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Reversal of novel oral anticoagulants in patients with major bleeding

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Abstract

Novel oral anticoagulants (NOACs) that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) are effective therapies for the prevention and treatment of thromboembolism with reduced bleeding complications compared with warfarin for some indications. However, specific antidotes to reverse the anticoagulant activity of NOACs in the event of major bleeding are not available. Evidence supporting non-specific prohemostatic therapies (prothrombin complex concentrate [PCC], activated prothrombin complex concentrate [aPCC], recombinant factor VIIa) in this setting is limited to healthy human volunteers, animal models, and in vitro studies. Clinical outcome data are lacking. Administration of PCC or aPCC may be considered in addition to supportive measures for patients with severe or life-threatening bleeding. Clinical studies are needed to establish the efficacy and safety of these treatments. Target-specific antidotes are in development and hold promise for NOAC reversal, but require further investigation.

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References

  1. Gross PL, Weitz JI (2009) New antithrombotic drugs. Clin Pharmacol Ther 86(2):139–146

    Article  CAS  Google Scholar 

  2. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64(3):292–303

    Article  PubMed  CAS  Google Scholar 

  3. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W (2008) The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 36(2):386–399

    Article  PubMed  CAS  Google Scholar 

  4. Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, Straub A (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939–an oral, direct Factor Xa inhibitor. J Thromb Haemost 3(3):514–521. doi:10.1111/j.1538-7836.2005.01166.x

    Article  PubMed  CAS  Google Scholar 

  5. Jiang X, Crain EJ, Luettgen JM, Schumacher WA, Wong PC (2009) Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 101(4):780–782

    PubMed  CAS  Google Scholar 

  6. Furugohri T, Isobe K, Honda Y, Kamisato-Matsumoto C, Sugiyama N, Nagahara T, Morishima Y, Shibano T (2008) DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 6(9):1542–1549. doi:10.1111/j.1538-7836.2008.03064.x

    PubMed  CAS  Google Scholar 

  7. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G (2005) Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 78(4):412–421. doi:10.1016/j.clpt.2005.06.011

    Article  PubMed  CAS  Google Scholar 

  8. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M (2005) Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939—an oral, direct Factor Xa inhibitor–after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61(12):873–880

    Article  PubMed  CAS  Google Scholar 

  9. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G (2012) Oral anticoagulant therapy: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e44S–e88S

    Article  PubMed  CAS  Google Scholar 

  10. Bayer PHarma AG. Xarelto (2011) summary of product characteristics http://www.xarelto.com/html/downloads/Xarelto_Summary_of_Product_Characteristics_Dec2011.pdf Accessed 12 May 2012

  11. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D (2009) Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 37(5):1056–1064. doi:10.1124/dmd.108.025569

    Article  PubMed  CAS  Google Scholar 

  12. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, Pinto D, Chen S, Bonacorsi S, Wong PC, Zhang D (2009) Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 37(1):74–81

    Article  PubMed  CAS  Google Scholar 

  13. Eriksson BI, Quinlan DJ, Weitz JI (2009) Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 48(1):1–22

    Article  PubMed  CAS  Google Scholar 

  14. Barrett YC, Wang J, Song Y, Pursley J, Wastall P, Wright R, Lacreta F, Frost C (2012) A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects. Thromb Haemost 107(5):916–924. doi:10.1160/TH11-09-0634

    Article  PubMed  CAS  Google Scholar 

  15. Frost C, Wang J, Nepal S, Schuster A, Barrett YC, Mosqueda-Garcia R, Reeves RA, Lacreta F (2012) Apixaban, an oral, direct factor Xa inhibitor: single-dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol. doi:10.1111/j.1365-2125.2012.04369.x

    Google Scholar 

  16. Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, Kunitada S (2010) Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 50(7):743–753. doi:10.1177/0091270009351883

    Article  PubMed  CAS  Google Scholar 

  17. Wolzt M, Samama MM, Kapiotis S, Ogata K, Mendell J, Kunitada S (2011) Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. Thromb Haemost 105(6):1080–1090. doi:10.1160/TH10-11-0705

    Article  PubMed  CAS  Google Scholar 

  18. Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W (2012) Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 126(20):2381–2391. doi:10.1161/CIRCULATIONAHA.112.115410

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  20. FDA (2011) Drug Safety Communication: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate), U.S. Food and Drug Administration http://www.fda.gov/drugs/drugsafety/ucm282724.htm#. Accessed 7 May 2012

  21. EudraVigilance Database, European Medicines Agency. http://eudravigilance.ema.europa.eu/human/index.asp. Accessed 12 May 2012

  22. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (2010) Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103(6):1116–1127

    Article  PubMed  Google Scholar 

  23. Lindahl TL, Baghaei F, Blixter IF, Gustafsson KM, Stigendal L, Sten-Linder M, Strandberg K, Hillarp A (2011) Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 105(2):371–378

    Article  PubMed  CAS  Google Scholar 

  24. Freyburger G, Macouillard G, Labrouche S, Sztark F (2011) Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 127(5):457–465

    Article  PubMed  CAS  Google Scholar 

  25. Stangier J, Feuring M (2012) Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 23(2):138–143

    Article  PubMed  CAS  Google Scholar 

  26. Hillarp A, Baghaei F, Fagerberg Blixter I, Gustafsson KM, Stigendal L, Sten-Linder M, Strandberg K, Lindahl TL (2011) Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 9(1):133–139

    Article  PubMed  CAS  Google Scholar 

  27. Barrett YC, Wang Z, Frost C, Shenker A (2010) Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 104(6):1263–1271

    Article  PubMed  CAS  Google Scholar 

  28. Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E (2010) Assessment of laboratory assays to measure rivaroxaban–an oral, direct factor Xa inhibitor. Thromb Haemost 103(4):815–825

    Article  PubMed  CAS  Google Scholar 

  29. Samama MM, Contant G, Spiro TE, Perzborn E, Guinet C, Gourmelin Y, Le Flem L, Rohde G, Martinoli JL (2012) Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 107(2):379–387

    Article  PubMed  CAS  Google Scholar 

  30. Samama MM, Guinet C (2011) Laboratory assessment of new anticoagulants. Clin Chem Lab Med 49(5):761–772

    Article  PubMed  CAS  Google Scholar 

  31. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ, Luettgen JM, Knabb RM (2008) Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 6(5):820–829

    Article  PubMed  CAS  Google Scholar 

  32. Van Ryn J, Litzenburger T, Waterman A, Canada K, Hauel N, Kroe-Barrett R, Singh S, Park J (2011) Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in in vitro and in vivo models. J Am Coll Cardiol 57:E1130

    Article  Google Scholar 

  33. van Ryn J, Litzenburger T, Gan G, Coble K, Schurer J (2012) In vitro characterization, pharmacokinetics and reversal of supratherapeutic doses of dabigatran-induced bleeding in rats by a specific antibody fragment antidote to dabigatran. ASH Annual Meet Abstr 120(21):3418

    Google Scholar 

  34. Toth J, Gan G, van Ryn J, Dursema H, Isler J, Coble K, Burke J, Lalovic B, Olson S (2012) Reversal of dabigatran’s anticoagulant activity in the monkey by a specific antidote and pharmacokinetic and pharmacodynamic modeling. ASH Annual meet abstr 120(21):22

    Google Scholar 

  35. Lu G, DeGuzman FR, Lakhotia S, Hollenbach SJ, Phillips DR, Sinha U (2008) Recombinant antidote for reversal of anticoagulation by factor Xa inhibitors. ASH Annual Meet Abstr 112(11):983

    Google Scholar 

  36. Lu GP, Peng L, Hollenbach SJ, Abe K, DeGuzman FR, Siu G, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2009) Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors. J Thromb Haemost 7:309

    Google Scholar 

  37. Hollenbach SJ, Lu G, Tan S, Lee G, Athiwat H, Inagaki M, Sinha U (2012) PRT064445 but not recombinant Fviia reverses rivaroxaban induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. ASH Annual Meet Abstr 120(21):3414

    Google Scholar 

  38. Truumees E, Gaudu T, Dieterichs C, Geck M, Stokes J (2012) Epidural hematoma & intra-operative hemorrhage in a spine trauma patient on pradaxa (R) [Dabigatran]. Spine 37(14):E863–E865

    Article  PubMed  Google Scholar 

  39. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, Bendszus M, Heiland S, van Ryn J, Veltkamp R (2011) Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 42(12):3594–3599

    Article  PubMed  Google Scholar 

  40. Morishima Y, Honda Y, Kamisato C, Furugohri T, Shibano T (2011) Reversal agents for edoxaban, a factor Xa inhibitor: effects of factor VIIa, anti-inhibitor coagulant complex, prothrombin complex concentrate, fresh plasma, and vitamin K. J Thromb Haemost 9:135

    Google Scholar 

  41. Narick C, Triulzi DJ, Yazer MH (2012) Transfusion-associated circulatory overload after plasma transfusion. Transfusion 52(1):160–165. doi:10.1111/j.1537-2995.2011.03247.x

    Article  PubMed  Google Scholar 

  42. Toy P, Gajic O, Bacchetti P, Looney, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirschler N, Sanchez Rosen R, Matthay MA, Group TS (2012) Transfusion-related acute lung injury: incidence and risk factors. Blood 119(7):1757–1767

    Article  PubMed  CAS  Google Scholar 

  43. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M (2011) Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124(14):1573–1579

    Article  PubMed  CAS  Google Scholar 

  44. Lambourne MD, Eltringham-Smith LJ, Gataiance S, Arnold DM, Crowther MA, Sheffield W (2012) Prothrombin complex concentrates reduce blood loss in mice rendered coagulopathic by warfarin but not dabigatran etexilate. Transfusion 52:56A–57A

    Article  Google Scholar 

  45. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM (2012) Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 116(1):94–102

    Article  PubMed  CAS  Google Scholar 

  46. Escolar G, Arellano-Rodrigo E, Reverter JC, Villalta J, Sanz V, Molina P, Diaz-Ricart M, Galan AM (2012) Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. Circulation 126:520–521

    Article  Google Scholar 

  47. Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T (2012) Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost 107(2):253–259

    Article  PubMed  CAS  Google Scholar 

  48. Hoffman MR, Volovyk Z, Monroe DM III (2012) Partial reversal of dabigatran effect by a prothrombin complex concentrate in a model of thrombin generation. ASH Annual Meet Abstr 120(21):3420

    Google Scholar 

  49. Dentali F, Marchesi C, Pierfranceschi MG, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 106(3):429–438

    Article  CAS  Google Scholar 

  50. Key NS, Negrier C (2007) Coagulation factor concentrates: past, present, and future. Lancet 370(9585):439–448

    Article  PubMed  CAS  Google Scholar 

  51. Gruber A, Marzec UM, Buetehorn U, Hanson S, Perzborn E (2008) Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. ASH Annual Meet Abstr 112(11):3825

    Google Scholar 

  52. Perzborn E, Tinel H (2008) FEIBA reverses the effects of a high-dose of rivaroxaban in rats. Pathophysiol Haemost Thromb 36:A40

    Google Scholar 

  53. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G (2012) Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 108(2):217–224

    Article  PubMed  CAS  Google Scholar 

  54. Chan HHW, Atkinson HM, Goncharenko M, Berry LR, Chan AKC (2011) Reversal of dabigatran using recombinant activated factor VII and activated prothrombin complex concentrates in thromboelastography assay. J Thromb Haemost 9:576–577

    Google Scholar 

  55. Ehrlich HJ, Henzl MJ, Gomperts ED (2002) Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 8(2):83–90

    Article  PubMed  CAS  Google Scholar 

  56. Aledort LM (2004) Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2(10):1700–1708

    Article  PubMed  CAS  Google Scholar 

  57. Wolzt M, Levi M, Sarich TC, Bostrom SL, Eriksson UG, Eriksson-Lepkowska M, Svensson M, Weitz JI, Elg M, Wahlander K (2004) Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 91(6):1090–1096

    PubMed  CAS  Google Scholar 

  58. Levi M, Levy JH, Andersen HF, Truloff D (2010) Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 363(19):1791–1800

    Article  PubMed  CAS  Google Scholar 

  59. Stangier J, Rathgen K, Stahle H, Mazur D (2010) Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 49(4):259–268

    Article  PubMed  CAS  Google Scholar 

  60. Wanek MR, Horn ET, Elapavaluru S, Baroody SC, Sokos G (2012) Safe use of hemodialysis for dabigatran removal before cardiac surgery. Ann Pharmacother 46(9):e21. doi:10.1345/aph.1R081

    Article  PubMed  Google Scholar 

  61. Lange J, Thiel C, Thiel K, Klingert W, Klingert K, Konigsrainer A, Formella S, Clemens A, van Ryn J, Schenk M (2012) Acceleration of dabigatran elimination by activated charcoal perfusion and hemodialysis in a pig model. ASH Annual Meet Abstr 120(21):2272

    Google Scholar 

  62. Bristol-Myers Squibb. Eliquis Product Monograph (2011) http://www.bmscanada.ca/static/products/en/pm_pdf/Eliquis_EN_PM.pdf. Accessed 12 May 2012

  63. Crescenzi G, Landoni G, Biondi-Zoccai G, Pappalardo F, Nuzzi M, Bignami E, Fochi O, Maj G, Calabro MG, Ranucci M, Zangrillo A (2008) Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials. Anesthesiology 109(6):1063–1076. doi:10.1097/ALN.0b013e31818db18b

    Article  PubMed  CAS  Google Scholar 

  64. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, Ker K (2011) Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane database of systematic rev. (3):CD001886. doi:10.1002/14651858.CD001886.pub4

  65. Siegal DM, Crowther MA (2012) Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. doi:10.1093/eurheartj/ehs408

    PubMed  Google Scholar 

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Conflict of interest

AC has served as a consultant or on an advisory board for Baxter, Bayer, CSL Behring, and Daiichi-Sankyo and has received research support from Baxter, Bayer, and Novo Nordisk. DS has no conflict of interest.

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Authors and Affiliations

  1. Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, ON, Canada

    Deborah M. Siegal

  2. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Adam Cuker

  3. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Adam Cuker

  4. Penn Comprehensive Hemophilia and Thrombosis Program, HUP, 3 Dulles, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Adam Cuker

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  1. Deborah M. Siegal
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Siegal, D.M., Cuker, A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis 35, 391–398 (2013). https://doi.org/10.1007/s11239-013-0885-0

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