Testa S, Paoletti O, Legnani C, et al.
Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants.
J Thromb Haemost.
2018;16:842-848.

Direct oral anticoagulants (DOACs) are administered in fixed doses without routine anticoagulant monitoring. There may be an occasional reason to check peak and/or trough levels in an individual patient to determine whether a patient is in the expected therapeutic range, sub-, or supratherapeutic (Table).1  A variety of expected on-therapy peak and trough drug level ranges have been published.2  Additionally, clinical laboratories performing DOAC drug level testing might list expected values in the explanatory comments of their reports. These ranges come from various populations (healthy volunteers, patients, or a mixture of both — scientifically not quite accurate, yet simple and practically presented in a summarizing peak/trough table2 ). All these values provide a rough guidance as to what drug levels to expect in patients on a DOAC.

Table. Possible Reasons for Direct Oral Anticoagulant (DOAC) Level Testing in Clinical Practice

Table. Possible Reasons for Direct Oral Anticoagulant (DOAC) Level Testing in Clinical Practice
1. Unexpected bleeding on a DOAC 
2. New thromboembolic event on a DOAC 
3. Suspicion for DOAC overdose 
4. Suspicion for non-adherence 
5. Extreme obesity or underweight5  
6. Status post bariatric surgery or upper intestinal tract resection surgery6  
7. Concomitant therapy with a drug that may signficantly affect DOAC pharmacokinetics 
8. Assessment prior to major surgery in patient with recent DOAC intake or signficantly impaired renal function 
9. Assessment of reversal of anticoagulation 
10. Athlete on long-term anticoagulation wishing to engage in contact sports7  
1. Unexpected bleeding on a DOAC 
2. New thromboembolic event on a DOAC 
3. Suspicion for DOAC overdose 
4. Suspicion for non-adherence 
5. Extreme obesity or underweight5  
6. Status post bariatric surgery or upper intestinal tract resection surgery6  
7. Concomitant therapy with a drug that may signficantly affect DOAC pharmacokinetics 
8. Assessment prior to major surgery in patient with recent DOAC intake or signficantly impaired renal function 
9. Assessment of reversal of anticoagulation 
10. Athlete on long-term anticoagulation wishing to engage in contact sports7  

While only limited data have been published as to whether peak or trough DOAC plasma levels correlate with bleeding and thrombotic complications, it has been shown that trough levels, at least of dabigatran and edoxaban, correlate with hemorrhagic and thrombotic complications.3,4  It is therefore enticing to think that adjustment of DOAC dosing in patients who have DOAC drug levels that are significantly outside the expected range might lead to better clinical outcomes such as avoidance of major bleeding and thrombotic events. However, dose adjustment studies addressing this issue have not been performed.

Given the limited available data correlating DOAC plasma levels with bleeding and thrombotic events, additional studies investigating such an association are interesting and useful and could lead to a better understanding as to which patient on a DOAC might bleed or develop thrombosis.

In this study, the researchers observed 565 consecutive patients with atrial fibrillation (AF) newly started on a DOAC. They performed DOAC-specific measurements. These included diluted thrombin time or anti-IIa level calibrated for dabigatran and anti-Xa level calibrated for rivaroxaban or apixaban, at trough (C-trough) at steady state within 15 to 25 days of starting treatment. For each DOAC, the C-trough range from the limit of quantification to the highest value was subdivided into four equal classes, and results were attributed to these quartiles. Thromboembolic complications occurring during one year of follow-up were recorded.

The main finding was that the incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest quartile was 2.4 percent and in the remaining three groups, 0 percent. The patients with thrombotic complications also had a higher mean CHADS2-VASc score than the total patient population (5.3 [95% CI, 4.3-6.3] vs. 3.0 [95% CI, 2.9-3.1]). Thrombotic events occurred only in DOAC-treated AF patients who had low plasma trough levels with a relatively high CHADS2-VASc score.

This publication does not have any impact on my current clinical practice. However, this type of study and future dose adjustment studies may eventually allow us to identify patients at high risk for DOAC-associated adverse outcomes in whom DOAC-level driven individualization of dosing might allow safer and more effective use of the DOACs.

1.
Baglin T, Hillarp A, Tripodi A, et al.
Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the subcommittee on control of anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis.
J Thromb Haemost.
2013; doi: 10.1111/jth.12149. [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pubmed/23347120
2.
Samuelson BT, Cuker A, Siegal DM, et al.
Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A Systematic Review.
Chest.
2017;151:127-138.
https://www.ncbi.nlm.nih.gov/pubmed/27637548
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;63:321-328.
https://www.ncbi.nlm.nih.gov/pubmed/24076487
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;385:2288-2295.
https://www.ncbi.nlm.nih.gov/pubmed/25769361
5.
Martin K, Beyer-Westendorf J, Davidson BL, et al.
Use of direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH.
J Thromb Haemost.
2016;14:1308-1313.
https://www.ncbi.nlm.nih.gov/pubmed/27299806
6.
Moll S, Martin KA.
Anticoagulant drug choice in patients who have had bariatric surgery – presently, DOACs are not the preferred choice.
Thromb Res.
2018;163:196-199.
https://www.ncbi.nlm.nih.gov/pubmed/29395241
7.
Berkowitz JN, Moll S.
Athletes and blood clots: individualized, intermittent anticoagulation management.
J Thromb Haemost.
2017;15:1051-1054.
https://www.ncbi.nlm.nih.gov/pubmed/28301715

Competing Interests

Dr. Moll indicated no relevant conflicts of interest.