pirogovestnikВестник Национального медико-хирургического центра им. Н.И. ПироговаBulletin of Pirogov National Medical & Surgical Center2072-82552782-3628Национальный медико-хирургический Центр им. Н.И. Пирогова10.25881/20728255_2025_20_3_126pirogovestnik-372Research ArticleОБЗОРЫ ЛИТЕРАТУРЫREVIEWS«ПОДВОДНЫЕ КАМНИ» ПРЯМЫХ ПЕРОРАЛЬНЫХ АНТИКОАГУЛЯНТОВTHE PITFALLS OF DIRECT ORAL ANTICOAGULANTSГительзонД. Г.GitelsonD. G.

Москва 

Moscow

danielgitelson@gmail.comВасильевА. Э.VasilievA. E.

Москва 

Moscow

ДанишянК. И.DanishianK. I.

Москва 

Moscow

ЗозуляН. И.ZozulyaN. I.

Москва 

Moscow

АбуговС. А.AbugovS. A.

Москва 

Moscow

ФГБУ «Национальный медицинский исследовательский центр гематологии»РоссияNational Hematology Research CenterRussian FederationФГБУ «Национальный медицинский исследовательский центр гематологии»РоссияNational Hematology Research CenterRussian FederationФГБНУ «Российский научный центр хирургии им. академика Б.В. Петровского»РоссияThe Russian Scientific Center of Surgery named after Academician B.V. PetrovskyRussian Federation202529082025203126129Copyright © Гительзон Д.Г., Васильев А.Э., Данишян К.И., Зозуля Н.И., Абугов С.А., 20252025Гительзон Д.Г., Васильев А.Э., Данишян К.И., Зозуля Н.И., Абугов С.А.Gitelson D.G., Vasiliev A.E., Danishian K.I., Zozulya N.I., Abugov S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://submit.pirogov-vestnik.ru/jour/article/view/372

За последние десятилетия антикоагулянтные препараты претерпели кардинальные изменения. Внедрение в клиническую практику прямых пероральных антикоагулянтов привело к их большому распространению для длительной пероральной антикоагулянтной терапии. Контроля за терапией стало меньше, а назначение препаратов происходит врачами многих специальностей. Эта система наблюдения за пациентами, получающими прямые пероральные антикоагулянты, является неоптимальной. А отсутствие антидотов для апиксабана и ривароксабана усугубляют проблему.

Anticoagulant drugs have undergone drastic changes in recent decades. The introduction of direct oral anticoagulants into clinical practice has led to their widespread use for long-term oral anticoagulant therapy. There is less control over therapy, and medications are prescribed by doctors of many specialties. This monitoring system for patients receiving direct oral anticoagulants is suboptimal. And the lack of antidotes for apixaban and rivaroxaban exacerbate the problem. 

прямые пероральные антикоагулянтыапиксабанривароксабандабигатранdirect oral anticoagulantsapixabanrivaroxabandabigatranReferencesHirsh J, Eikelboom JW, Chan NC. Fifty years of research on antithrombotic therapy: achievements and disappointments. Eur J Intern Med. 2019; 70: 1-7.Hirsh J, Eikelboom JW, Chan NC. Fifty years of research on antithrombotic therapy: achievements and disappointments. Eur J Intern Med. 2019; 70: 1-7.Modan B, Shani M, Schor S, Modan M. Reduction of hospital mortality from acute myocardial infarction by anticoagulant therapy. N Engl J Med. 1975; 292(26): 1359-62.Modan B, Shani M, Schor S, Modan M. Reduction of hospital mortality from acute myocardial infarction by anticoagulant therapy. N Engl J Med. 1975; 292(26): 1359-62.Verstraete M. Heparin and thrombosis: a seventy year long story. Haemostasis. 1990; 20(1): 4-11.Verstraete M. Heparin and thrombosis: a seventy year long story. Haemostasis. 1990; 20(1): 4-11.Levine MN, Hirsh J. Clinical use of low molecular weight heparins and heparinoids. Semin Thromb Hemost. 1988; 14(1): 116-25.Levine MN, Hirsh J. Clinical use of low molecular weight heparins and heparinoids. Semin Thromb Hemost. 1988; 14(1): 116-25.Beyer-Westendorf J. What have we learned from real-world NOAC studies in venous thromboembolism treatment? Thromb Res. 2018; 163: 83-91.Beyer-Westendorf J. What have we learned from real-world NOAC studies in venous thromboembolism treatment? Thromb Res. 2018; 163: 83-91.Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015; 313(19): 1950-62. Erratum in: JAMA. 2015; 314(8): 83-7.Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015; 313(19): 1950-62. Erratum in: JAMA. 2015; 314(8): 83-7.Choay J. Biologic studies on chemically synthesized pentasaccharide and tetrasaccharide fragments. Semin Thromb Hemost. 1985; 11(2): 81-5.Choay J. Biologic studies on chemically synthesized pentasaccharide and tetrasaccharide fragments. Semin Thromb Hemost. 1985; 11(2): 81-5.Bauer KA. Fondaparinux sodium: a selective inhibitor of factor Xa. Am J Health Syst Pharm. 2001; 58(2): S14-7.Bauer KA. Fondaparinux sodium: a selective inhibitor of factor Xa. Am J Health Syst Pharm. 2001; 58(2): S14-7.Gustafsson D. Oral direct thrombin inhibitors in clinical development. J Intern Med. 2003; 254(4): 322-34.Gustafsson D. Oral direct thrombin inhibitors in clinical development. J Intern Med. 2003; 254(4): 322-34.Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005; 3(1): 103-11.Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005; 3(1): 103-11.Perzborn E, Strassburger J, Wilmen A, Pohlmann J, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939–an oral, direct factor Xa inhibitor. J Thromb Haemost. 2005; 3(3): 514-21.Perzborn E, Strassburger J, Wilmen A, Pohlmann J, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939–an oral, direct factor Xa inhibitor. J Thromb Haemost. 2005; 3(3): 514-21.Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and metaanalysis of subgroups. Thrombosis. 2013; 2013: 640-723.Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and metaanalysis of subgroups. Thrombosis. 2013; 2013: 640-723.Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulants for atrial fibrillation and venous thromboembolism: a systematic review and meta-analyses. Clin Ther. 2017; 39(7): 1456-1478.Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulants for atrial fibrillation and venous thromboembolism: a systematic review and meta-analyses. Clin Ther. 2017; 39(7): 1456-1478.Olie RH, ten Cate H. Heparins, fondaparinux, hirudin, bivalirudin, argatroban, and danaparoid. In: De Caterina R, Moliterno DJ, Kristensen SD, editors. The ESC Textbook of Thrombosis. Oxford: Oxford University Press; 2024. P.87-100.Olie RH, ten Cate H. Heparins, fondaparinux, hirudin, bivalirudin, argatroban, and danaparoid. In: De Caterina R, Moliterno DJ, Kristensen SD, editors. The ESC Textbook of Thrombosis. Oxford: Oxford University Press; 2024. P.87-100.Olie RH, Winckers K, Rocca B, Ten Cate H. Oral anticoagulants beyond warfarin. Annu Rev Pharmacol Toxicol. 2024; 64: 551-75.Olie RH, Winckers K, Rocca B, Ten Cate H. Oral anticoagulants beyond warfarin. Annu Rev Pharmacol Toxicol. 2024; 64: 551-75.Joosten LPT, van Doorn S, van de Ven PM, Köhlen BTG, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation. 2024; 149(4): 279-89.Joosten LPT, van Doorn S, van de Ven PM, Köhlen BTG, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation. 2024; 149(4): 279-89.Chao TF, Liu CJ, Lin YJ, Chang SL, et al. Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study. Circulation. 2018; 138(1): 37-47.Chao TF, Liu CJ, Lin YJ, Chang SL, et al. Oral anticoagulation in very elderly patients with atrial fibrillation: a nationwide cohort study. Circulation. 2018; 138(1): 37-47.Ten Cate H. Monitoring new oral anticoagulants, managing thrombosis, or both? Thromb Haemost. 2012; 107(5): 803-5.Ten Cate H. Monitoring new oral anticoagulants, managing thrombosis, or both? Thromb Haemost. 2012; 107(5): 803-5.Harenberg J, Gosselin RC, Cuker A, Becattini C, et al. Algorithm for rapid exclusion of clinically relevant plasma levels of direct oral anticoagulants in patients using the DOAC dipstick: an expert consensus paper. Thromb Haemost. 2024; 124(8): 770-7.Harenberg J, Gosselin RC, Cuker A, Becattini C, et al. Algorithm for rapid exclusion of clinically relevant plasma levels of direct oral anticoagulants in patients using the DOAC dipstick: an expert consensus paper. Thromb Haemost. 2024; 124(8): 770-7.Glund S, Moschetti V, Norris S, Stangier 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.Glund S, Moschetti V, Norris S, Stangier 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.Connolly SJ, Sharma M, Cohen AT, Demchuk AM, et al. Andexanet for factor Xa inhibitor-associated acute intracerebral hemorrhage. N Engl J Med. 2024; 390(19): 1745-55.Connolly SJ, Sharma M, Cohen AT, Demchuk AM, et al. Andexanet for factor Xa inhibitor-associated acute intracerebral hemorrhage. N Engl J Med. 2024; 390(19): 1745-55.Gulpen AJW, Ten Cate H, Henskens YMC, van Oerle R, Wetzels R, Schalla S, et al. The daily practice of direct oral anticoagulant use in patients with atrial fibrillation; an observational cohort study. PLoS One. 2019; 14(6): e0217302.Gulpen AJW, Ten Cate H, Henskens YMC, van Oerle R, Wetzels R, Schalla S, et al. The daily practice of direct oral anticoagulant use in patients with atrial fibrillation; an observational cohort study. PLoS One. 2019; 14(6): e0217302.Testa S, Legnani C, Antonucci E, Paoletti O, Dellanoce C, Cosmi B, et al. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2019; 17(7): 1064-72.Testa S, Legnani C, Antonucci E, Paoletti O, Dellanoce C, Cosmi B, et al. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2019; 17(7): 1064-72.De Jong MJ, Saadan H, Hellenbrand DLS, Ten Cate H, et al. The DOAC-FRAIL study, evaluation of direct oral anticoagulant-levels in acutely admitted frail older patients: an exploratory study. J Am Geriatr Soc. 2024; 72(7): 2249-53.De Jong MJ, Saadan H, Hellenbrand DLS, Ten Cate H, et al. The DOAC-FRAIL study, evaluation of direct oral anticoagulant-levels in acutely admitted frail older patients: an exploratory study. J Am Geriatr Soc. 2024; 72(7): 2249-53.Palareti G, Testa S, Legnani C, Dellanoce C, et al. More early bleeds associated with high baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study. Blood Adv. 2024; 8(18): 4913-23.Palareti G, Testa S, Legnani C, Dellanoce C, et al. More early bleeds associated with high baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study. Blood Adv. 2024; 8(18): 4913-23.Bernier M, Lancrerot SL, Parassol N, Lavrut T, et al. Therapeutic drug monitoring of direct oral anticoagulants may increase their benefit-risk ratio. J Cardiovasc Pharmacol. 2020; 76(4): 472-7.Bernier M, Lancrerot SL, Parassol N, Lavrut T, et al. Therapeutic drug monitoring of direct oral anticoagulants may increase their benefit-risk ratio. J Cardiovasc Pharmacol. 2020; 76(4): 472-7.Bejjani A, Bikdeli B. Direct oral anticoagulants: quick primer on when to use and when to avoid. Thromb Haemost. 2024.Bejjani A, Bikdeli B. Direct oral anticoagulants: quick primer on when to use and when to avoid. Thromb Haemost. 2024.Rennenberg RJ, van Varik BJ, Schurgers LJ, Hamulyak K, et al. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood. 2010; 115(24): 5121-3.Rennenberg RJ, van Varik BJ, Schurgers LJ, Hamulyak K, et al. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood. 2010; 115(24): 5121-3.Brodsky S, Eikelboom J, Hebert LA. Anticoagulant-related nephropathy. J Am Soc Nephrol. 2018; 29(12): 2787-93.Brodsky S, Eikelboom J, Hebert LA. Anticoagulant-related nephropathy. J Am Soc Nephrol. 2018; 29(12): 2787-93.Chiasakul T, Zwicker JI. The impact of warfarin on overall survival in cancer patients. Thromb Res. 2022; 213(1): S113-9.Chiasakul T, Zwicker JI. The impact of warfarin on overall survival in cancer patients. Thromb Res. 2022; 213(1): S113-9.Engelbertz C, Marschall U, Feld J, Makowski L, et al. Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: a retrospective German claims data analysis. J Intern Med. 2024; 296(4): 362-76.Engelbertz C, Marschall U, Feld J, Makowski L, et al. Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: a retrospective German claims data analysis. J Intern Med. 2024; 296(4): 362-76.Weitz JI, Eikelboom JW. What is the future of factor XI inhibitors? Circulation. 2022; 146(25): 1899-902.Weitz JI, Eikelboom JW. What is the future of factor XI inhibitors? Circulation. 2022; 146(25): 1899-902.Gigante B, Ten Cate H. Factor XI inhibitors in patients with cardiovascular disease and a high risk of bleeding: a cautionary tale. Nat Rev Cardiol. 2023; 20(8): 511-2.Gigante B, Ten Cate H. Factor XI inhibitors in patients with cardiovascular disease and a high risk of bleeding: a cautionary tale. Nat Rev Cardiol. 2023; 20(8): 511-2.Gailani D, Gruber A. Targeting factor XI and factor XIa to prevent thrombosis. Blood. 2024; 143(15): 1465-75.Gailani D, Gruber A. Targeting factor XI and factor XIa to prevent thrombosis. Blood. 2024; 143(15): 1465-75.Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015; 372(3): 232-40.Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015; 372(3): 232-40.Nopp S, Kraemmer D, Ay C. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med. 2022; 9: 903029.Nopp S, Kraemmer D, Ay C. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med. 2022; 9: 903029.Patel SM, Ruff CT. Will factor XI inhibitors replace current anticoagulants for stroke prevention in atrial fibrillation? Curr Cardiol Rep. 2024; 26(9): 911-7.Patel SM, Ruff CT. Will factor XI inhibitors replace current anticoagulants for stroke prevention in atrial fibrillation? Curr Cardiol Rep. 2024; 26(9): 911-7.Nolte CH. Factor XI inhibitors – rising stars in anti-thrombotic therapy? J Neurol Sci. 2024; 464: 123157.Nolte CH. Factor XI inhibitors – rising stars in anti-thrombotic therapy? J Neurol Sci. 2024; 464: 123157.Raffo C, Capodanno D. Factor XI inhibition in patients with acute coronary syndrome. Eur Heart J Suppl. 2024; 26(1): i29-34.Raffo C, Capodanno D. Factor XI inhibition in patients with acute coronary syndrome. Eur Heart J Suppl. 2024; 26(1): i29-34.Piccini JP, Patel MR, Steffel J, Ferdinand K, et al. Asundexian versus apixaban in patients with atrial fibrillation. N Engl J Med. 2024; 392(1): 23-32.Piccini JP, Patel MR, Steffel J, Ferdinand K, et al. Asundexian versus apixaban in patients with atrial fibrillation. N Engl J Med. 2024; 392(1): 23-32.Jain SS, Mahaffey KW, Pieper KS, Shimizu W, et al. Milvexian vs apixaban for stroke prevention in atrial fibrillation: the LIBREXIA atrial fibrillation trial rationale and design. Am Heart J. 2024; 277: 145-58.Jain SS, Mahaffey KW, Pieper KS, Shimizu W, et al. Milvexian vs apixaban for stroke prevention in atrial fibrillation: the LIBREXIA atrial fibrillation trial rationale and design. Am Heart J. 2024; 277: 145-58.

The authors declare that there are no conflicts of interest present.