Therapeutic monitoring of direct oral anticoagulants — an 8-year observational study
Abstract
Introduction: For years, anticoagulants have been the basic group of drugs that slow down, inhibit or prevent blood clotting by inhibiting thrombin formation or reducing its activity. Treatment with DOACs does not require routine anticoagulation monitoring due to their wide therapeutic index. However, there are circumstances where it may be necessary to know the drug levels to manage the risk of side effects or to confirm laboratory efficacy. In such a situation, an indication for DOAC laboratory testing could be the suspicion of excessively high or low DOAC levels. The aim of this article was to determine trends in concentrations of DOACs in a real life population of patients.
Material and methods: Consultations in clinical pharmacology extended with DOAC level assessments were performer in the Department of Cardiology and Clinical Pharmacology. The trial was designed as a retrospective analysis of laboratory analyses and included 480 laboratory tests performed in 236 patients.
Results: Mean CHA2DS2-VASc scoring 3.91 ±1.92 and HAS-BLED scoring 3.57 ±1.75 indicated high risks of both thrombosis and bleeding. Geometric mean of trough concentrations for dabigatran, rivaroxaban and apixaban were 91.53 ng/mL, 62.74 ng/mL and 124.81 ng/mL, whereas peak concentrations for all DOACs were significantly higher, at 220.80 ng/mL (p < 0.0001), 116.59 ng/mL (p < 0.0001) and 186.18 ng/mL (p =0.0354), respectively. Values for males and females did not differ significantly. Dose adjustment, performed according to rules described for every drug in registered drug characteristics, did not change significantly concentrations. Trough concentrations higher than 20 ng/mL were found at the 10th percentile for all DOACs, but higher at 40 ng/mL at the 5th percentile was found only for apixaban. Peak concentration lower than 400 ng/mL were for the 95th percentile for apixaban and for the 90th percentile for dabigatran and rivaroxaban.
Conclusion: Monitoring-based pharmacotherapy with DOACs should be restricted only to specific clinical settings; in the general population, it is not necessary. Recently, in many experienced centers, therapeutic drug monitoring of DOACs has gained great importance in selected clinical settings and it very likely will soon become commonplace in clinical practice.
Keywords: therapeutic drug monitoringTDMdabigatranrivaroxabanapixabandirect oral anticoagulantDOAC
References
- Hindricks G, Potpara T, Dagres N, 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 Force 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.
- Mekaj YH, Mekaj AY, Duci SB, et al. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015; 11: 967–977.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007; 146(12): 857–867.
- Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013; 34(27): 2094–2106.
- Reilly PA, Lehr T, Haertter S, et al. 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.
- Padrini R. Clinical pharmacokinetics and pharmacodynamics of direct oral anticoagulants in patients with renal failure. Eur J Drug Metab Pharmacokinet. 2019; 44(1): 1–12.
- Cohen AT, Hamilton M, Mitchell SA, et al. Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis. PLoS One. 2015; 10(12): e0144856.
- Venker BT, Ganti BR, Lin H, et al. Safety and efficacy of new anticoagulants for the prevention of venous thromboembolism after hip and kee arthroplasty: a meta-analysis. J Arthroplasty. 2017; 32(2): 645–652.
- 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.
- Czuprynska J, Patel JP, Arya R. Current challenges and future prospects in oral anticoagulant therapy. Br J Haematol. 2017; 178(6): 838–851.
- Almutairi AR, Zhou L, Gellad WF, 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.e36.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361(12): 1139–1151.
- Patel MR, Mahaffey K, Garg J, et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365(10): 883–891.
- Giugliano RP, Ruff CT, Braunwald E, et al. ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369(22): 2093–2104.
- Grześk G, Janiszewska E, Malinowski B, et al. Adherence in patients with atrial fibrillation treated with dabigatran. Kardiol Pol. 2018; 76(11): 1562–1563.
- Grześk G, Woźniak-Wiśniewska A, Błażejewski J, et al. The interactions of nintedanib and oral anticoagulants-molecular mechanisms and clinical implications. Int J Mol Sci. 2020; 22(1).
- Zawilska K. [Laboratory assessment of the anticoagulant effects of the new oral anticoagulants — when, why and with which assays?] [Polish]. J Transfus Med. 2014; 7(3): 93–96.
- Kitchen S, Gray E, Mackie I, et al. BCSH committee. Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol. 2014; 166(6): 830–841.
- Samuelson BT, Cuker A, Siegal DM, et al. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest. 2017; 151(1): 127–138.
- Samuelson BT, Cuker A, Siegal DM, et al. Measurement and reversal of the direct oral anticoagulants. Blood Rev. 2017; 31(1): 77–84.
- Góralczyk T, Undas A. Oznaczanie aktywności antykoagulacyjnej bezpośrednich doustnych antykoagulantów — aktualny stan wiedzy i doświadczenia własne laboratorium. Diagn Lab. 2017; 53(3): 161–168.
- Witkowski M, Witkowska M, Smolewski P. [The latest recommendations on the use of new oral anticoagulants in routine practice] [Article in Polish]. Postepy Hig Med Dosw (Online). 2016; 70: 43–55.
- Lippi G, Favaloro EJ. Recent guidelines and recommendations for laboratory assessment of the direct oral anticoagulants (DOACs): is there consensus? Clin Chem Lab Med. 2015; 53(2): 185–197.
- Grześk G, Stolarek W, Kasprzak M, et al. Therapeutic drug monitoring of digoxin-20 years of experience. Pharmacol Rep. 2018; 70(1): 184–189.
- Lin SY, Tang SC, Kuo CH, et al. Factors affecting serum concentration of dabigatran in Asian patients with non-valvular atrial fibrillation. J Formos Med Assoc. 2019; 118(7): 1154–1160.
- 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.
- Billoir P, Barbay V, Joly LM, et al. Anti-Xa oral anticoagulant plasma concentration assay in real life: rivaroxaban and apixaban quantification in emergency with LMWH calibrator. Ann Pharmacother. 2019; 53(4): 341–347.
- Park SHo, Seo YH, Park PW, et al. Evaluation of global laboratory methods and establishing on-therapy ranges for monitoring apixaban and rivaroxaban: Experience at a single institution. J Clin Lab Anal. 2019; 33(5): e22869.
- Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014; 64(11): 1128–1139.
- Cho HJ, Kang YJ, Sung SM, et al. Effects of dabigatran and rivaroxaban on stroke severity according to the results of routine coagulation tests. PLoS One. 2020; 15(10): e0240483.
