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Current insights into the possible role of laboratory monitoring of effectiveness and safety of direct oral anticoagulants



The article is devoted to the discussion of modern approaches to the use of laboratory methods to improve the tactics of using direct oral anticoagulants (DOACs) therapy. Clinical situations in which it may be reasonable to use data on the blood concentration of DOACs are given, including very old age, a marked deviation from the norm of body weight or impaired renal function. Data on the role of measuring the blood level of DOACs are considered in cases of the development of diseases or complications in which information is required on the preservation of the anticoagulant effect of DOACs, for example, in the development of severe bleeding or the need for urgent surgical intervention. The advantages and limitations of modern laboratory methods for assessing the blood concentration of DOACs are discussed. It is emphasized that one of the main advantages of using DOACs is the absence of the need to monitor laboratory parameters in most patients. Data from pharmacological studies are presented that may be useful in explaining the mechanisms that determine the higher safety of some DOACs compared to others. Promising methods for assessing the blood level of DOACs, as well as the possibility of using less specific reagents for assessing the concentration of DOACs, are considered. The possibility of using less specific, but more accessible methods for assessing the blood concentration of factor Xa inhibitors, in particular, a reagent for assessing the level of the antifactor, which is used to determine the blood level of heparin, is being considered. The opinions of experts on the role of assessing the blood level of DOACs and the possibility of tactics for selecting doses of DOACs based on laboratory analysis data are given.

About the Authors

S. R. Gilyarevsky
Russian Medical Academy of Continuing Professional Education
Russian Federation

Sergey R. Gilyarevsky


N. K. Vereina
South-Ural state medical university
Russian Federation

Natalia K. Vereina


M. V. Golshmid
Russian Medical Academy of Continuing Professional Education
Russian Federation

Maria V. Golshmid



1. Chan N., Sager P.T., Lawrence J., Ortel T., Reilly P., Berkowitz S., Kubitza D., Eikelboom J., Florian J., Stockbridge N., Rose M., Temple R., Seltzer J.H. Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants? Am Heart J. 2018;199:59—67. doi: 10.1016/j.ahj.2017.10.002.

2. Chan N.C., Eikelboom J.W., Weitz J.I. Evolving Treatments for Arterial and Venous Thrombosis: Role of the Direct Oral Anticoagulants. Circ Res. 2016;118(9):1409—1424. doi: 10.1161/CIRCRESAHA.116.306925.

3. Lee J.J, Ha A.C.T., Dorian P., Verma M., Goodman S.G., Friedrich J.O. Meta-Analysis of Safety and Efficacy of Direct Oral Anticoagulants Versus Warfarin According to Time in Therapeutic Range in Atrial Fibrillation. Am J Cardiol. 2021;140:62—68. doi: 10.1016/j.amjcard.2020.10.064.

4. Gosselin R.C., Adcock D.M., Bates S.M., Douxfils J., Favaloro E.J., Gouin-Thibault I., Guillermo C., Kawai Y., Lindhoff-Last E., Kitchen S. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018;118(03):437—450. doi: 10.1055/s-0038-1627480.

5. Douxfils J., Ageno W., Samama C.M., Lessire S., Ten Cate H., Verhamme P., Dogné J.M., Mullier F. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018;16(02):209—219. doi: 10.1111/jth.13912.

6. Toorop M.M.A., Lijfering W.M., Scheres L.J.J. The relationship between DOAC levels and clinical outcomes: The measures tell the tale. J Thromb Haemost. 2020;18(12):3163—3168. doi: 10.1111/jth.15104.

7. Douxfils J., Mullier F., Dogné J.M. Dose tailoring of dabigatran etexilate: obvious or excessive? Expert Opin Drug Saf. 2015;14(8):1283—1289. doi: 10.1517/14740338.2015.1049995.

8. Kato E.T., Giugliano R.P., Ruff C.T., Koretsune Y., Yamashita T., Kiss R.G., Nordio F., Murphy S.A., Kimura T., Jin J., Lanz H., Mercuri M., Braunwald E., Antman E.M. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2016;5(05):e003432. doi: 10.1161/JAHA.116.003432.

9. Buckley L.F., Rybak E., Aldemerdash A., Cheng J.W., Fanikos J. Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age. Clin Cardiol 2017;40(01):46—52. doi: 10.1002/clc.22591.

10. Chan K.E., Giugliano R.P., Patel M.R., Abramson S., Jardine M., Zhao S., Perkovic V., Maddux F.W., Piccini J.P. Nonvitamin K anticoagulant agents in patients with advanced chronic kidney disease or on dialysis with AF. J Am Coll Cardiol 2016;67(24):2888—2899. doi: 10.1016/j.jacc.2016.02.082. Erratum in: J Am Coll Cardiol. 2016;68(25):2920.

11. Levy J.H., Ageno W., Chan N.C., Crowther M., Verhamme P., Weitz J.I. 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 (03):623—627. doi: 10.1111/jth.13227.

12. Lindhoff-Last E. Direct oral anticoagulants (DOAC) - Management of emergency situations. Hamostaseologie. 2017;37(4):257—266. doi: 10.5482/HAMO-16-11-0043.

13. Gendron N., Gay J., Lemoine M., Gaussem P., Lillo-Le-Louet A., Smadja D.M. Usefulness of initial plasma dabigatran concentration to predict rebound after reversal. Haematologica 2018;103 (05):e226—e229. doi: 10.3324/haematol.2017.183400.

14. Steffel J., Verhamme P., Potpara T.S., Albaladejo P., Antz M., Desteghe L., Haeusler K.G., Oldgren J., Reinecke H., Roldan-Schilling V., Rowell N., Sinnaeve P., Collins R., Camm A.J., Heidbüchel H.; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330—1393. doi: 10.1093/eurheartj/ehy136.

15. Tripodi A. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures: reply. J Thromb Haemost. 2016;14(12):2559—2561. doi: 10.1111/jth.13513.

16. Tripodi A. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures. J Thromb Haemost. 2016;14(7):1325—1327. doi: 10.1111/jth.13344.

17. Tripodi A., Marongiu F., Moia M., Palareti G, Pengo V, Poli D, Prisco D, Testa S, Zanazzi M. The vexed question of whether or not to measure levels of direct oral anticoagulants before surgery or invasive procedures. Intern Emerg Med. 2018;13(7):1029—1036. doi: 10.1007/s11739-018-1854-6.

18. Albaladejo P., Bonhomme F., Blais N., Collet J.P., Faraoni D., Fontana P., Godier A., Llau J., Longrois D., Marret E., Mismetti P., Rosencher N., Roullet S., Samama C.M., Schved J.F., Sié P., Steib A., Susen S.; French Working Group on Perioperative Hemostasis (GIHP). Management of direct oral anticoagulants in patients undergoing elective surgeries and invasive procedures: Updated guidelines from the French Working Group on Perioperative Hemostasis (GIHP) - September 2015. Anaesth Crit Care Pain Med. 2017;36(1):73—76. doi: 10.1016/j.accpm.2016.09.002.

19. Rimsans J., Douxfils, J., Smythe, M.A., Gosselin R.C. Overview and Practical Application of Coagulation Assays in Managing Anticoagulation with Direct Oral Anticoagulants (DOACs). Curr Pharmacol Rep 6, 241–259 (2020). doi: 10.1007/s40495-020-00232-7.

20. Douketis J.D., Spyropoulos A.C., Duncan J., Carrier M., Le Gal G., Tafur A.J., Vanassche T., Verhamme P., Shivakumar S., Gross P.L., Lee A.Y.Y., Yeo E., Solymoss S., Kassis J., Le Templier G., Kowalski S., Blostein M., Shah V., MacKay E., Wu C., Clark N.P., Bates S.M., Spencer F.A., Arnaoutoglou E., Coppens M., Arnold D.M., Caprini J.A., Li N., Moffat K.A., Syed S., Schulman S. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179(11):1469—1478. doi: 10.1001/jamainternmed.2019.2431..

21. Shaw J.R., Li N., Vanassche T., Coppens M., Spyropoulos A.C., Syed S., Radwi M., Duncan J., Schulman S., Douketis J.D. Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure. Blood Adv. 2020;4(15):3520—3527. doi: 10.1182/bloodadvances.2020002335.

22. Martin K., Beyer-Westendorf J., Davidson B.L., Huisman M.V., Sandset P.M., Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308—1313. doi: 10.1111/jth.13323.

23. Moll S., Crona D.J., Martin K. Direct oral anticoagulants in extremely obese patients: OK to use? Res Pract Thromb Haemost. 2018;3(2):152—155. doi: 10.1002/rth2.12178.

24. Jamieson M.J., Byon W., Dettloff R.W., Crawford M., Gargalovic P.S., Merali S.J., Onorato J., Quintero A.J., Russ C. Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data. Am J Cardiovasc Drugs. 2022;22(6):615—631. doi: 10.1007/s40256-022-00524-x.

25. Testa S., Legnani C., Antonucci E., Paoletti O., Dellanoce C., Cosmi B., Pengo V., Poli D., Morandini R., Testa R., Tripodi A., Palareti G.; Coordinator of START2-Register. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2019;17(7):1064—1072. doi: 10.1111/jth.14457.

26. Testa S., Paoletti O., Legnani C., Dellanoce C., Antonucci E., Cosmi B., Pengo V., Poli D., Morandini R., Testa R., Tripodi A., Palareti G. Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2018;16(5):842—848. doi: 10.1111/jth.14001.

27. Salmonson T., Dogné J.M., Janssen H., Garcia Burgos J., Blake P. Non-vitamin-K oral anticoagulants and laboratory testing: now and in the future: Views from a workshop at the European Medicines Agency (EMA). Eur Heart J Cardiovasc Pharmacother. 2017;3:(1):42—47. doi: 10.1093/ehjcvp/pvw032.

28. European Medicines Agency. Workshop on the role of pharmacokinetic and pharmacodynamic measurements in the use of direct oral anticoagulants. http://⁄4pages/news_and_events/events/2015/08/ event_detail_001181.jsp&mid1⁄4WC0b01ac058004d5c3 (23 November 2015).

29. Meinel T.R., Wilson D., Gensicke H., Scheitz J.F., Ringleb P., Goganau I., Kaesmacher J., Bae H.J., Kim D.Y., Kermer P., Suzuki K., Kimura K., Macha K., Koga M., Wada S., Altersberger V., Salerno A., Palanikumar L. Zini A., Forlivesi S., Kellert L., Wischmann J., Kristoffersen E.S., Beharry J., Barber P.A., Hong J.B., Cereda C., Schlemm E., Yakushiji Y., Poli S., Leker R., Romoli M., Zedde M., Curtze S., Ikenberg B., Uphaus T., Giannandrea D., Portela P.C., Veltkamp R., Ranta A., Arnold M., Fischer U., Cha J.K., Wu T.Y., Purrucker J.C., Seiffge D.J.; DOAC-IVT Writing Group for the International DOAC-IVT, TRISP, and CRCS-K-NIH Collaboration. Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants. JAMA Neurol. 2023;80(3):233—243. doi: 10.1001/jamaneurol.2022.4782. Erratum in: JAMA Neurol. 2023;80(4):422.

30. Willmann S., Thelen K., Kubitza D., Lensing A.W.A., Frede M., Coboeken K., Stampfuss J., Burghaus R., Mück W., Lippert J. Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study. Thromb J. 2018;16:32. doi: 10.1186/s12959-018-0185-1.

31. Rahman M., George C., Monagle P. Hot topics in coagulation testing: Important considerations for testing children for bleeding/thrombotic disorders. Int J Lab Hematol. 2020 Jun;42 Suppl 1:68—74. doi: 10.1111/ijlh.13198. PMID: 32543062.

32. Sarode R. Direct oral anticoagulant monitoring: what laboratory tests are available to guide us? Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):194–197. doi: 10.1182/hematology.2019000027.

33. Douxfils J., Adcock D.M., Bates S.M., Favaloro E.J., Gouin-Thibault I., Guillermo C., Kawai Y., Lindhoff-Last E., Kitchen S., Gosselin R.C. 2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost. 2021;121(8):1008—1020. doi: 10.1055/a-1450-8178.

34. Tarn D., Shih K., Tseng C., Thomas A., Schwartz J.B. Reasons for Nonadherence to the Direct Oral Anticoagulant Apixaban. JACC Adv. 2023 Jan, 2(1). doi: 10.1016/j.jacadv.2022.100175.

35. Samoš M., Bolek T., Stančiaková L., Péč M.J., Brisudová K., Škorňová I., Staško J., Mokáň M., Kubisz P. Tailored Direct Oral Anticoagulation in Patients with Atrial Fibrillation: The Future of Oral Anticoagulation? J Clin Med. 2022;11(21):6369. doi: 10.3390/jcm11216369.

36. Reilly P.A., Lehr T., Haertter S., Connolly S.J., Yusuf S., Eikelboom J.W., Ezekowitz M.D., Nehmiz G., Wang S., Wallentin L.; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321—328. doi: 10.1016/j.jacc.2013.07.104.

37. Sakaguchi T., Osanai H., Murase Y., Ishii H., Nakashima Y., Asano H., Suzuki S., Takefuji M., Inden Y., Sakai K., Murohara T., Ajioka M. Monitoring of anti-Xa activity and factors related to bleeding events: A study in Japanese patients with nonvalvular atrial fibrillation receiving rivaroxaban. J Cardiol. 2017;70(3):244—249. doi: 10.1016/j.jjcc.2016.11.013.

38. Gao H., Li Y., Sun H., Huang X., Chen H., Lin W., Chen M. Trough Concentration Deficiency of Rivaroxaban in Patients With Nonvalvular Atrial Fibrillation Leading to Thromboembolism Events. J Cardiovasc Pharmacol. 2022;80(6):869—876. doi: 10.1097/FJC.0000000000001360.

39. Sin C.F., Wong K.P., Wong H.M., Siu C.W., Yap D.Y.H. Plasma Rivaroxaban Level in Patients With Early Stages of Chronic Kidney Disease-Relationships With Renal Function and Clinical Events. Front Pharmacol. 2022;13:888660. doi: 10.3389/fphar.2022.888660.

40. Škorňová I., Samoš M., Bolek T., Kamenišťáková A., Stančiaková L., Galajda P., Staško J., Kubisz P., Mokáň M. Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study. J Cardiovasc Pharmacol. 2021;78(1):e122—e127. doi: 10.1097/FJC.0000000000001038.

41. Nosáľ V., Petrovičová A., Škorňová I., Bolek T., Dluhá J., Stančiaková L., Sivák Š., Babálová L., Hajaš G., Staško J., Kubisz P., Kurča E., Samoš M., Mokáň M. Plasma levels of direct oral anticoagulants in atrial fibrillation patients at the time of embolic stroke: a pilot prospective multicenter study. Eur J Clin Pharmacol. 2022;78(4):557—564. doi: 10.1007/s00228-022-03280-8.

42. Favaloro E.J., Pasalic L., Curnow J., Lippi G. Laboratory Monitoring or Measurement of Direct Oral Anticoagulants (DOACs): Advantages, Limitations and Future Challenges. Curr Drug Metab. 2017;18(7):598—608. doi: 10.2174/1389200218666170417124035.

43. Yates SG, Smith S, Tharpe W, Shen YM, Sarode R. Can an anti-Xa assay for low-molecular-weight heparin be used to assess the presence of rivaroxaban? Transfus Apher Sci. 2016;55(2):212-215. doi: 10.1016/j.transci.2016.06.005..

44. Sabor L, Raphaël M, Dogné JM, Mullier F, Douxfils J. Heparin-calibrated chromogenic anti-Xa assays are not suitable to assess the presence of significant direct factor Xa inhibitors levels. Thromb Res. 2017;156:36-38. doi: 10.1016/j.thromres.2017.05.024.

45. Margetić S., Ćelap I., Delić Brkljačić D., Pavlović N., Šupraha Goreta S., Kobasić I., Lovrenčić-Huzjan A., Bašić Kes V. Chromogenic anti-FXa assay calibrated with low molecular weight heparin in patients treated with rivaroxaban and apixaban: possibilities and limitations. Biochem Med (Zagreb). 2020;30(1):010702. doi: 10.11613/BM.2020.010702.

46. Sairaku A., Nakano Y, Onohara Y, Hironobe N, Matsumura H, Shimizu W, Kihara Y. Residual anticoagulation activity in atrial fibrillation patients with temporary interrupted direct oral anticoagulants: Comparisons across 4 drugs. Thromb Res. 2019;183:119—123. doi: 10.1016/j.thromres.2019.10.006.

47. Artang R., Dias J.D., Walsh M., Bliden K., Nielsen J.D., Anderson M., Thurston B.C., Tantry U.S., Hartmann J., Gurbel P.A. Measurement of Anticoagulation in Patients on Dabigatran, Rivaroxaban, and Apixaban Therapy by Novel Automated Thrombelastography. TH Open. 2021;5(4):e570—e576. doi: 10.1055/a-1692-1415.


For citations:

Gilyarevsky S.R., Vereina N.K., Golshmid M.V. Current insights into the possible role of laboratory monitoring of effectiveness and safety of direct oral anticoagulants. Rational Pharmacotherapy in Cardiology. 2023;19(3):290-297. (In Russ.) EDN: GUEZKX

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