Vnitr Lek 2023, 69(7):438-451 | DOI: 10.36290/vnl.2023.087

The potential use of laboratory monitoring during individualizing the dosage of direct oral anticoagulants - a literature review

Kateřina Zyková1, Anna Rejman Patková1, Miroslav Penka2, Josef Malý1
1 Katedra sociální a klinické farmacie, Farmaceutická fakulta UK v Hradci Králové
2 Oddělení klinické hematologie FN Brno

Introduction and Aim: Direct oral anticoagulants (DOACs) are administered in fixed daily doses without the need for routine monitoring. Despite significant inter-patient variability in systemic exposure, data regarding populations predisposed to abnormal concentrations are limited. The objective of this literature review was to analyse selected factors that may significantly influence DOAC concentrations within clinical settings, emphasising situations in which laboratory monitoring of DOACs might be applicable.

Methods: Publications from Pubmed and Scopus databases assessing the effect of advanced age, altered renal function, sarcopenia, obesity, medication adherence, and drug interactions on DOAC concentrations, as determined by anti-Xa activity or diluted thrombin time were included.

Results: In total, 34 studies fulfilled the inclusion criteria. Among the assessed factors, increasing age, renal function, decreasing weight, frailty, medication adherence, and drug interactions demonstrated a statistically significant impact on therapeutic DOAC concentrations. Conversely, the influence of obesity was inconclusive.

Conclusion: Therapeutic monitoring of DOAC concentrations in patients with the above-mentioned factors could optimize treatment outcomes.

Keywords: aged, apixaban, dabigatran, drug interactions, drug monitoring, edoxaban, frailty, medication adherence, renal insufficiency, rivaroxaban.

Accepted: October 19, 2023; Published: October 26, 2023  Show citation

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Zyková K, Rejman Patková A, Penka M, Malý J. The potential use of laboratory monitoring during individualizing the dosage of direct oral anticoagulants - a literature review. Vnitr Lek. 2023;69(7):438-451. doi: 10.36290/vnl.2023.087.




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References

  1. Kampouraki E, Avery P, Biss T, et al. Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients. Br J Haematol. 2021;195(5):790-801. Go to original source... Go to PubMed...
  2. Bendayan M, Mardigyan V, Williamson D, et al. Muscle Mass and Direct Oral Anticoagulant Activity in Older Adults With Atrial Fibrillation. J Am Geriatr Soc. 2021; 69(4):1012-1018. Go to original source... Go to PubMed...
  3. Salvi F, Marchetti A, D'Angelo F, et al. Adverse drug events as a cause of hospitalization in older adults. Drug Saf. 2012;35 Suppl 1:29-45. Go to original source... Go to PubMed...
  4. Ogilvie IM, Newton N, Welner SA et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(7):638-645.e4. Go to original source... Go to PubMed...
  5. Martin K, Moll S. Direct oral anticoagulant drug level testing in clinical practice: A single institution experience. Thromb Res. 2016;143:40-44. Go to original source... Go to PubMed...
  6. Testa S, Legnani C, Antonucci E, et al. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2019; 17(7):1064-1072. Go to original source... Go to PubMed...
  7. Denny NDR, Keighley L, Siganporia Z, et al. A level­‑headed approach to measuring direct oral anticoagulants: A 2-year retrospective analysis of DOAC levels from a tertiary UK centre. Int J Lab Hematol. 2019;41(2):200-207. Go to original source... Go to PubMed...
  8. Chan NC, Coppens M, Hirsh J, et al. Real­‑world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost. 2015;13(3):353-359. Go to original source... Go to PubMed...
  9. Silva VM, Scanavacca M, Darrieux F, et al. Routine Coagulation Tests in Patients With Nonvalvular Atrial Fibrillation Under Dabigatran and Rivaroxaban Therapy: An Affordable and Reliable Strategy? Clin Appl Thromb Hemost. 2019;25:1076029619835053. Go to original source... Go to PubMed...
  10. Miklič M, Mavri A, Vene N, et al. Intra- and inter- individual rivaroxaban concentrations and potential bleeding risk in patients with atrial fibrillation. Eur J Clin Pharmaco.l 2019;75(8):1069-1075. Go to original source... Go to PubMed...
  11. Sennesael AL, Larock AS, Douxfils J, et al. Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. Thromb J. 2018;16:28. Go to original source... Go to PubMed...
  12. Schellings MWM, Boonen K, Schmitz EMH, et al. Determination of dabigatran and rivaroxaban by ultra­‑performance liquid chromatography­‑tandem mass spectrometry and coagulation assays after major orthopaedic surgery. Thromb Res. 2016;139:128-134. Go to original source... Go to PubMed...
  13. Gulpen AJW, Ten Cate H, Henskens YMC, 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. Go to original source... Go to PubMed...
  14. Committee for Medicinal Products for Human Use Assessment Report for Pradaxa. [cit. 2023-10-16]. Available from: WWW: https://www.ema.europa.eu/en/documents/assessment­‑report/pradaxa­‑epar­‑public­‑assessment­‑report_en.pdf
  15. Toorop MMA, van Rein N, Nierman MC, et al. Inter- and intra­‑individual concentrations of direct oral anticoagulants: The KIDOAC study. J Thromb Haemost. 2022; 20(1):92-103. Go to original source... Go to PubMed...
  16. Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non­‑Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612-1676. Go to original source... Go to PubMed...
  17. Tripodi A, Ageno W, Ciaccio M, et al. Position Paper on laboratory testing for patients on direct oral anticoagulants. A Consensus Document from the SISET, FCSA, SIBioC and SIPMeL. Blood Transfus. 2018;16(5):462-470.
  18. Ten Cate H, Olie RH, Ten Cate­‑Hoek AJ, et al. Direct oral anticoagulants: When to consider laboratory testing? Int J Lab Hematol. 2018; 40 Suppl 1:30-33. Go to original source... Go to PubMed...
  19. Dunois C. Laboratory Monitoring of Direct Oral Anticoagulants (DOACs). Biomedicines. 2021;9(5). Go to original source... Go to PubMed...
  20. Lin SY, Kuo CH, Yeh SJ, et al. Real­‑World Rivaroxaban and Apixaban Levels in Asian Patients With Atrial Fibrillation. Clin Pharmacol Ther. 2020;107(1):278-286. Go to original source... Go to PubMed...
  21. Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants. Thromb Haemost. 2018;118(3):437-450. Go to original source... Go to PubMed...
  22. Wright C, Brown R, Cuker A. Laboratory measurement of the direct oral anticoagulants: Indications and impact on management in clinical practice. Int J Lab Hemato.l 2017; 39 Suppl 1:31-36. Go to original source... Go to PubMed...
  23. Douxfils J, Adcock DM, Bates SM, et al. 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. Go to original source... Go to PubMed...
  24. Penka M, Novotný J. Co lze očekávat od monitoringu DOACs. Interv Akut Kardiol. 2020;19(4):215-221. Go to original source...
  25. Edwina AE, Dia N, Dreesen E, et al. Insights into the Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Older Adults with Atrial Fibrillation: A Structured Narrative Review. Clin Pharmacokinet. 2023;62(3):351-373. Go to original source... Go to PubMed...
  26. Liu Z, Xie Q, Xiang Q, et al. Anti­‑FXa­‑IIa activity test in Asian and its potential role for drug adherence evaluation in patients with direct oral anticoagulants: a nationwide multi­‑center synchronization study. Cardiovasc Diagn Ther. 2020;10(5):1293-1302. Go to original source... Go to PubMed...
  27. Alalawneh M, Awaisu A, Rachid O. Rivaroxaban Pharmacokinetics in Obese Subjects: A Systematic Review. Clin Pharmacokinet. 2022;61(12):1677-1695. Go to original source... Go to PubMed...
  28. Gregorová J, Tašková I, et al. Antikoagulační terapie. Maxdorf. 2022. ISBN 978-80-7345-728-0.
  29. Moner­‑Banet T, Alberio L, Bart PA. Does One Dose Really Fit All? On the Monitoring of Direct Oral Anticoagulants: A Review of the Literature. Hamostaseologie. 2020;40(2):184-200. Go to original source... Go to PubMed...
  30. Patel JP, Byrne RA, Patel RK, et al. Progress in the monitoring of direct oral anticoagulant therapy. Br J Haematol. 2019;184(6):912-924. Go to original source... Go to PubMed...
  31. Rottenstreich A, Zacks N, Kleinstern G, et al. Direct­‑acting oral anticoagulant drug level monitoring in clinical patient management. J Thromb Thrombolysis. 2018;45(4):543-549. Go to original source... Go to PubMed...
  32. Šinigoj P, Malmström RE, Vene N et al. Dabigatran Concentration: Variability and Potential Bleeding Prediction In "Real­‑Life" Patients With Atrial Fibrillation. Basic Clin Pharmacol Toxicol. 2015;117(5):323-329. Go to original source... Go to PubMed...
  33. Skeppholm M, Hjemdahl P, Antovic JP, et al. On the monitoring of dabigatran treatment in "real life" patients with atrial fibrillation. Thromb Res. 2014;134(4):783-789. Go to original source... Go to PubMed...
  34. Kaserer A, Schedler A, Jetter A, et al. Risk Factors for Higher­‑than­‑Expected Residual Rivaroxaban Plasma Concentrations in Real­‑Life Patients. Thromb Haemost. 2018;118(5):808-817. Go to original source... Go to PubMed...
  35. Sin CF, Wong KP, Wong TF, et al. Plasma apixaban levels in Chinese patients with chronic kidney disease­‑Relationship with renal function and bleeding complications. Front Pharmacol. 2022;13:928401. Go to original source... Go to PubMed...
  36. Hu YF, Liao JN, Chern CM, et al. Identification and management of noncompliance in atrial fibrillation patients receiving dabigatran: the role of a drug monitor. Pacing Clin Electrophysiol. 2015;38(4):465-471. Go to original source... Go to PubMed...
  37. Schnierer M, Samoš M, Bolek T et al. The Effect of Proton Pump Inhibitor Withdrawal on Dabigatran Etexilate Plasma Levels in Patients With Atrial Fibrillation: A Washout Study. J Cardiovasc Pharmacol. 2020;75(4):333-335. Go to original source... Go to PubMed...
  38. Wongcharoen W, Pacharasupa P, Norasetthada L, et al. Anti­‑Factor Xa Activity of Standard and Japan­‑Specific Doses of Rivaroxaban in Thai Patients With Non­‑Valvular Atrial Fibrillation. Circ J. 2020;84(7):1075-1082. Go to original source... Go to PubMed...
  39. Martin AC, Thomas W, Mahir Z, et al. Direct Oral Anticoagulant Concentrations in Obese and High Body Weight Patients: A Cohort Study. Thromb Haemost. 2021;121(2):224-233. Go to original source... Go to PubMed...
  40. Speed V, Green B, Roberts LN, et al. Fixed dose rivaroxaban can be used in extremes of bodyweight: A population pharmacokinetic analysis. J Thromb Haemost. 2020; 18(9):2296-2307. Go to original source... Go to PubMed...
  41. Piran S, Traquair H, Chan N, et al. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study. Res Pract Thromb Haemost. 2018;2(4):684-688. Go to original source... Go to PubMed...
  42. Kim JH, Shelat N, Ji CS. Apixaban and Rivaroxaban Anti­‑Xa Concentration Utilization in Clinical Practice. J Cardiovasc Pharmacol. 2023; 81(2):165-170. Go to original source... Go to PubMed...
  43. Sennesael AL, Larock AS, Hainaut P, et al. The Impact of Strong Inducers on Direct Oral Anticoagulant Levels. Am J Med. 2021;134(10):1295-1299. Go to original source... Go to PubMed...
  44. Škorňová I, Samoš M, Bolek T, et al. Does atorvastatin therapy change the anti­‑Xa activity in xabans­‑treated patients with atrial fibrillation? Pharmacol Res Perspect. 2021; 9(3):e00730. Go to original source... Go to PubMed...
  45. Camporese G, Bernardi D, Bernardi E, et al. Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation. Vascul Pharmacol. 2020;130:106682. Go to original source... Go to PubMed...
  46. Perlman A, Hochberg­‑Klein S, Choshen Cohen L, et al. Management strategies of the interaction between direct oral anticoagulant and drug­‑metabolizing enzyme inducers. J Thromb Thrombolysis. 2019;47(4):590-595. Go to original source... Go to PubMed...
  47. Suwa M, Morii I, Kino M. Rivaroxaban or Apixaban for Non­‑Valvular Atrial Fibrillation - Efficacy and Safety of Off­‑Label Under­‑Dosing According to Plasma Concentration. Circ J. 2019;83(5):991-999. Go to original source... Go to PubMed...
  48. Chang M, Yu Z, Shenker A, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56(5):637-645. Go to original source... Go to PubMed...
  49. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end­‑stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-636. Go to original source... Go to PubMed...
  50. Frost C, Shenker A, Gandhi MD, et al. Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban. Br J Clin Pharmacol. 2014;78(4):877-885. Go to original source... Go to PubMed...
  51. Wasan SM, Feland N, Grant R, et al. Validation of apixaban anti­‑factor Xa assay and impact of body weight. Thromb Res. 2019;182:51-55. Go to original source... Go to PubMed...
  52. Testa S, Prandoni P, Paoletti O, et al. Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: The Cremona experience. J Thromb Haemost. 2020;18(6):1320-1323. Go to original source... Go to PubMed...
  53. Magnocavallo M, Bellasi A, Mariani MV, et al. Thromboembolic and Bleeding Risk in Atrial Fibrillation Patients with Chronic Kidney Disease: Role of Anticoagulation Therapy. J Clin Med. 2020;10(1). Go to original source... Go to PubMed...
  54. Thompson LE, Davis BH, Narayan R, et al. Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics. Clin Pharmacol Ther. 2023;113(3):585-599. Go to original source... Go to PubMed...
  55. Hinojar R, Jiménez­‑Natcher JJ, Fernández­‑Golfín C, et al. New oral anticoagulants: a practical guide for physicians. Eur Heart J Cardiovasc Pharmacother. 2015;1(2):134-145. Go to original source... Go to PubMed...
  56. Pradaxa - Souhrn údajů o přípravdu. [cit. 2023-06-05]. Available from: WWW: https://www.ema.europa.eu/en/documents/product­‑information/pradaxa­‑epar­‑product­‑information_cs.pdf
  57. Rota E, Testa L, Di Brigida G, et al. The management of patients with acute ischemic stroke while on direct oral anticoagulants (DOACs): data from an Italian cohort and a proposed algorithm. J Thromb Thrombolysis. 2020;50(3):732-738. Go to original source... Go to PubMed...
  58. Limdi NA, Beasley TM, Sun J, et al. Thromboembolic and Hemorrhagic Outcomes in the Direct Oral Anticoagulant Trials Across the Spectrum of Kidney Function. Clin Pharmacol Ther. 2021;109(6):1593-1605. Go to original source... Go to PubMed...
  59. Chatterjee S, Sardar P, Giri JS, et al. Treatment discontinuations with new oral agents for long­‑term anticoagulation: insights from a meta­‑analysis of 18 randomized trials including 101,801 patients. Mayo Clin Proc. 2014;89(7):896-907. Go to original source... Go to PubMed...
  60. Eliquis - Souhrn údajů o přípravku. [cit. 2023-06-30]. Available from: WWW: https://www.ema.europa.eu/en/documents/product­‑information/eliquis­‑epar­‑product­‑information_cs.pdf
  61. Reilly PA, Lehr T, Haertter S, et al. 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. Go to original source... Go to PubMed...
  62. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: Observations from the ARISTOTLE trial. Eur Heart J. 2014;35(28):1864-1872. Go to original source... Go to PubMed...
  63. Xue QL. The frailty syndrome: definition and natural history. Clin Geriatr Med. 2011; 27(1):1-15. Go to original source... Go to PubMed...
  64. Committee for Medicinal Products for Human Use. Reflection paper on physical frailty: instruments for baseline characterisation of older populations in clinical trials [Internet].
  65. Cruz­‑Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412-423. Go to original source... Go to PubMed...
  66. Park CS, Choi EK, Kim HM, et al. Increased risk of major bleeding in underweight patients with atrial fibrillation who were prescribed non­‑vitamin K antagonist oral anticoagulants. Heart Rhythm. 2017;14(4):501-507. Go to original source... Go to PubMed...
  67. Topinková E, Berková M, Mádlová P, et al. "Krátká baterie pro testování fyzické zdatnosti seniorů" a její využití pro diagnózu geriatrické křehkosti v klinické praxi. Geriatrie a Gerontologie 2013;2(1):43-49.
  68. Verrest L, Wilthagen EA, Beijnen JH, et al. Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty­‑Related Diseases: A Systematic Review. Clin Pharmacokinet. 2021;60(9):1149-1169. Go to original source... Go to PubMed...
  69. Andrade J, Khairy P, Dobrev D et al. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res. 2014;114(9):1453-1468. Go to original source... Go to PubMed...
  70. Zhao Y, Guo M, Li D, et al. Pharmacokinetics and Dosing Regimens of Direct Oral Anticoagulants in Morbidly Obese Patients: An Updated Literature Review. Clin Appl Thromb Hemost. 2023;29:10760296231153638. Go to original source... Go to PubMed...
  71. Russo V, Cattaneo D, Giannetti L, et al. Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity. Clin Ther. 2021; 43(9):e255-e263. Go to original source... Go to PubMed...
  72. Martin KA, Beyer­‑Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882. Go to original source... Go to PubMed...
  73. Malá­‑Ládová K, Voříšková E, Košťálová B, et al. Terminologie adherence k léčbě - prvotní konsenzuální překlad pomocí Delphi metody. Vnitř Lék. 2022;68(E-2):22-28.Další literatura u autora a na www.casopisvnitrnilekarstvi.cz Go to original source...
  74. Blomström Lundqvist C, Själander S, Garcia Rodriguez LA et al. Impact of non­‑adherence to direct oral anticoagulants amongst Swedish patients with non­‑valvular atrial fibrillation: results from a real­‑world cost­‑utility analysis. J Med Econ. 2022;25(1):1085-1091. Go to original source... Go to PubMed...
  75. Yao X, Abraham NS, Alexander GC, et al. Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation. J Am Heart Assoc. 2016;5(2). Go to original source... Go to PubMed...
  76. Schulman S, Shortt B, Robinson M, et al. Adherence to anticoagulant treatment with dabigatran in a real­‑world setting. J Thromb Haemost. 2013;11(7):1295-1299. Go to original source... Go to PubMed...
  77. Ozaki AF, Choi AS, Le QT, et al. Real­‑World Adherence and Persistence to Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Systematic Review and Meta­‑Analysis. Circ Cardiovasc Qual Outcomes. 2020;13(3):e005969. Go to original source... Go to PubMed...
  78. Brízido C, Ferreira AM, Lopes P, et al. Medication adherence to direct anticoagulants in patients with non­‑valvular atrial fibrillation - A real world analysis. Revista portuguesa de cardiologia 2021; 40(9): 669-675. Go to original source...
  79. Lexicomp. [cit. 2023-07-24]. Available from: https://www­‑uptodate­‑com./drug­‑interactions/?source=responsive_home#di­‑druglist
  80. Micromedex. [cit. 2023-07-24]. Available from: https://www.micromedexsolutions.com/home/dispatch
  81. Databáze lékových interakcí DrugAgency. [cit.-2023-07-24]. Available from: https://www.drugagency.cz/
  82. Bixby AL, Lichvar AB, Salerno D, et al. Use of direct­‑acting oral anticoagulants in solid organ transplantation: A systematic review. Pharmacotherapy. 2021;41(1):28-43. Go to original source... Go to PubMed...
  83. Parker K, Chu J, Morton M, et al. Can direct oral anticoagulants be used in kidney transplant recipients? Clin Transplan.t 2021;35(12):e14474. Go to original source... Go to PubMed...
  84. Wang CL, Wu VCC, Tu HT, et al. Risk of major bleeding associated with concomitant use of anticancer drugs and direct oral anticoagulant in patients with cancer and atrial fibrillation. J Thromb Thrombolysis. 2022;53(3):633-645. Go to original source... Go to PubMed...




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