Plasma concentrations of factor Xa inhibitors and stroke risk in patients with atrial fibrillation

Aim. To determine plasma concentrations of direct oral anticoagulants (DOACs) in patients with ischemic stroke (IS) associated with atrial fibrillation (AF) and to compare them with DOAC levels in patients with AF but without IS receiving similar therapy. Material and methods. A prospective cohort study was conducted at the Vascular Center of S.P. Botkin Moscow City Clinical Hospital from April 2022 to April 2023. The study included 82 patients with cardioembolic stroke on the background of AF (main group) and 130 AF patients without stroke or transient ischemic attack (TIA) (control group). All patients had been receiving DOACs (apixaban or rivaroxaban) for at least 3 months. Diagnostic workup included brain computed tomography, сarotid ultrasound, laboratory tests, and stroke severity assessment by NIH Stroke Scale (NIHSS). Plasma DOAC concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The lower limit of quantification (LLOQ) was 5 ng/mL.
Results. Patients in the main group had significantly more frequent subtherapeutic DOAC concentrations below the LLOQ compared to the control group (52.4% vs. 1.5%, p<0.001). Subgroup analysis revealed that 58.5% of patients on rivaroxaban and 41.4% of patients on apixaban had concentrations below LLOQ, compared to 2.5% and 0% in the control group, respectively (p<0.001 for both). Inappropriately reduced DOAC doses were observed in 45.1% of the primary group versus 19.2% of controls (p<0.001). Stroke severity assessed by NIHSS and mortality did not differ significantly between patients with DOAC concentrations below LLOQ and those with therapeutic levels. Patients with stroke had a higher CHA2DS2-VASc risk score, with a median of 6 points (p<0.001).
Conclusion. A significant proportion of patients with AF and cardioembolic ischemic stroke exhibit plasma concentrations of DOACs below LLOQ, which may contribute to stroke occurrence despite prescribed therapy. These findings emphasize the need to develop clinical criteria for selecting patients who require DOAC concentration monitoring and personalized therapy to reduce the risk of thrombotic events.

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