Is there a Role for Measuring Direct Oral Anticoagulant Levels in Select Patients?
Main Article Content
Direct oral anticoagulants are recommended as first line therapy for patients with atrial fibrillation and venous thromboembolic disease. Measurement of drug levels or pharmacodynamic effect is not recommended during treatment. Dose adjustments are based on age, weight, kidney function and drug-drug interactions. These adjustments are generally based on an estimate of their effect on drug concentration. DOAC dosing recommendations differ across the world. These differences in prescribing recommendations result in different levels of DOAC exposure in patients with identical clinical characteristics. Additionally, data from clinical trials has shown that drug levels may vary significantly in individual patients with identical clinical characteristics despite taking the same prescribed dose. More concerning is that current prescribing recommendations provide cut points for dose adjustments, as an example age 80 or greater in the case of apixaban in atrial fibrillation, which may result in dramatically higher drug concentrations in patients with significantly higher bleeding risk.
Data from outcome trials in both atrial fibrillation and venous thromboembolism have provided mean-median drug concentrations for each of the DOACs. These trial results appear to demonstrate that once a threshold DOAC plasma concentration is reached, higher concentrations fail to provide significant added ischemic stroke reduction while at the same time add an increased risk of bleeding. Bleeding remains a significant problem with DOACs and is associated with an increase in short and long-term mortality, ischemic stroke, myocardial infarction, cost, and drug interruption and discontinuation.
Over the past years, our clinic has been assessing DOAC concentration in patients at risk for under or over exposure. Based on our experience, clinical characteristics alone appear to be insufficient, as a significant number of patients with characteristics suggesting high exposure would be under-dosed using a purely clinical approach and an even greater number, who are at elevated risk of bleeding would have had excessive levels, if prescribing were based strictly on the established dose reduction criteria. We propose, and provide our supporting clinical experience, that measuring DOAC levels in select patients will increase the margin of safety of these medications without compromising efficacy.
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
2. Pradaxa prescribing information. Accessed December 20, 2022. https://content.boehringer-ingelheim.com/DAM/c669f898-0c4e-45a2-ba55-af1e011fdf63/pradaxa%20capsules-us-pi.pdf
3. 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. doi:10.1016/j.jacc.2013.07.104
4. Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385(9984):2288-2295. doi:10.1016/S0140-6736(14)61943-7
5. New Oral Anticoagulants Pharmacokinetics, Pharmacodynamics, and Exposure- Response. Public Workshop - In Vitro Diagnostic Testing for Direct Oral Anticoagulants, October 26, 2015. http://wayback.archive-it.org/7993/20170113121529/http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM473317.pdf. Accessed December 20, 2022.
6. Eliquis prescribing information. Accessed December 20, 2022. https://packageinserts.bms.com/pi/pi_eliquis.pdf
7. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039
8. European Medicine Agency (2018) Eliquis: EPAR-product information. Accessed December 20, 2022. https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdf
9. Rocca B, Fox KAA, Ajjan RA, et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J. 2018;39(19):1672-1686f. doi:10.1093/eurheartj/ehy066
10. The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med. 2013;369(15):1406-1415. doi:10.1056/NEJMoa1306638
11. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907
12. Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol. 2014;63(20):2141-2147. doi:10.1016/j.jacc.2014.02.549
13. Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015;36(20):1264-1272. doi:10.1093/eurheartj/ehu463
14. Bahit MC, Lopes RD, Wojdyla DM, et al. Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation. Heart. 2017;103(8):623-628. doi:10.1136/heartjnl-2016-309901
15. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, 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
16. Baruch L, Sherman O, Otero Mostacero D. Abstract 11796: Adequacy of Blood Concentration of Direct Oral Anticoagulants in Obese Patients and Their Impact on Clinical Care. Circulation. 2018;138(Suppl_1):A11796-A11796.
17. Sukumar S, Gulilat M, Linton B, et al. Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation. J Am Geriatr Soc. 2019;67(9):1902-1906. doi:10.1111/jgs.15982
18. 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. doi:10.1016/j.amjmed.2021.06.003
19. European Medicine Agency (2021) Xarelto: EPAR-product information. https://www.ema.europa.eu/en/documents/product-information/xarelto-epar-product-information_en.pdf. Accessed December 20, 2022
20. Sherman O, Otero D, Baruch L. Appropriateness of blood concentrations of direct oral anticoagulants in patients at high risk of under or over exposure. In: Journal of Thrombosis and Thrombolysis. Vol 47. SPRINGER VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, Netherlands; 2019:611-612.
21. Baruch L, Sherman O, Otero D, Lopez Loyo PD. Abstract 10877: Impact of Blood Concentration of the Direct Oral Anticoagulant Apixaban on Clinical Care of Nonagenarians and the Very Old. Circulation. 2019;140(Suppl_1):A10877-A10877.
22. Xarelto prescribing information. Accessed December 20, 2022. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf. Accessed December 20, 2022
23. Savaysa prescribing information. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Savaysa&inline=true. Accessed December 20, 2022.
24. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. doi:10.1056/NEJMoa1302507
25. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638
26. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. doi:10.1056/NEJMoa1007903
27. EINSTEIN–PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. doi:10.1056/NEJMoa1113572
28. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561
29. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. doi:10.1056/NEJMoa0906598
30. 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. doi:10.1016/S0140-6736(13)62343-0
31. Abstract 11900: Should Venous Thromboembolism Patients Treated With DOACs Be Dose Adjusted Like Patients With Atrial Fibrillation: Lessons From Apixaban | Circulation. Accessed December 20, 2022. https://www-ahajournals-org.eresources.mssm.edu/doi/abs/10.1161/circ.146.suppl_1.11900
32. 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. doi:10.7326/0003-4819-146-12-200706190-00007