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СПЕЦИФИЧЕСКИЕ АНТИДОТЫ К НОВЫМ ПЕРОРАЛЬНЫМ АНТИКОАГУЛЯНТАМ

https://doi.org/10.21518/2307-1109-2016-1-81-94

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Аннотация

Профиль безопасности у новых пероральных антикоагулянтов (НОАК) (ривароксабан, апиксабан, эдоксабан, дабигатран) лучше, чем у варфарина. Однако риск больших (в т. ч. жизнеугрожающих) кровотечений составляет не менее 2,3—3,1% в год. В настоящее время на разных этапах изучения и клинического внедрения находятся три специфических антидота к НОАК. Идаруцизумаб представляет собой моноклональное антитело, немедленно и необратимо связывающее дабигатран. Андексанет альфа представляет собой рекомбинантную модифицированную молекулу Ха-фактора, который связывает и блокирует действие пероральных и парентеральных ингибиторов Ха-фактора (ривароксабана, апиксабана, эдоксабана, фондапаринукса, гепаринов). В настоящее время уже проходит исследование 3b фазы с участием андексанета, в конце2016 г. — начале2017 г. ожидается разрешение его применения в клинической практике. Цирапарантаг представляет собой малую молекулу, нековалентно связывающуюся как с ингибиторами Ха-фактора, так и с дабигатраном (т. е. являющуюся универсальным антидотом). На данном этапе опубликованы многообещающие результаты исследования 1 фазы с участием арипазина. В статье рассмотрены практические аспекты применения антидотов, тактика лечения жизнеугрожающих кровотечений на фоне лечения НОАК. 

Об авторе

О. О. Шахматова
Институт клинической кардиологии им. А. Л. Мясникова Российского кардиологического научно-производственного комплекса, Москва
Россия
Кандидат медицинских наук


Список литературы

1. Weitz JI. Anticoagulation therapy in 2015: where we are and where we are going. J Thromb Thrombolysis, 2015, 39: 264-272.

2. Ruff CT, Giugliano RP, Braunwald E et al. Comparison of the ef_cacy and safety of new oral anticoagulants with warfarin in patients with atrial _brillation: a meta-analysis of randomised trials. Lancet, 2014, 383: 955-962.

3. Majeed A, Hwang HG, Connolly SJ et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation, 2013, 128: 2325-2332.

4. Piccini JP, Garg J, Patel MR et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J, 2014, 35: 1873-1880.

5. Kaatz S, Kouides PA, Garcia DA et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol, 2012, 87: S141-S145.

6. Miesbach W, Seifried E. New direct oral anticoagulantscurrent therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost, 2012, 108: 625-632.

7. Masotti L, Lorenzini G, Seravalle C et al. Management of new oral anticoagulants related life threatening or major bleedings in real life: a brief report. J Thromb Thrombolysis, 2015, 39(4): 427-433.

8. Beyer-Westendorf J, Ebertz F, FЪrster K 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): 1247-1257.

9. Beyer-Westendorf J, FЪrster K, Pannach S et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood, 2014, 124(6): 955-962.

10. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Eng J Med, 2011, 365: 2002-2012.

11. Ruff CT, Giugliano RP, Braunwald E 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): 955-962.

12. Van der Hulle T, Kooiman J, Den Exter PL et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboem bolism: a systematic review and meta-analysis. J Thromb Haemost, 2014, 12(3): 320-328.

13. Glund S, Stangier J, Schmohl M et al. Safety, tolerability, and ef_cacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, doubleblind phase 1 trial. Lancet, 2015, 386: 680-690.

14. Schiele F, van Ryn J, Canada K et al. A speci_c antidote for dabigatran: functional and structural characterization. Blood, 2014, 121(18): 3554-3562.

15. Becker RC. The biochemistry, enzymology and pharmacology of non-vitamin K anticoagulant drug reversal agents and antidotes. J Thromb Thrombolysis, 2016, 41: 273-278.

16. Honickel M, Treutler S, van Ryn J et al. Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab. J Thromb Haemost, 2015, 113(4): 671909.

17. Grottke O, Zentai C, van Ryn J et al. Binding of dabigatran to its specific antidote, idarucizumab, is not influenced by infusion solutions used during resuscitation in a porcine hemorrhagic shock model: 6AP3_6 (абстракт). Eur J Anaesthesiology, 2014, 31: 97.

18. Glund S, Moschetti V, Norris S 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: 943-951.

19. Glund S, Stangier J, Schmohl M et al. 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 (abstract).

20. Pollack CV Jr, Reilly PA, Bernstein R et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a speci_c reversal agent for dabigatran. Thromb Haemost, 2015, 114: 198-205.

21. Pollack CV Jr, Reilly PA, Eikelboom J et al. Idarucizumab for dabigatran reversal. N Engl J Med, 2015, 373: 511-520.

22. Frontera JA, Lewin III JJ, Rabinstein AA et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Neurocrit Care, 2016, 24(1): 6-46.

23. Lu G, DeGuzman FR, Hollenbach SJ et al. A speci_c antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med, 2013, 19: 446-451.

24. Lu G, DeGuzman FR, Hollenbach SJ et al. Reversal of low molecular weight heparin and fondaparinux by a recombinant antidote (r-antidote, PRT064445). Circulation, 2010, 122: A12420.

25. Слайды к докладу Mark Crowther на научной сессии Американского общества сердца 2014 г. ANNEXA™-A: 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. http://my.americanheart.org/idc/groups/ahamahpublic/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf.

26. Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol, 2015, 35: 1736-1745.

27. Shah N, Rattu MA. Reversal agents for anticoagulants: focus on andexanet alfa. Am Student Res J, 2014, 1: 1628.

28. Hollenbach S, Lu G, Deguzman F et al. Bolus administration of PRT064445, a recombinant factor Xa inhibitor antidote, reverses blood loss and PD markers in a rat model following enoxaparin-induced anticoagulation. Presented at the European Society of Cardiology Congress, Munich, Germany, August 25-29, 2012.

29. Lu G, DeGuzman F, Lakhotia S et al. Recombinant antidote for reversal of anticoagulation by factor Xa inhibitors. Blood, 2008, 112: 983.

30. Pine P, Hollenbach S, Tan S et al. Andexanet alfa reverses edoxaban-induced anticoagulation in a rabbit liver laceration model of acute bleeding. Presented at the European Society of Cardiology Congress, London, August 29—September 2, 2015.

31. Hollenbach S, Lu G, Tan S et al. PRT064445 but not rfVIIa or PCC reverses rivaroxaban induced anticoagulation as measured by reduction in blood loss in a rabbit liver laceration model. Presented at the 54th annual meeting of the American Society of Hematology, Atlanta, December 8—11, 2012.

32. Crowther MA, Kitt M, McClure M et al. Randomized, doubleblind, placebo-controlled single ascending dose pharmacokinetic and pharmacodynamic study of PRT064445, a universal antidote for faxtor Xa inhibitors (abstract). Arterioscler Thromb Vasc Biol, 2013, 33: A10.

33. Crowther M, Lu G, Conley PB et al. Reversal of factor Xa inhibitors-induced anticoagulation in healthy subjects by andexanet alfa. Crit Care Med, 2014, 42(12): A1469.

34. Crowther MA, Levy G, Lu G et al. A phase 2 randomized, double-blind, placebocontrolled trial demonstrat ing reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Presented at the 56th annual meeting of the American Society of Hematology, San Francisco, December 6—9, 2014.

35. Crowther MA, Mathur V, Kitt M et al. 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. Presented at the 55th annual meeting of the American Society of Hematology, New Orleans, December 7—10, 2013.

36. Crowther MA, Kittl E, Lorenz T et al. A phase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors. J Thromb Haemost, 2013, 11(Suppl 2): OC 20.1.

37. Siegal DM, Curnutte JT, Connolly SJ et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med, 2015, 373: 2413-2424.

38. Laulicht B, Bakhru S, Jiang X et al. Antidote for new oral anticoagulants: mechanism of action and binding speci_city of PER977. Presented at the 24th congress of the international society on thrombosis and haemostasis, Amsterdam, June 29 — July 4, 2013. Abstract (http://www.eventureonline.com/eventure/publicAbstractView.do?id=226718&congress Id=6839).

39. Bakhru S, Laulicht B, Jiang X et al. PER977: a synthetic small molecule which reverses over-dosage and bleeding by the new oral anticoagulants. Circulation, 128: A18809.

40. Bakhru S, Laulicht B, Jiang X et al. Reversal of anticoagulant-induced bleeding in external and internal bleeding models by PER977, a small molecule anticoagulant antidote. Circulation, 130: A19361.

41. Hollenbach S, Lu G, DeGuzman F et al. Abstract 14657: andexanet-alfa and PER977 (Arapazine) correct blood loss in a rabbit liver laceration model — only andexanet reverses markers of fXa-mediated anticoagulation. Circulation, 2014, 130(Suppl 2): A14657.

42. G Lu, J Kotha, JM Cardenas et al. In Vitro Characterization of Andexanet Alfa (PRT064445), a Specific fXa Inhibitor Antidote versus Aripazine (PER977), a Non-specific Reversal Agent. Circulation, 2014, 130: A18218.

43. Ansell JE, Bakhru S, Laulicht BE et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Eng J Med, 2014, 339: 2141-2142.

44. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI for the Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost, 2016, 14: 623-627.

45. Sartori MT, Prandoni P. How to effectively manage the event of bleeding complications when using anticoagulants. Expert Rev Hematol, 2016, 9(1): 37-50.

46. Abo-Salem E, Becker RC. Reversal of novel oral anticoagulants. Current Opinion in Pharmacology, 2016, 27: 86-91.


Для цитирования:


Шахматова О.О. СПЕЦИФИЧЕСКИЕ АНТИДОТЫ К НОВЫМ ПЕРОРАЛЬНЫМ АНТИКОАГУЛЯНТАМ. Атеротромбоз. 2016;(1):81-94. https://doi.org/10.21518/2307-1109-2016-1-81-94

For citation:


Shakhmatova O.O. SPECIFIC ANTIDOTES TO NEW ORAL ANTICOAGULANTS. Atherothrombosis Journal. 2016;(1):81-94. (In Russ.) https://doi.org/10.21518/2307-1109-2016-1-81-94

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ISSN 2307-1109 (Print)
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