A Study of Serial Monitoring of the Direct Anti-XA Inhibitors: A Lesson of What Test to Order and When to Order It

Abstract

The new direct anti‐Xa inhibitors (DXIs) are a class of anti‐blood‐clotting medication. DXIs do not require routine monitoring. Nonetheless, there is lack of consensus on how to monitor patients on DXIs that are at risk of bleeding or have subtherapeutic drug levels. Herein we present our experience using several methods to monitor rivaroxaban and apixaban in a serial study of compliance. Blood samples were received from 7 patients on rivaroxaban 20 mg once daily and 9 patients on apixaban (8 patients on 5 mg twice daily and 1 patient on 2.5 mg twice a day) enrolled in a randomized 12‐week study in adults diagnosed with ischemic stroke. All patients enrolled were receiving treatment for at least a month. Blood samples were obtained at baseline and weeks 4, 8, and 12. Informed consent was obtained before entering the study. The study was approved by an institutional review board. Rivaroxaban and apixaban levels were measured using two FXa chromogenic assays from Biophen and Stago. We observed a strong correlation between the two chromogenic FXa assays (R2 > 0.9). Using the FXa assay as the reference (gold standard), we then studied the sensitivity of clottable coagulation assays, including prothrombin time (PT), partial thromboplastin time (PTT), and dilute Russell viper venom (DRVVT), to monitor DXIs. PT/PTT was weakly sensitive to rivaroxaban levels. PT was prolonged in 58.8% (10/17) of the results, and PTT was prolonged in 61.1% (11/18) of the results. The sensitivity of PT/PTT to detect apixaban was poor. PT was prolonged in 44.8% (13/29) of the results, and PTT was prolonged in 38.7% (12/31) of the results. We observed a weakly positive linear correlation between prolongation of PT/PTT with increasing rivaroxaban levels (R2 value of 0.41 for PT and 0.37 for PTT), whereas no positive correlation was observed between PT/PTT and apixaban levels (R2 value of 0.01 for PT and 0.05 for PTT). All the samples from patients on rivaroxaban had DRVVT times above the normal range, and only two samples (2/32, 6%) from patients on apixaban had DRVVT results within normal limits. Moreover, DRVVT showed a weakly positive linear correlation for rivaroxaban (R2 = 0.49), yet poor correlation for apixaban (R2 = 0.01). Given the weak linearity of DRVVT with increasing DXI levels, DRVVT should only be used to detect the presence of DXIs with careful attention given to possible interferences such as lupus anticoagulants. Chromogenic FXa assays are more reliable to monitor DXI levels. However, we observed a broad range of DXI levels dependent on the time gap from last dose and also a large intrapatient variability. We recommend that blood samples be drawn at peak intervals and that decisions on adjusting doses be based on serial DXI drug‐level measures at peak time.