Plasma levels of direct Xa inhibitors apixaban and rivaroxaban in patients with venous thromboembolism in clinical practice

Abstract

Direct oral anticoagulants (DOACs) are used as a more effective and safe alternative to vitamin K antagonists, with a simpler dosing strategy and a stable pharmacokinetic profile. However, existing data on individual variations in DOAC plasma levels suggest that determining on-treatment levels may be beneficial in certain clinical situations. This study assesses the interindividual DOAC variations and determines acceptable therapeutic ranges of plasma levels of apixaban and rivaroxaban in patients with venous thromboembolism (VTE), including a subgroup with inherited thrombophilia (THRPH). Drug levels were measured by anti-Xa chromogenic assays, performed with Innovance heparin tests (Siemens) using rivaroxaban- and apixaban-specific Biophen Hyphen calibrators and controls on CS 2500i coagulometer. The analysis included 198 patients with deep vein thrombosis and/or pulmonary embolism, 106 received apixaban 2 x 5 mg/d and 92 received rivaroxaban 20 mg/OD. The ranges (median, 5th-95th percentile) of rivaroxaban  peak levels in VTE group (n = 92) was 234 ng/ml (102-388) and did not differ from plasma levels in VTE with THRPH (n = 27) 220 ng/ml (85-415), p = 0.488. Observed ranges of apixaban trough levels were similar in VTE group 76 ng/ml (32–148) vs 72 ng/ml (44-135) in subgroup VTE with THRPH. A moderate correlation was found between apixaban levels and patient age (r = 0.428, p < 0.001), while the correlation between rivaroxaban levels and age was weaker (r = 0.184, p = 0.045). In the VTE-THRPH subgroup, a moderate inverse relationship was observed between apixaban levels and patient weight (r = -0.530, p = 0.016). The coefficient of variation for rivaroxaban levels in the VTE-THRPH group was significantly higher (48%) compared to other groups. Due to plasma levels falling outside the expected therapeutic range in 12% (23/198) of patients, individualized treatment adjustments were made, including switching to another DOAC or VKA or modifying the dosage. Additionally, plasma levels below the 5th percentile of the defined ranges were observed in 5 of 198 patients receiving concomitant carbamazepine or valproate therapy. In conclusion, anti-Xa measurement of apixaban and rivaroxaban provided an opportunity to individualize anticoagulant therapy.

Keywords

• anti-Xa levels
• apixaban
• rivaroxaban
• interindivi