Record Details

SPECIFIC ANTIDOTES TO NEW ORAL ANTICOAGULANTS

Atherothrombosis Journal

View Archive Info
 
 
Field Value
 
Title SPECIFIC ANTIDOTES TO NEW ORAL ANTICOAGULANTS
СПЕЦИФИЧЕСКИЕ АНТИДОТЫ К НОВЫМ ПЕРОРАЛЬНЫМ АНТИКОАГУЛЯНТАМ
 
Creator O. Shakhmatova O.; A.L. Myasnikov Research Institute of Clinical Cardiology, Russian Cardiology Research and Production Complex, Moscow
О. Шахматова О.; Институт клинической кардиологии им. А. Л. Мясникова Российского кардиологического научно-производственного комплекса, Москва
 
Subject antidote; bleeding; novel anticoagulants; praxbind; idarucizumab; andexanet; annexa; ciraparantag; aripazin; dabigatran; rivaroxaban; apixaban; edoxaban
антидот; кровотечение; новые антикоагулянты; праксбайнд; идаруцизумаб; андексанет; аннекса; цирапарантаг; арипазин; дабигатран; ривароксабан; апиксабан; эдоксабан
 
Description Safety profiles of the novel oral anticoagulants (NOAC) (rivaroxaban, apixaban, edoxaban,  dabigatran) are better than that of warfarin. However, the risk (including lifethreatening) of bleeding  is no less than 2.3–3.1% per year. Three specific antidotes  to NOAC are currently  in different phases of clinical  trial and implementation. Idarucizumab  is a monoclonal  antibody which immediately and completely  reverses the anticoagulation effect of dabigatran. Andexanet  alfa is a recombinant, modified factor Xa molecule  that binds and inhibits the effects of oral and parenteral factor Xa inhibitors  (rivaroxaban, apixaban,  edoxaban, fondaparinux, heparins).  Andexanet  is already in 3b Phase, and at the end of 2016  — beginning  of 2017 it is expected  to be approved  for clinical  use. Ciraparantag  is a small molecule,  non-covalently binding to factor Xa inhibitors, and dabigatran  (i.e., a universal  antidote).  Recently, promising results of phase 1 trials involving aripazin were published. The article  tells about the practical  aspects of the use of antidotes, treatment  approaches for life-threatening bleeding  during treatment  with NOAC.
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. 
 
Publisher «REMEDIUM GROUP» Ltd.
 
Contributor —
—
 
Date 2016-07-01
 
Type info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
—
—
 
Format application/pdf
 
Identifier http://www.aterotromboz.ru/jour/article/view/83
10.21518/2307-1109-2016-1-81-94
 
Source Atherothrombosis Journal; № 1 (2016); 81-94
Атеротромбоз; № 1 (2016); 81-94
2307-1109
10.21518/2307-1109-2016-1
 
Language rus
 
Relation http://www.aterotromboz.ru/jour/article/view/83/129
Weitz JI. Anticoagulation therapy in 2015: where we are and where we are going. J Thromb Thrombolysis, 2015, 39: 264-272.
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.
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.
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.
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.
Miesbach W, Seifried E. New direct oral anticoagulantscurrent therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost, 2012, 108: 625-632.
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.
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.
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.
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.
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.
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.
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.
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.
Becker RC. The biochemistry, enzymology and pharmacology of non-vitamin K anticoagulant drug reversal agents and antidotes. J Thromb Thrombolysis, 2016, 41: 273-278.
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.
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.
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.
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).
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.
Pollack CV Jr, Reilly PA, Eikelboom J et al. Idarucizumab for dabigatran reversal. N Engl J Med, 2015, 373: 511-520.
Frontera JA, Lewin III JJ, Rabinstein AA et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Neurocrit Care, 2016, 24(1): 6-46.
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.
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.
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.
Crowther M, Crowther MA. Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol, 2015, 35: 1736-1745.
Shah N, Rattu MA. Reversal agents for anticoagulants: focus on andexanet alfa. Am Student Res J, 2014, 1: 1628.
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.
Lu G, DeGuzman F, Lakhotia S et al. Recombinant antidote for reversal of anticoagulation by factor Xa inhibitors. Blood, 2008, 112: 983.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
Sartori MT, Prandoni P. How to effectively manage the event of bleeding complications when using anticoagulants. Expert Rev Hematol, 2016, 9(1): 37-50.
Abo-Salem E, Becker RC. Reversal of novel oral anticoagulants. Current Opinion in Pharmacology, 2016, 27: 86-91.
 
Rights Authors who publish with this journal agree to the following terms:Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
Авторы, публикующие в данном журнале, соглашаются со следующим:Авторы сохраняют за собой авторские права на работу и предоставляют журналу право первой публикации работы на условиях лицензии Creative Commons Attribution License, которая позволяет другим распространять данную работу с обязательным сохранением ссылок на авторов оригинальной работы и оригинальную публикацию в этом журнале.Авторы сохраняют право заключать отдельные контрактные договорённости, касающиеся не-эксклюзивного распространения версии работы в опубликованном здесь виде (например, размещение ее в институтском хранилище, публикацию в книге), со ссылкой на ее оригинальную публикацию в этом журнале.Авторы имеют право размещать их работу в сети Интернет (например в институтском хранилище или персональном сайте) до и во время процесса рассмотрения ее данным журналом, так как это может привести к продуктивному обсуждению и большему количеству ссылок на данную работу (См. The Effect of Open Access).