Register
Forgot your password?

Direct oral anticoagulants: focus on expanding indications

Authors: Safiullina Z.M.1, Mezhonov E.M.1 2, Vyalkina Yu.A.1, Shalaev S.V. 1 2

Company: 1 Tyumen State Medical University, Tyumen, Russian Federation
2 Regional Clinical Hospital No. 1, Tyumen, Russian Federation

For correspondence:  Sign in or register.

Type:  Reviews


DOI: https://doi.org/10.24022/1997-3187-2025-19-3-272-284

For citation: Safiullina Z.M., Mezhonov E.M., Vyalkina Yu.A., Shalaev S.V. Direct oral anticoagulants: focus on expanding indications. Creative Cardiology. 2025; 19 (3): 272–284 (in Russ.). DOI: 10.24022/1997-3187-2025-19-3-272-284

Received / Accepted:  18.04.2025 / 15.07.2025

Keywords: direct oral anticoagulants atrial fibrillation venous thromboembolism left ventricular thrombosis end-stage chronic kidney disease peripheral artery disease



Subscribe 🔒

 

Abstract

The review discusses the impact of direct oral anticoagulants (DOACs) on clinical practice over the past decade, new areas of application, and practical issues of treatment with these drugs. The current issues and practical aspects of the use of DOACs in atrial fibrillation (AF), the problems of using these drugs in elderly and “fragile” patients, and the features of DOACs in the treatment of venous thromboembolism associated with oncological pathology are analyzed. The data of new DOACs studies in cardioversion, subclinical AF, and left ventricular thrombosis are presented, and controversial issues of DOACs use in terminal chronic kidney disease (CKD) are discussed. The practical aspects of DOACs treatment in peripheral artery disease are discussed based on the latest ACC and AHA (2024) and ESC (2024) recommendations. The risk of bleeding remains a problem when using any available anticoagulant, which requires a personalized approach to treatment, taking into account the individual risk of thromboembolic complications and bleeding. This is especially true for certain categories of patients, including “fragile” elderly patients with AF, patients with end-stage CKD, and patients with cancer.

The purpose of the work is to discuss, based on modern research and literature data, the expansion of indications for the appointment of DOACs.

References

  1. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldg-ren J., Parekh A. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009; 361: 1139–1151. DOI: 10.1056/NEJMoa0905561
  2. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011; 365: 883–891. DOI: 10.1056/NEJMoa1009638
  3. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011; 365: 981–992. DOI: 10.1056/NEJMoa1107039
  4. Giugliano R.P., Ruff C.T., Braunwald E., Murphy S.A., Wiviott S.D., Halperin J.L. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2013; 369: 2093–2104. DOI: 10.1056/NEJMoa1310907
  5. Connolly S.J., Karthikeyan G., Ntsekhe M., Haileamlak A., El Sayed A., El Ghamrawy A. et al. Rivaroxaban in rheumatic heart disease- associated atrial fibrillation. N. Engl. J. Med. 2022; 387: 978–988. DOI: 10.1056/NEJMoa2209051
  6. Eikelboom J.W., Connolly S.J., Brueckmann M., Granger C.B., Kappetein A.P., Mack M.J. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N. Engl. J. Med. 2013; 369: 1206–1214. DOI: 10.1056/NEJMoa1300615
  7. Wang T.Y., Svensson L.G., Wen J., Vekstein A., Gerdisch M., Rao V.U. et al. Apixaban or warfarin in patients with an On-X mechanical aortic valve. N. Engl. J. Med. Evid. 2023; 2 (7). DOI: 10.1056/EVIDoa2300067
  8. Hart R.G., Sharma M., Mundl H., Kasner S.E., Bangdiwala S.I., Berkowitz S.D. et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N. Engl. J. Med. 2018; 378: 2191–2201. DOI: 10.1056/NEJMoa1802686
  9. Diener H.C., Sacco R.L., Easton J.D., Granger C.B., Bernstein R.A., Uchiyama S. et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N. Engl. J. Med. 2019; 380: 1906–1917. DOI: 10.1056/NEJMoa1813959
  10. Geisler T., Keller T., Martus P., Poli K., Serna-Higuita L.M., Schreieck J. et al. Apixaban versus aspirin for embolic stroke of undetermined source. N. Engl. J. Med. Evid. 2023; 3 (1). DOI: 10.1056/EVIDoa2300235
  11. Pengo V., Denas G., Zoppellaro G., Jose S.P., Hoxha A., Ruffatti A. et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018; 132: 1365–1371. DOI: 10.1182/blood-2018-04-848333
  12. Cohen H., Hunt B.J., Efthymiou M., Arachchillage D.R., Ma-ckie I.J., Clawson S. et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016; 3: e426–e436. DOI: 10.1016/S2352-3026(16) 30079-5
  13. Goldhaber S.Z., Eriksson H., Kakkar A., Schellong S., Feuring M., Fraessdorf M. et al. Efficacy of dabigatran versus warfarin in patients with acute venous thromboembolism in the presence of thrombophilia: findings from RE-COVER®, RE-COVER™ II, and RE-MEDY™. Vasc. Med. 2016; 21: 506–514. DOI: 10.1177/1358863X16668588
  14. Ordi-Ros J., Sáez-Comet L., Pérez-Conesa M., Vidal X., Riera-Mestre A., Castro-Salomó A. et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann. Intern. Med. 2019; 171: 685–694. DOI: 10.7326/M19-0291
  15. Ageno W., Caramelli B., Donadini M.P. Girardi L., Riva N. Changes in the landscape of anticoagulation: a focus on direct oral anticoagulants. Lancet Haematol. 2024; 11 (12): e938–e950. DOI: 10.1016/S2352-3026(24)00281-3
  16. Kakkar A.K., Mueller I., Bassand J.P., Fitzmaurice D.A., Goldhaber S.Z., Goto S. et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS One. 2013; 8 (5): e63479. DOI: 10.1371/journal.pone.0063479
  17. Poli D., Antonucci E., Ageno W., Berteotti M., Falanga A., Pengo V. et al. Inappropriate underdosing of direct oral anticoagulants in atrial fibrillation patients: results from the START2-AF registry. J. Clin. Med. 2024; 13: 2009. DOI: 10.3390/jcm13072009
  18. Tzeis S., Savvari P., Skiadas I., Patsilinakos S., Stamatelopoulos K., Kourouklis S. et al. Right drug, wrong dosage: insights from the PAVE- AF antithrombotic study in older patients with atrial fibrillation. J. Thromb. Thrombol. 2021; 51: 81–88. DOI: 10.1007/s11239-020-02167-8
  19. Joosten L.P.T., van Doorn S., van de Ven P.M., Köhlen B.T.G., Nierman M.C., Koek H.L. 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. Circ ulation. 2024; 149: 279–289. DOI: 10.1161/CIRCULATIONAHA.123.066485
  20. Schäfer A., Flierl U., Berliner D., Bauersachs J. Anticoagulants for stroke prevention in atrial fibrillation in elderly patients. Cardiovasc. Drugs. Ther. 2020; 34 (4): 555–568. DOI: 10.1007/s10557-020-06981-3
  21. Silverio A., Di Maio M., Prota C., De Angelis E., Radano I., Citro R. et al. Safety and efficacy of non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: systematic review and meta-analysis of 22 studies and 440 281 patients. Eur. Heart J. Cardiovasc. Pharmacother. 2021; 7 (FI1): f20–29. DOI: 10.1093/ehjcvp/pvz073
  22. Bul M., Shaikh F., McDonagh J., Ferguson C. Frailty and oral anticoagulant prescription in adults with atrial fibrillation: a systematic review. Aging. Med. (Milton). 2022; 6 (2): 195–206. DOI: 10.1002/agm2.12214
  23. Søgaard M., Ording A.G., Skjøth F., Larsen T.B., Nielsen P.B. et al. Effectiveness and safety of direct oral anticoagulation vs. warfarin in frail patients with atrial fibrillation. Eur. Heart J. Cardiovasc. Pharmacother. 2024; 10 (2): 137–146. DOI: 10.1093/ehjcvp/pvad091
  24. Proietti M., Romiti G.F., Raparelli V., Diemberger I., Boriani G., Dalla Vecchia L.A. et al. Frailty prevalence and impact on outcomes in patients with atrial fibrillation: a systematic review and meta-analysis of 1,187,000 patients. Ageing Res. Rev. 2022: 79: 101652. DOI: 10.1016/j.arr.2022.101652
  25. Cappato R., Ezekowitz M.D., Klein A.L., Camm A.J., Ma C.S., Le Heuzey J.Y. et al., on behalf of the X-VeRT Investigators. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur. Heart J. 2014; 35 (47): 3346–3355. DOI: 10.1093/eurheartj/ehu367
  26. Ezekowitz M.D., Pollack C.V. Jr, Halperin J.L., England R.D., VanPelt Nguyen S., Spahr J. et al. Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial. Eur. Heart J. 2018; 39 (32): 2959–2971. DOI: 10.1093/eurheartj/ehy148
  27. Healey J.S., Lopes R.D., Granger C.B., Alings M., Rivard L., McIntyre W.F. et al. Apixaban for stroke prevention in subclinical atrial fibrillation. N. Engl. J. Med. 2024; 390 (2): 107–117. DOI: 10.1056/NEJMoa2310234
  28. Bahmaid R.A., Ammar S., Al-Subaie S., Soofi M.A., Mhish H., Yahia M.A. Efficacy of direct oral anticoagulants on the resolution of left ventricular thrombus – a case series and literature review. JRSMCardiovasc. Dis. 2019; 8: 2048004019839548. DOI: 10.1177/2048004019839548
  29. Albabtain M.A., Alhebaishi Y., Al-Yafi O., Soofi M.A., Mhish H., Yahia M.A. et al. Rivaroxaban versus warfarin for the management of left ventricle thrombus. Egypt Heart J. 2021; 73 (1): 41. DOI: 10.1186/s43044-021-00164-7
  30. Vranckx P., Halvorsen S. Cracking the clot: the RIVAWAR trial challenges warfarin's reign in left ventricular thrombus post-acute coronary syndrome. Eur. Heart J. Acute Cardiovasc. Care. 2025; 14 (4): 243–244. DOI: 10.1093/ehjacc/zuaf052
  31. Hindricks G., Potpara T., Dagres N., Arbelo E., Bax J.J., Blomström-Lundqvist C. et al.; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task F orce for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur. Heart J. 2021; 42 (5): 373–498. DOI: 10.1093/eurheartj/ehaa612
  32. Van Gelder I.C., Rienstra M., Bunting K.V., Casado-Arroyo R., Caso V., Crijns H.J.G.M. et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2024; 45(36): 3314–3414. DOI: 10.1093/eurheartj/ehae176
  33. Mezhonov E.M., Safiullina Z.M., Vyalkina Yu.A., Shalaev S.V. Effectiveness and safety of direct oral anticoagulants in patients with atrial fibrillation and chronic kidney disease: a systematic review and meta-analysis of clinical trials. Rational Pharmacotherapy in Cardiology. 2024; 20 (5): 514–524 (in Russ.). DOI: 10.20996/1819-6446-2024-3092
  34. De Vriese A.S., Caluwé R., Pyfferoen L., De Bacquer D., De Boeck K., Delanote J. et al. Multicenter randomized control-led trial of vitamin K antagonist replacement by rivaroxaban with or without vitamin K2 in hemodialysis patients with atrial fibrillation: the Valkyrie study. J. Am. Soc. Nephrol. 2020; 31: 186–196. DOI: 10.1681/ASN.2019060579
  35. De Vriese A.S., Caluwé R., Van Der Meersch H., De Boeck K., De Bacquer D. Safety and efficacy of vitamin K antagonists versus rivaroxaban in hemodialysis patients with atrial fibrillation: a multicenter randomized controlled trial. J. Am. Soc. Nephrol. 2021; 32: 1474–1483. DOI: 10.1681/ASN.2020111566
  36. Pokorney S.D., Chertow G.M., Al-Khalidi H.R., Gallup D., Dignacco P., Mussina K. et al. Apixaban for patients with atrial fibrillation on hemodialysis: a multicenter randomized controlled trial. Circulation. 2022; 146: 1735–1745. DOI: 10.1161/CIRCULATIONAHA.121.054990
  37. Reinecke H., Engelbertz C., Bauersachs R., Breithardt G., Echterhoff H.H., Gerß J. et al. A randomized controlled trial comparing apixaban with the vitamin K antagonist phenprocoumon in patients on chronic hemodialysis: the AXADIA-AFNET 8 study. Circulation. 2023; 147: 296–309. DOI: 10.1161/CIRCULATIONAHA.122.062779
  38. Joglar J.A., Chung M.K., Armbruster A.L., Benjamin E.J., Chyou J.Y., Cronin E.M. et al. 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology / American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2024; 83 (1): 109–279. DOI: 10.1016/j.jacc.2023.08.017
  39. Van Kuijk J.P., Flu W.J., Welten G.M., Hoeks S.E., Chonchol M., Vidakovic R. et al. Long-term progno sis of patients with peripheral arterial disease with or without polyvascular atherosclerotic disease. Eur. Heart J. 2010; 31: 992–999. DOI: 10.1093/eurheartj/ehp553
  40. Anand S.S., Bosch J., Eikelboom J.W., Connolly S.J., Diaz R., Widimsky P. et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018; 391: 219–229. DOI: 10.1016/S0140-6736(17)32409-1
  41. Anand S.S., Caron F., Eikelboom J.W., Bosch J., Dyal L., Aboyans V. et al. Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial. J. Am. Coll. Cardiol. 2018; 71: 2306–2315. DOI: 10.1016/j.jacc.2018.03.008
  42. Bonaca M.P., Bauersachs R.M., Anand S.S., Debus E.S., Nehler M.R., Patel M.R. et al. Rivaroxaban in peripheral artery disease after revascularization. N. Engl. J. Med. 2020; 382: 1994–2004. DOI: 10.1056/NEJMoa2000052
  43. Moll F., Baumgartner I., Jaff M., Nwachuku C., Tangelder M., Ansel G. et al. Edoxaban plus aspirin vs dual antiplatelet therapy in endovascular treatment of patients with peripheral artery disease: results of the ePAD trial. J. Endovasc. Ther. 2018; 25: 158–168. DOI: 10.1177/1526602818760488
  44. Gornik H.L., Aronow H.D., Goodney P.P., Arya S., Brewster L.P., Byrd L. et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/ SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American College of Cardiology / American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2024; 83 (24): 2497–2604. DOI: 10.1016/j. jacc. 2024.02.013
  45. Mazzolai L., Teixido-Tura G., Lanzi S., Boc V., Bossone E., Brodmann M. et al. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur. Heart J. 2024; 45 (36): 3538–3700. DOI: 10.1093/eurheartj/ehae179
  46. Raskob G.E., van Es N., Verhamme P., Carrier M., Di Nisio M., Garcia D. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N. Engl. J. Med. 2018; 378: 615–624. DOI: 10.1056/NEJMoa1711948
  47. Young A.M., Marshall A., Thirlwall J., Chapman O., Lokare A., Hill C. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J. Clin. Oncol. 2018; 36: 2017–2023. DOI: 10.1200/JCO.2018. 78.8034
  48. McBane R.D., Wysokinski W.E., Le-Rademacher J.G., Zemla T., Ashrani A., Tafur A. et al. Apixaban and dalteparin in active malignancy- associated venous thromboembolism: the ADAM VTE trial. J. Thromb. Haemost. 2020; 18: 411–421. DOI: 10.1111/jth.14662
  49. Agnelli G., Becattini C., Meyer G., Muñoz A., Huisman M.V., Connors J.M. et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N. Engl. J. Med. 2020; 382: 1599–1607. DOI: 10.1056/NEJMoa1915103
  50. Planquette B., Bertoletti L., Charles-Nelson A., Laporte S., Grange C., Mahé I. et al. Rivaroxaban vs dalteparin in cancer-associated thromboembolism: a randomized trial. Chest. 2022; 161: 781–790. DOI: 10.1016/j.chest.2021.09.037
  51. Frere C., Farge D., Schrag D., Prata P.H., Connors J.M. Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials. J. Hematol. Oncol. 2022; 15: 69. DOI: 10.1186/s13045-022-01289-1
  52. Mahé I., Carrier M., Didier M., Chidiac J., Vicaut E., Falvo N. et al. Extended reduced-dose apixaban for cancer-associated venous thromboembolism. N. Engl. J. Med. 2025; 392: 1363–1373. DOI: 10.1056/NEJMoa2416112
  53. Grover S.P., Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler. Thromb. Vasc. Biol. 2019; 39: 331–338. DOI: 10.1161/ATVBAHA.118.312130

About Authors

  • Zemfira M. Safiullina, Dr. Med. Sci., Professor of the Chair of Cardiology and Cardiac Surgery with an Emergency Care Course; ORCID
  • Evgeniy M. Mezhonov, Dr. Med. Sci., Associate Professor, Professor of the Chair of Cardiology and Cardiac Surgery with an Emergency Care Course1, Cardiologist2; ORCID
  • Yuliya A. Vyalkina, Cand. Med. Sci., Associate Professor of the Chair of Hospital Therapy with a Course in Endocrinology; ORCID
  • Sergey V. Shalaev, Dr. Med. Sci., Professor, Corresponding Member of the Russian Academy of Sciences, Chief of the Chair of Cardiology and Cardiac Surgery with an Emergency Care Course1, Head of the Heart and Vascular Center2; ORCID

Chief Editor

Elena Z. Golukhova, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, Director of Bakoulev National Medical Research Center for Cardiovascular Surgery


Sort by