Laboratory Measurement of the Anticoagulant Activity of the Non–Vitamin K Oral Anticoagulants

Abstract

Background The target-specific oral anticoagulant agents (TSOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. Objectives This study’s objective is to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. Methods We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Results We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 0.92–0.99) and ecarin-based assays (R2 0.92–1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. In terms of rivaroxaban and apixaban, anti-Xa activity is linear (R2 0.89–1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Conclusions Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in TSOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

“…Testy czynności układu krzepnięcia nie dostarczają zbyt wielu informacji u pacjentów otrzymujących NOAC, z wyjątkiem APTT w przypadku dabigatranu. Istnieją jednak bardziej swoiste testy układu krzepnięcia, takie jak czas trombinowy w rozcieńczonym osoczu (Hemoclot) w odniesieniu do dabigatranu oraz kalibrowane ilościowe oznaczenia czynnika Xa w przypadku inhibitorów czynnika Xa [503]. Te testy nie zawsze są jednak łatwo dostępne i często nie są potrzebne, gdy leczy się krwawienie [504].…”

Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment

“…The correlation between dabigatran and the APTT is curvilinear. Linear dose response is followed by flattening at about 300 ng/mL [62]. The percentage of normal APTT samples with dabigatran concentrations of 40-160 ng/mL may reach 26% [58].…”

“…APTT reagents are much more sensitive to rivaroxaban and edoxaban than to apixaban [52]. Clotting time of apixaban enriched (100 ng/mL) samples was prolonged only 1.1 times compared with the control, when measured using 10 different APTT reagents [62]. Double CT was obtained at rivaroxaban concentrations and ranged from 330 to 637 ng/mL depending on the reagent [56].…”

“…The presence of dabigatran in plasma results in the prolongation of the APTT in a concentration-and a reagent-dependent manner [60,61]. Samples containing dabigatran in the amount of 120 ng/mL tested using different APTT reagents may give results from 26 to 92 s [62]. The correlation between dabigatran and the APTT is curvilinear.…”

Measuring and Reversing the Effect of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs)

“…Activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of the anticoagulant activity, because dabigatran has prolonged the aPTT in a concentration-dependent manner in both ex-vivo and in-vitro studies. 6 However, it has been shown to be less sensitive at supratherapeutic levels of dabigatran 7 and dependent on the reagents used, 8 suggesting that each laboratory should perform dose-response studies to determine the sensitivity of their local aPTT method for dabigatran. Prothrombin time (PT/INR) was found to be less sensitive than other assays and cannot be recommended.…”