Advertisement

Direct oral anticoagulants: a review on the current role and scope of reversal agents

  • Rahul ChaudharyEmail author
  • Tushar Sharma
  • Jalaj Garg
  • Ajaypaul Sukhi
  • Kevin Bliden
  • Udaya Tantry
  • Mohit Turagam
  • Dhanunjaya Lakkireddy
  • Paul Gurbel
Article
  • 92 Downloads

Abstract

New guideline recommendations prefer direct oral anticoagulants (DOACs) over warfarin in DOAC-eligible patients with atrial fibrillation and patients with venous thromboembolism. As expected with all antithrombotic agents, there is an associated increased risk of bleeding complications in patients receiving DOACs that can be attributed to the DOAC itself, or other issues such as acute trauma, invasive procedures, or underlying comorbidities. For the majority of severe bleeding events, the widespread approach is to withdraw the DOAC, then provide supportive measures and “watchful waiting” with the expectation that the bleeding event will resolve with time. However, urgent reversal of anticoagulation may be advantageous in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Until recently, the lack of specific reversal agents, has affected the uptake of these agents in clinical practice despite a safer profile compared to warfarin in clinical trials. In cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, idarucizumab has been recently approved for reversal of anticoagulation in dabigatran-treated patients and andexanet alfa for factor Xa inhibitor-treated treated patients. The current review summarizes the current clinical evidence and scope of these agents with the potential impact on DOAC use in clinical practice.

Keywords

DOACs Andexanet alfa Apixaban Dabigatran Edoxaban Betrixaban Idarucizumab Reversal Rivaroxaban 

Notes

Author contributions

RC—Concept and design; analysis and interpretation of data; revising the intellectual content; and final approval of the version to be published. TS—Critical writing; and final approval of the version to be published. JG—Analysis and interpretation of data; critical writing with revision of intellectual content; and final approval of the version to be published. AS—Interpretation of data; revising the intellectual content; and final approval of the version to be published. KB—Concept and design; analysis and interpretation of data; revising the intellectual content; and final approval of the version to be published. UT—Interpretation of data; revising the intellectual content; and final approval of the version to be published. MT—Concept and design; revising the intellectual content; and final approval of the version to be published. DL—Concept and design; revising the intellectual content; and final approval of the version to be published. PG—Concept and design; interpretation of data; revising the intellectual content; and final approval of the version to be published.

Compliance with ethical standards

Conflict of interest

Paul Gurbel reports serving as a consultant for Daiichi Sankyo/Lilly, Bayer, AstraZeneca, Accumetrics, Merck, Medtronic, Janssen, CSL, and Haemonetics; receiving grants from the National Institutes of Health, Daiichi Sankyo, Lilly, CSL, AstraZeneca, Haemonetics, Harvard Clinical Research Institute, and Duke Clinical Research Institute; receiving payment for lectures, including service on speakers’ bureaus, from Lilly, Daiichi Sankyo, and Merck; receiving payment for development of educational presentations from Merck, the Discovery Channel, and Pri-Med; Dr. Gurbel is holding stock or stock options in Merck, Medtronic, and Pfizer; and holding patents in the area of personalized antiplatelet therapy and interventional cardiology. No other authors report any potential conflicts of interest.

Ethical approval

An approval by an ethics committee was not applicable.

References

  1. 1.
    Wardrop D, Keeling D (2008) The story of the discovery of heparin and warfarin. Br J Haematol 141(6):757–763.  https://doi.org/10.1111/j.1365-2141.2008.07119.x Google Scholar
  2. 2.
    January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW (2019) AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients With atrial fibrillation. Circulation.  https://doi.org/10.1161/cir.0000000000000665 Google Scholar
  3. 3.
    Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L (2016) Antithrombotic Therapy for VTE disease: CHEST guideline and expert panel report. Chest 149(2):315–352.  https://doi.org/10.1016/j.chest.2015.11.026 Google Scholar
  4. 4.
    Sandau KE, Funk M, Auerbach A, Barsness GW, Blum K, Cvach M, Lampert R, May JL, McDaniel GM, Perez MV, Sendelbach S, Sommargren CE, Wang PJ, American Heart Association Council, American Heart Association Council on C, Stroke N, Council on Clinical C, Council on Cardiovascular Disease in the Y (2017) Update to practice standards for electrocardiographic monitoring in hospital settings: a scientific statement from the American Heart Association. Circulation 136(19):e273–e344.  https://doi.org/10.1161/CIR.0000000000000527 Google Scholar
  5. 5.
    Benjamin EM, Klugman RA, Luckmann R, Fairchild DG, Abookire SA (2013) Impact of cardiac telemetry on patient safety and cost. Am J Manag Care 19(6):e225–e232Google Scholar
  6. 6.
    Najafi N, Cucina R, Pierre B, Khanna R (2018) Assessment of a targeted electronic health record intervention to reduce telemetry duration: a cluster-randomized clinical trial. JAMA Intern Med.  https://doi.org/10.1001/jamainternmed.2018.5859 Google Scholar
  7. 7.
    Dressler R, Dryer MM, Coletti C, Mahoney D, Doorey AJ (2014) Altering overuse of cardiac telemetry in non-intensive care unit settings by hardwiring the use of American Heart Association guidelines. JAMA Intern Med 174(11):1852–1854.  https://doi.org/10.1001/jamainternmed.2014.4491 Google Scholar
  8. 8.
    Pokorney SD, Simon DN, Thomas L, Fonarow GC, Kowey PR, Chang P, Singer DE, Ansell J, Blanco RG, Gersh B, Mahaffey KW, Hylek EM, Go AS, Piccini JP, Peterson ED, Registry Outcomes, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I (2015) Patients’ time in therapeutic range on warfarin among US patients with atrial fibrillation: results from ORBIT-AF registry. Am Heart J 170(1):141–148.e141.  https://doi.org/10.1016/j.ahj.2015.03.017 Google Scholar
  9. 9.
    Caldeira D, Cruz I, Morgado G, Stuart B, Gomes C, Martins C, Joao I, Pereira H (2014) Evaluation of time in therapeutic range in anticoagulated patients: a single-center, retrospective, observational study. BMC Res Notes 7:891.  https://doi.org/10.1186/1756-0500-7-891 Google Scholar
  10. 10.
    van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ (2006) Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest 129(5):1155–1166.  https://doi.org/10.1378/chest.129.5.1155 Google Scholar
  11. 11.
    Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, Dunn AS, Kunz R (2012) Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e326S–e350S.  https://doi.org/10.1378/chest.11-2298 Google Scholar
  12. 12.
    Ziakas PD, Kourbeti IS, Poulou LS, Vlachogeorgos GS, Mylonakis E (2018) Medicare part D prescribing for direct oral anticoagulants in the United States: cost, use and the “rubber effect”. PLoS ONE 13(6):e0198674.  https://doi.org/10.1371/journal.pone.0198674 Google Scholar
  13. 13.
    Zhu J, Alexander GC, Nazarian S, Segal JB, Wu AW (2018) Trends and variation in oral anticoagulant choice in patients with atrial fibrillation, 2010–2017. Pharmacotherapy 38(9):907–920.  https://doi.org/10.1002/phar.2158 Google 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, Committee R-LS, Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151.  https://doi.org/10.1056/NEJMoa0905561 Google Scholar
  15. 15.
    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, Investigators RA (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891.  https://doi.org/10.1056/NEJMoa1009638 Google Scholar
  16. 16.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, Committees A, Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992.  https://doi.org/10.1056/NEJMoa1107039 Google Scholar
  17. 17.
    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, Investigators EA-T (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104.  https://doi.org/10.1056/NEJMoa1310907 Google Scholar
  18. 18.
    Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, Group R-CS (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361(24):2342–2352.  https://doi.org/10.1056/nejmoa0906598 Google Scholar
  19. 19.
    Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C, Investigators R-CIT (2014) Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 129(7):764–772.  https://doi.org/10.1161/CIRCULATIONAHA.113.004450 Google Scholar
  20. 20.
    Investigators E, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510.  https://doi.org/10.1056/NEJMoa1007903 Google Scholar
  21. 21.
    Investigators E-P, Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366(14):1287–1297.  https://doi.org/10.1056/NEJMoa1113572 Google Scholar
  22. 22.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI, Investigators A (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808.  https://doi.org/10.1056/NEJMoa1302507 Google Scholar
  23. 23.
    Hokusai VTEI, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415.  https://doi.org/10.1056/NEJMoa1306638 Google Scholar
  24. 24.
    Chai-Adisaksopha C, Crowther M, Isayama T, Lim W (2014) The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 124(15):2450–2458.  https://doi.org/10.1182/blood-2014-07-590323 Google Scholar
  25. 25.
    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.  https://doi.org/10.1016/S0140-6736(13)62343-0 Google Scholar
  26. 26.
    Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M (2015) Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 13(11):2012–2020.  https://doi.org/10.1111/jth.13139 Google Scholar
  27. 27.
    Inohara T, Xian Y, Liang L, Matsouaka RA, Saver JL, Smith EE, Schwamm LH, Reeves MJ, Hernandez AF, Bhatt DL, Peterson ED, Fonarow GC (2018) Association of intracerebral hemorrhage among patients taking non-vitamin k antagonist vs vitamin k antagonist oral anticoagulants with in-hospital mortality. JAMA 319(5):463–473.  https://doi.org/10.1001/jama.2017.21917 Google Scholar
  28. 28.
    Kakkos SK, Kirkilesis GI, Tsolakis IA (2014) Editor’s Choice—efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 48(5):565–575.  https://doi.org/10.1016/j.ejvs.2014.05.001 Google Scholar
  29. 29.
    Raval AN, Cigarroa JE, Chung MK, Diaz-Sandoval LJ, Diercks D, Piccini JP, Jung HS, Washam JB, Welch BG, Zazulia AR, Collins SP, American Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac C, General Cardiology Committee of the Council on Clinical C, Council on Cardiovascular Disease in the Y, Council on Quality of C, Outcomes R (2017) Management of patients on non-vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 135(10):e604–e633.  https://doi.org/10.1161/cir.0000000000000477 Google Scholar
  30. 30.
    Xu Y, Schulman S, Dowlatshahi D, Holbrook AM, Simpson CS, Shepherd LE, Wells PS, Giulivi A, Gomes T, Mamdani M, Khuu W, Frymire E, Johnson AP, Bleeding Effected by Direct Oral Anticoagulants Study G (2017) Direct oral anticoagulant- or warfarin-related major bleeding: characteristics, reversal strategies, and outcomes from a multicenter observational study. Chest 152(1):81–91.  https://doi.org/10.1016/j.chest.2017.02.009 Google Scholar
  31. 31.
    Rincon F, Mayer SA (2013) The epidemiology of intracerebral hemorrhage in the United States from 1979 to 2008. Neurocrit Care 19(1):95–102.  https://doi.org/10.1007/s12028-012-9793-y Google Scholar
  32. 32.
    Lee SM, Choi NK, Lee BC, Cho KH, Yoon BW, Park BJ (2013) Caffeine-containing medicines increase the risk of hemorrhagic stroke. Stroke 44(8):2139–2143.  https://doi.org/10.1161/STROKEAHA.111.674077 Google Scholar
  33. 33.
    Qureshi AI, Mendelow AD, Hanley DF (2009) Intracerebral haemorrhage. Lancet 373(9675):1632–1644.  https://doi.org/10.1016/S0140-6736(09)60371-8 Google Scholar
  34. 34.
    Wendelboe AM, Raskob GE (2016) Global burden of thrombosis: epidemiologic aspects. Circ Res 118(9):1340–1347.  https://doi.org/10.1161/CIRCRESAHA.115.306841 Google Scholar
  35. 35.
    Gomez-Outes A, Lecumberri R, Suarez-Gea ML, Terleira-Fernandez AI, Monreal M, Vargas-Castrillon E (2015) Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: a systematic review. J Cardiovasc Pharmacol Ther 20(5):490–500.  https://doi.org/10.1177/1074248415575154 Google Scholar
  36. 36.
    Bliden KP, Chaudhary R, Mohammed N, Muresan AA, Lopez-Espina CG, Cohen E, Raviv G, Doubleday M, Zaman F, Mathew B, Tantry US, Gurbel PA (2017) Determination of non-vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system. J Thromb Thrombolysis 43(4):437–445.  https://doi.org/10.1007/s11239-017-1477-1 Google Scholar
  37. 37.
    Hunt BJ, Levi M (2016) Engineering reversal—finding an antidote for direct oral anticoagulants. N Engl J Med 375(12):1185–1186.  https://doi.org/10.1056/NEJMe1610510 Google Scholar
  38. 38.
    Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J (2012) Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 87(Suppl 1):S141–S145.  https://doi.org/10.1002/ajh.23202 Google Scholar
  39. 39.
    Siegal DM, Garcia DA, Crowther MA (2014) How I treat target-specific oral anticoagulant-associated bleeding. Blood 123(8):1152–1158.  https://doi.org/10.1182/blood-2013-09-529784 Google Scholar
  40. 40.
    Ross B, Miller MA, Ditch K, Tran M (2014) Clinical experience of life-threatening dabigatran-related bleeding at a large, tertiary care, academic medical center: a case series. J Med Toxicol 10(2):223–228.  https://doi.org/10.1007/s13181-013-0364-1 Google Scholar
  41. 41.
    Dumkow LE, Voss JR, Peters M, Jennings DL (2012) Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health Syst Pharm 69(19):1646–1650.  https://doi.org/10.2146/ajhp120055 Google Scholar
  42. 42.
    Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield WP (2012) Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 10(9):1830–1840.  https://doi.org/10.1111/j.1538-7836.2012.04863.x Google Scholar
  43. 43.
    Dickneite G, Hoffman M (2014) Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 111(2):189–198.  https://doi.org/10.1160/TH13-05-0431 Google Scholar
  44. 44.
    Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T (2013) A specific antidote for dabigatran: functional and structural characterization. Blood 121(18):3554–3562.  https://doi.org/10.1182/blood-2012-11-468207 Google Scholar
  45. 45.
    Ingelheim B (2014) U.S. FDA grants breakthrough therapy designation to pradaxa (dabigatran etexilate) specific investigational antidoteGoogle Scholar
  46. 46.
    Ingelheim B (2015) Idarucizumab* reverses the anticoagulant effect of dabigatran within minutes in patient study. https://www.boehringer-ingelheim.com/press-release/idarucizumab-reverses-anticoagulant-effect-dabigatran-within-minutes-patient-study. Accessed 2 Oct 2018
  47. 47.
    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.  https://doi.org/10.1056/NEJMoa1502000 Google Scholar
  48. 48.
    Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, Lang B, Ramael S, Moschetti V, Gruenenfelder F, Reilly P, Kreuzer J (2015) 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 386(9994):680–690.  https://doi.org/10.1016/S0140-6736(15)60732-2 Google Scholar
  49. 49.
    FDA Approves Praxbind® (idarucizumab), Specific Reversal Agent for Pradaxa® (dabigatran etexilate) (2015) https://www.boehringer-ingelheim.com/press-release/fda-approves-praxbind-idarucizumab-specific-reversal-agent-pradaxa-dabigatran. Accessed 1 Oct 2018
  50. 50.
    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.  https://doi.org/10.1056/NEJMoa1707278 Google Scholar
  51. 51.
    Ingelheim B (2018) FDA provides full approval to Praxbind, specific reversal agent for Pradaxa. https://www.boehringer-ingelheim.us/press-release/fda-provides-full-approval-praxbind-specific-reversal-agent-pradaxa. Accessed 2 Oct 2018
  52. 52.
    Pollack CV Jr, Reilly PA, Bernstein R, Dubiel R, Eikelboom J, Glund S, Huisman MV, Hylek E, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Sellke F, Stangier J, Steiner T, Wang B, Weitz JI (2015) Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 114(1):198–205.  https://doi.org/10.1160/TH15-03-0192 Google Scholar
  53. 53.
    Spronk HMH, Jv Ryn, Zentai C, Ht Cate, Rossaint R, Grottke O (2013) Resuscitation With different volume expanders does not influence coagulation after antidoting dabigatran with its specific fab in a pig model of hemorrhagic shock. Blood 122(21):3649Google Scholar
  54. 54.
    Ryn JV, Schmoll M, Pillu H, Gheyle L, Brys J, Moschetti V, Glund S, Reilly P, Stangier J (2018) Effect of dabigatran on the ability to generate fibrin at a wound site and its reversal by idarucizumab, the antidote to dabigatran, in healthy volunteers: an exploratory marker of blood loss. Circulation 130(suppl_2):18403Google Scholar
  55. 55.
    Glund S, Moschetti V, Norris S, Stangier J, Schmohl M, van Ryn J, Lang B, Ramael S, Reilly P (2015) A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 113(5):943–951.  https://doi.org/10.1160/TH14-12-1080 Google Scholar
  56. 56.
    Ingelheim B (2015) Prescribing information: Boehringer Ingelheim. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Praxbind/Praxbind.pdf. Accessed 1 Oct 2018
  57. 57.
    Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (2015) Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 373(25):2413–2424.  https://doi.org/10.1056/NEJMoa1510991 Google Scholar
  58. 58.
    Pharmaceuticals P (2013) Portola pharmaceuticals receives breakthrough therapy designation from FDA for andexanet alfa (PRT4445*), investigational factor Xa inhibitor antidoteGoogle Scholar
  59. 59.
    Pharmaceuticals P (2015) Portola pharmaceuticals receives FDA orphan drug designation for andexanet alfa, its breakthrough-designated factor Xa inhibitor antidoteGoogle Scholar
  60. 60.
    Wendling P (2018) FDA approves first factor Xa inhibitor antidote, andexxa. https://www.medscape.com/viewarticle/896182. Accessed 2 Oct 2018
  61. 61.
    Portola Pharmaceuticals I (2018) Coagulation factor Xa recombinant, inactivated-zhzo (Rx). https://reference.medscape.com/drug/andexxa-andexanet-alfa-coagulation-factor-xa-recombinant-inactivated-zhzo-999945. Accessed 4 Oct 2018
  62. 62.
    Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19(4):446–451.  https://doi.org/10.1038/nm.3102 Google Scholar
  63. 63.
    Lu G, Pine P, Leeds JM, DeGuzman F, Pratikhya P, Lin J, Malinowski J, Hollenbach SJ, Curnutte JT, Conley PB (2018) Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model. PLoS ONE 13(3):e0195122.  https://doi.org/10.1371/journal.pone.0195122 Google Scholar
  64. 64.
    Genmin Lu JPL, Curnutte John T, Conley Pamela B (2017) Effect of andexanet-TFPI interaction on in vitro thrombin formation and coagulation markers in the TF-pathway. Blood 130(Suppl 1):629Google Scholar
  65. 65.
    Dabi A, Koutrouvelis AP (2018) Reversal strategies for intracranial hemorrhage related to direct oral anticoagulant medications. Crit Care Res Pract 2018:4907164.  https://doi.org/10.1155/2018/4907164 Google Scholar
  66. 66.
    Grottke O, Akman N, Conley PB, Honickel M (2018) The impact of andexanet alfa in a porcine polytrauma model under apixaban anticoagulation: investigation of hemostatic safety and efficacy. Circulation 136(Suppl 1):A20205Google Scholar
  67. 67.
    Milling TJ Jr, Kaatz S (2016) Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Emerg Med 34(11S):39–45.  https://doi.org/10.1016/j.ajem.2016.09.052 Google Scholar
  68. 68.
    Conley PB, Pine P, Deguzman F, Canivel D, Malinowski J, Escobar E, Der K, Lin J, Leeds JM, Lu G, Curnutte JT (2017) Andexanet alfa reduces betrixaban-induced blood loss in a rabbit liver laceration model of acute bleeding. Eur Heart J 38(Suppl 1):6208.  https://doi.org/10.1093/eurheartj/ehx493.P6208 Google Scholar
  69. 69.
    Genmin Lu PP, De Guzman F, Canivel D, Malinowski J, Pratikhya P, Lin J, Leeds JM, Curnutte JT, Conley PB (2017) Reversal of anticoagulation effects of rivaroxaban and associated bleeding in a rabbit acute hemorrhage model by andexanet alfa vs. coagulation replacement factors. Neurology 88(16 supplement):5.054Google Scholar
  70. 70.
    Siegal D, Lu G, Leeds JM, Karbarz M, Castillo J, Mathur V, Hutchaleelaha A, Sinha U, Kitt M, McClure M, Hollenbach SJ, Curnutte JT, Conley PB, Crowther M (2017) Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv 1(21):1827–1838.  https://doi.org/10.1182/bloodadvances.2017007112 Google Scholar
  71. 71.
    Mark Crowther GGL, Genmin Lu, Leeds Janet, Lin Joyce, Pratikhya Pratikhya, Conley Pamela B, Connolly Stuart, Curnutte John T (2014) 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 124(21):4269Google Scholar
  72. 72.
    Mark Crowther GL, Leeds Janet M, Lin Joyce, Conley Pamela B, Gold Alexander, Connolly Stuart J, Curnutte John T (2016) Reversal of betrixaban-induced anticoagulation in healthy volunteers by andexanet alfa. Blood 128(22):143Google Scholar
  73. 73.
    Administration USFD (2018) ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo). https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm606681.htm. Accessed 10 Oct 2018
  74. 74.
    Tummala R, Kavtaradze A, Gupta A, Ghosh RK (2016) Specific antidotes against direct oral anticoagulants: a comprehensive review of clinical trials data. Int J Cardiol 214:292–298.  https://doi.org/10.1016/j.ijcard.2016.03.056 Google Scholar
  75. 75.
    Hu TY, Vaidya VR, Asirvatham SJ (2016) Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag 12:35–44.  https://doi.org/10.2147/VHRM.S89130 Google Scholar
  76. 76.
    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, Investigators A (2016) Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375(12):1131–1141.  https://doi.org/10.1056/NEJMoa1607887 Google Scholar
  77. 77.
    Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, Yue P, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Demchuk AM, Pallin DJ, Concha M, Goodman S, Leeds J, Souza S, Siegal DM, Zotova E, Meeks B, Ahmad S, Nakamya J, Milling TJ Jr, Investigators A (2019) Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 380(14):1326–1335.  https://doi.org/10.1056/NEJMoa1814051 Google Scholar
  78. 78.
    Steele AP, Lee JA, Dager WE (2018) Incomplete dabigatran reversal with idarucizumab. Clin Toxicol 56(3):216–218.  https://doi.org/10.1080/15563650.2017.1349911 Google Scholar
  79. 79.
    Melmed KR, Lyden P, Gellada N, Moheet A (2017) Intracerebral hemorrhagic expansion occurs in patients using non-vitamin K antagonist oral anticoagulants comparable with patients using warfarin. J Stroke Cerebrovasc Dis 26(8):1874–1882.  https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.04.025 Google Scholar
  80. 80.
    Sheikh-Taha M (2019) Idarucizumab for reversal of dabigatran: single-center real-world experience. Am J Cardiovasc Drugs 19(1):59–64.  https://doi.org/10.1007/s40256-018-0300-5 Google Scholar
  81. 81.
    Lu VM, Phan K, Rao PJ, Sharma SV, Kasper EM (2019) Dabigatran reversal by idarucizumab in the setting of intracranial hemorrhage: a systematic review of the literature. Clin Neurol Neurosurg 181:76–81.  https://doi.org/10.1016/j.clineuro.2019.04.013 Google Scholar
  82. 82.
    van der Wall SJ, van Rein N, van den Bemt B, Kruip M, Meijer K, Te Boome LCJ, Simmers TA, Alings AMW, Tieleman R, Klok FA, Huisman MV, Westerweel PE (2019) Performance of idarucizumab as antidote of dabigatran in daily clinical practice. Europace 21(3):414–420.  https://doi.org/10.1093/europace/euy220 Google Scholar
  83. 83.
    Held V, Eisele P, Eschenfelder CC, Szabo K (2016) Idarucizumab as antidote to intracerebral hemorrhage under treatment with dabigatran. Case Rep Neurol 8(3):224–228.  https://doi.org/10.1159/000452096 Google Scholar
  84. 84.
    Tsai LK, Lin HJ, Chua SK, Liao PC, Yang YP, Chou PC, Lee CW, Lin MJ, Chen HM, Yeh JT, Li YH (2018) Real-world experience with idarucizumab to reverse anticoagulant effect in dabigatran-treated patients: report of 11 cases from Taiwan. J Stroke Cerebrovasc Dis 27(2):e27–e33.  https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.044 Google Scholar
  85. 85.
    Singh S, Nautiyal A, Belk KW (2019) Real world outcomes associated with idarucizumab: population-based retrospective cohort study. Am J Cardiovasc Drugs.  https://doi.org/10.1007/s40256-019-00360-6 Google Scholar
  86. 86.
    Raco V, Ahuja T, Green D (2018) Assessment of patients post reversal with idarucizumab. J Thromb Thrombolysis 46(4):466–472.  https://doi.org/10.1007/s11239-018-1723-1 Google Scholar
  87. 87.
    Kupper C, Feil K, Klein M, Feuerecker R, Lucking M, Thanbichler F, Dietrich D, Zerkaulen I, Jandl M, Marziniak M, Poppert H, Wunderlich S, Topka H, Dieterich M, Kellert L (2019) Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa(R) in clinical routine (MR REPAIR). J Neurol.  https://doi.org/10.1007/s00415-019-09492-w Google Scholar
  88. 88.
    Culbreth SE, Rimsans J, Sylvester K, Pallin DJ, Connors JM (2019) Andexanet alfa: the first 150 days. Am J Hematol 94(1):E21–E24.  https://doi.org/10.1002/ajh.25326 Google Scholar
  89. 89.
    Flaherty D, Connors JM, Singh S, Sylvester KW, Rimsans J, Cornella L (2019) Andexanet alfa for urgent reversal of apixaban before aortic surgery requiring cardiopulmonary bypass: a case report. A A Pract.  https://doi.org/10.1213/XAA.0000000000001052 Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Hospital Internal MedicineMayo ClinicRochesterUSA
  2. 2.Indiana University BloomingtonBloomingtonUSA
  3. 3.Sinai Hospital of BaltimoreBaltimoreUSA
  4. 4.Medical College of WisconsinMilwaukeeUSA
  5. 5.Inova Center for Thrombosis Research and Drug DevelopmentInova Heart and Vascular InstituteFalls ChurchUSA
  6. 6.Helmsley Electrophysiology Center in the Department of Cardiology and Icahn School of Medicine at Mount SinaiNew YorkUSA
  7. 7.University of Kansas, Medical CenterKansas CityUSA

Personalised recommendations