Real-World Assessment of Direct Oral Factor Xa Inhibitors: Dosing Appropriateness, Drug Exposure, and Inter-Platform Comparability of Chromogenic Anti-Xa Assays

Abstract

Background/Objectives: Direct oral factor Xa inhibitors (DOACs) show substantial interindividual exposure variability in real-world practice, yet interpretation of plasma drug concentrations remains challenging because routine monitoring is not standardized. This study evaluated dosing appropriateness, plasma drug exposure measured by chromogenic anti-factor Xa assays, inter-platform comparability, and associations with routine coagulation tests. Methods: This single-center retrospective study included 392 plasma samples from 292 patients with atrial fibrillation treated with apixaban (n = 207), edoxaban (n = 147), or rivaroxaban (n = 38). Post-dose outpatient spot samples were analyzed using Sysmex CS-5100 and CN-6000 analyzers with two chromogenic anti-factor Xa assay systems (BIOPHEN™ DiXaI and BIOPHEN™ Heparin LRT) and drug-specific calibrators. Correlations between routine assays (prothrombin time [PT]/international normalized ratio [INR], activated partial thromboplastin time [aPTT]) and DOAC concentrations, as well as inter-platform agreement, were assessed using Spearman’s rank correlation and Passing-Bablok regression. Dosing appropriateness was determined according to Food and Drug Administration-approved labeling. Results: Overall dosing appropriateness was 69.2% (edoxaban 73.3%, apixaban 70.5%, rivaroxaban 45.5%), whereas inappropriate underdosing was the predominant prescribing pattern (26.9%), particularly among patients without formal dose-reduction criteria. PT/INR demonstrated the strongest correlation with edoxaban concentrations (rs = 0.83, p < 0.001). Inter-analyzer correlation between the CS-5100 and CN-6000 was excellent (r = 0.885–0.996), with LRT reagents providing highly consistent results across platforms. Conclusions: Real-world outpatient DOAC concentrations demonstrated substantial variability and frequent off-label underdosing. Chromogenic anti-factor Xa assays showed strong inter-platform agreement, particularly with LRT reagents, supporting their analytical reliability for laboratory assessment of DOAC exposure. Because exact dosing times were unavailable, these concentrations should be interpreted as heterogeneous spot samples rather than standardized pharmacokinetic reference intervals; these findings may nonetheless support individualized interpretation of outpatient spot sample DOAC concentrations in selected clinical settings.