Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation

Alenka Mavri,Anton Pohanka,Marko Miklič,Lisbeth Söderblom,Nina Vene,Jovan Antovic,Rickard E. Malmström,Mojca Božič-Mijovski

doi:10.1038/s41598-021-93372-9

Abstract

In some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6–8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC–MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC–MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.

Highlights

IntroductionMeasurements of anticoagulant effect of apixaban may be needed
In some clinical situations, measurements of anticoagulant effect of apixaban may be needed
Apixaban concentration determined by LC–MS/MS showed significant correlation with the two different anti-Xa assays performed in two different laboratories (Fig. 1, upper panel), both methods underestimated apixaban concentration as shown by the Bland–Altman plot (Fig. 1, lower panel)

Summary

Introduction

Measurements of anticoagulant effect of apixaban may be needed. That there was a significant intra- and interindividual variability in apixaban trough and peak concentrations. Oral, reversible, and highly selective inhibitor of activated factor X (FXa) that inhibits free and clot-bound FXa, as well as prothrombinase activity, which inhibits clot growth It has been approved for clinical use in several thromboembolic disorders, including reduction of stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary e mbolism. The AVERROES pharmacokinetic substudy demonstrated considerable variability in anti-Xa levels in patients with atrial fibrillation receiving apixaban and found no association between apixaban trough anti-Xa levels and risk of both major bleeding and stroke. Only "expected ranges" for apixaban levels have been reported, while therapeutic ranges have not been defined

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