scholar 

  55. Skeppholm M, Al-Aieshy F, Berndtsson M, Al-Khalili F, Ronquist-Nii Y, Soderblom L, et al. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thromb Res. 2015;136(1):148–53.

    Article  PubMed  CAS  Google Scholar 

  56. Bristol-Myers Squibb. Summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf. Accessed 9 Jul 2015.

  57. Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost. 2010;104(3):633–41.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Hospital Unit West, Herning, Denmark

    Steen Husted & Willemijn J. Comuth

  2. Department of Cardiology, Heartcenter, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

    Freek W. A. Verheugt

  3. Department of Clinical Biochemistry, Hospital Unit West, Gl. Landevej 61, 7400, Herning, Denmark

    Willemijn J. Comuth

Authors
  1. Steen Husted
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Freek W. A. Verheugt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Willemijn J. Comuth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Willemijn J. Comuth.

Ethics declarations

Funding

No sources of funding were used to assist in the preparation of this study.

Conflicts of interest

Steen Husted has participated on the advisory board for Bayer, Bristol-Myers Squibb, Pfizer and Boehringer Ingelheim and has received speaker fees from Bayer, Bristol-Myers Squibb and Boehringer-Ingelheim. Freek Verheugt has received consulting fees from Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. Willemijn Comuth has received the Young Thrombosis Researchers Group laboratory exchange grant from the European Society of Cardiology Working Group on Thrombosis and a hospital donation from Boehringer Ingelheim. She has received speaker fees from Bayer and Boehringer Ingelheim, and non-financial support from Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Stago, Siemens and ANIARA.

Steen Husted, Freek Verheugt and Willemijn Comuth have not been involved in any activities related to NOAC reversal agents, which are the topic of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Husted, S., Verheugt, F.W.A. & Comuth, W.J. Reversal Strategies for NOACs: State of Development, Possible Clinical Applications and Future Perspectives. Drug Saf 39, 5–13 (2016). https://doi.org/10.1007/s40264-015-0357-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-015-0357-x

Keywords

Search

Navigation