What recommendations are available for laboratory monitoring of direct oral anticoagulants (DOAC)?

Direct oral anticoagulants (DOACs) are a newer class of medications consisting of the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, and betrixaban.^1,2 The first DOAC, dabigatran, was approved by the Food and Drug Administration (FDA) in 2010. Prior to dabigatran’s approval, warfarin, a vitamin K antagonist, was the only oral anticoagulant on the market. Warfarin is associated with significant food and drug interactions and dosing is highly variable. Because of this, frequent laboratory monitoring is required to ensure optimal dosing. In contrast, DOACs have predictable pharmacokinetics and pharmacodynamics, allowing them to be given at a fixed dose without routine therapeutic monitoring.³ In clinical trials, fixed dose DOACs showed noninferior efficacy compared to dose-adjusted warfarin, with significantly less bleeding.¹ As a result, DOACs have become a viable and more convenient alternative to warfarin in numerous clinical scenarios. The concentration of DOACs varies widely between patients, indicating a potential need for monitoring of anticoagulant effects.⁴ Additionally, suboptimal drug levels may lead to adverse events and decreased efficacy. Because of this, there may be a desire to monitor DOAC therapy in certain clinical situations.

DOAC laboratory monitoring recommendations and guidelines

No U.S. guidelines provide recommendations on routine DOAC concentration monitoring or indications for monitoring.^5-8 To date, there are no FDA-approved tests for monitoring anticoagulant effects of DOACs; although, several qualitative and quantitative tests have utility in monitoring levels. The International Council for Standardization in Haematology (ICSH) published recommendations for laboratory monitoring of DOACs in 2018, which discuss potential qualitative and quantitative methods for laboratory monitoring.⁹ The ICSH does not make any recommendations regarding appropriateness or indications for monitoring, but instead focuses on performing and interpreting assays. According to the prescribing information for DOACs, laboratory monitoring is not recommended because there is significant variability in laboratory changes leading to low utility of results.^10-14 Of note, the American Heart Association, American College of Cardiology (ACC), and Heart Rhythm Society recommend routine monitoring of renal and hepatic function for patients taking a DOAC.⁷

Potential indications for monitoring

Several potential indications for monitoring anticoagulant effects have been proposed to ensure safety and efficacy.^3,15 Monitoring could be considered when there is a concern for drug accumulation, such as with renal failure, liver failure, and in elderly patients. This would allow clinicians to adjust dosing to decrease adverse events due to low clearance. In patients with acute thrombosis while on a DOAC, laboratory testing may be useful for determining whether the thrombosis was caused by DOAC failure. Monitoring may play a role in patients with obesity (>120 kg) or low bodyweight (<50 kg), when drug concentrations may be lower or higher than expected, respectively. Additionally, monitoring could be utilized in patients with prior gastrointestinal surgery to ensure adequate absorption. Some laboratory tests could also be utilized to check adherence to medications. Drug interactions have been proposed as another indication for monitoring. Laboratory monitoring may provide useful information during emergencies, such as trauma, overdose, bleeding, and prior to urgent procedures and surgeries. Laboratory results could enable clinicians to make informed decisions about administering reversal agents.

Timing of DOAC levels

When monitoring DOAC levels for anticoagulant effects, the timing of the last dose should be taken into consideration.¹⁶ This is a notable difference compared to warfarin monitoring of the international normalized ratio (INR). Both peak and trough levels may have utility in monitoring, depending on the clinical scenario. In general, trough levels should be utilized to evaluate clearance, such as in the case of elderly patients, renal failure, and liver failure.^9,15 Peak levels are optimal to confirm absorption. A level can be obtained at any time point in an emergency setting or when assessing adherence; however, the time since last dose should ideally be recorded. Table 1 outlines the timing of the peak and trough blood concentrations for each DOAC.

Qualitative coagulation assays

Direct oral anticoagulants affect the results of common coagulation panels, such as activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT).^3,8,9,15 As a result, these laboratory parameters have the potential to qualitatively monitor DOAC levels. These coagulation panels are widely available and fast. Qualitative tests are not sensitive or specific and do not reflect a dose-response relationship. The ICSH recommendations note that PT and aPTT are not reliable to detect the presence of all DOACs, and they should not be utilized to quantify DOAC concentrations. Thrombin time may be useful for detecting dabigatran levels; however, it is not sensitive to factor Xa inhibitors. The reagents used when performing these tests can affect the results, and sensitive reagents are required to detect changes. Qualitative tests may be useful for gauging whether a patient has any effects of anticoagulation, such as in the cases of checking adherence or emergencies. The 2017 ACC consensus statement on the management of bleeding in the setting of anticoagulation states that a PT and aPTT should be obtained in all patients; however, they note significant limitations with available tests in monitoring DOACs.¹⁷ Table 2 outlines common laboratory changes with each DOAC and potential interpretations of those tests, as outlined by both the ACC and ICSH.

Quantitative assays

Several quantitative tests may be useful in determining the anticoagulant effect of DOACs by measuring the plasma drug concentration.^8,9 There are a variety of laboratory monitoring assays that can be used including the liquid chromatography-mass spectrometry/mass spectrometry (LCMS/MS). Anti-factor Xa levels can be used for factor Xa inhibitors, and dilute thrombin time (dTT), ecarin chromogenic assay (ECA), and ecarin clotting time (ECT) can be used for dabigatran. These tests may not be as readily available within institutions and have a longer turnaround time than quantitative tests. Concentration levels are estimated to vary by approximately 30 to 40% between patients on rivaroxaban, and 30% with apixaban and dabigatran. The variability may limit the use of levels for monitoring.¹⁵ Additionally, quantitative tests lack a standardized therapeutic range, and studies have yet to show a correlation between DOAC level and clinical outcomes. Expected peak and trough levels have been extrapolated from available clinical data, providing a reference for interpretation of laboratory results.⁹ Information on betrixaban levels is limited, since it was recently approved in 2017.¹⁸ Table 3 presents the expected peak and trough DOAC concentrations outlined in the ICSH guideline.

The ICSH recommends the use of trough drug level assessment, if nonemergent testing is necessary.⁹ Liquid chromatography-mass spectrometry/mass spectrometry is considered the gold-standard for measuring DOAC concentrations. Drug-calibrated anti-factor Xa, dTT, ECA, and ETT are comparable to LCMS/MS and can be considered for quantification of drug levels. The ACC notes that the anti-factor Xa assay can be utilized as a quantitative test if it is calibrated with low molecular weight heparin.¹⁷ If this is the case, a lack of anti-Xa activity would indicate that DOAC levels are not likely to contribute to bleeding or surgical risk.

Conclusion

One advantage of DOAC use over warfarin is the predictable pharmacokinetic/pharmacodynamic profile, which mitigates the need for frequent monitoring to guide dosing.¹ Fixed-dose DOACs have similar efficacy and decreased bleeding compared to dose-adjusted warfarin. Because of this, routine monitoring of DOAC concentrations is not recommended by guidelines at this time.^5-8 Monitoring of drug levels has been suggested for certain clinical scenarios, given the wide variability in drug level concentrations; however, no clinical studies have linked DOAC levels or monitoring with clinical outcomes.^3,4 The ICSH issued recommendations to guide laboratory assessment of DOAC levels, outlining the use and interpretation of multiple quantitative and qualitative assays.⁹ Although there are no FDA-approved DOAC concentration assays or a validated therapeutic range, ICSH provides ranges for expected peak and trough levels in the event that monitoring is desired.

References

1. Weitz J. Antiplatelet, anticoagulant, and fibrinolytic drugs. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill; 2018: chap 114. Accessed June 22^nd, 2020. https://accessmedicine.mhmedical.com/content.aspx?sectionid=192018816&bookid=2129#192019037
2. Gosselin RC, Adcock DM, Douxfils J. An update on laboratory assessment for direct oral anticoagulants (DOACs). Int J Lab Hematol. 2019;41 suppl 1:33-39. doi: 10.1111/ijlh.12992
3. Conway SE, Hwang AY, Ponte CD, Gums JG. Laboratory and clinical monitoring of direct acting oral anticoagulants: What clinicians need to know. Pharmacotherapy. 2017;37(2):236-248. doi: 10.1002/phar.1884
4. 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. doi: 10.1055/a-1113-0655
5. Lip GYH, Banerjee D, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST Guideline and Expert Panel report. Chest. 2018;154(5):1121-1201. doi: 10.1016/j.chest.2018.07.040.
6. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026
7. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation. 2019;140(2):e125-e151. doi: 10.1161/CIR. 0000000000000665
8. Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: A practical guide to common challenges. J Am Heart Assoc. Published online June 15, 2020. doi: 10.1161/JAHA.120.017559
9. 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(03):437-450. doi: 10.1055/s-0038-1627480
10. Dabigatran. Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc.; 2019.
11. Eliquis. Prescribing information. Bristol-Myers Squibb; 2019.
12. Xarelto. Prescribing information. Janssen Pharmaceuticals, Inc.; 2020.
13. Savaysa. Prescribing information. Daiichi Sankyo Inc.; 2020.
14. Bevyxxa. Prescribing information. Portola Pharmaceuticals, Inc.; 2019.
15. Patel JP, Byrne RA, Patel RK, Arya R. Progress in the monitoring of direct oral anticoagulant therapy. Br J Haematol. 2019;184(6):912-924. doi: 10.1111/bjh.15756
16. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17(10):1467-1507. doi: 10.1093/europace/euv309
17. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. doi: 10.1016/j.jacc.2017.09.1085
18. Siriez R, Evrard J, Dogne JM, et al. Betrixaban: Impact on routine and specific coagulation assays – a practical laboratory guide. Thromb Haemost. 2018;118(7):1203-1214. doi: 10.1055/s-0038-1657772

Prepared by:
Amanda Gerberich, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2020

The information presented is current as June 23, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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