Comparison of prothrombin time tests used in the monitoring of edoxaban and their evaluation as indicators of the reversal effect

Abstract

Clinical demand for the prompt assessment of the activity of direct-acting factor Xa inhibitors in the emergency care setting is increasing. In the present study, we examined whether prothrombin time (PT) tests can serve as a clinically useful indicator of anti-factor Xa activity. In the first series, the in vitro effect of edoxaban on PT was evaluated by spiking human plasma with edoxaban and measuring PT using three different commercial PT tests. In the second series, the reversal effect of prothrombin complex concentrates (PCC) and activated PCC (aPCC) in edoxaban-spiked plasma was evaluated. In the third series, PT of plasma samples from patients administered either 15 or 30 mg/day of edoxaban was assessed, and the results were compared with edoxaban concentrations determined by a calibrated anti-factor Xa activity assay. The spike test revealed that all PT reagents positively correlated with edoxaban. The sensitivity to edoxaban varied among the three reagents and Triniclot(®) Excel S showed the best performance. Prolonged PT by edoxaban was reversed by PCC and aPCC in a dose-dependent manner; however, complete reversal was not achieved. Positive correlation between anti-factor Xa activity and PT was shown in the clinical samples at the edoxaban range from 0 to >300 ng/mL.

Effects of the oral, direct factor Xa inhibitor edoxaban on routine coagulation assays, lupus anticoagulant and anti-Xa assays

“…Thus, examination of the figure illustrating the PT dose-response curves published by Douxfils et al indicates that the edoxaban concentration needed for a doubling of the PT baseline clotting time, according to our definition, would be close to the values we report here. Two other studies have also published PT response curves for edoxaban, without reporting any calculated CT 2 -values, and an examination of the graphs for those PT reagents used in our study it can be concluded that the edoxaban needed for doubling the basal PT clotting time is near what we report [13,16].…”

“…With this knowledge about the inadequate PT and APTT sensitivities for DOACs, it cannot be advised to rely on these assays in the assessment of the anticoagulant effect [12]. However, so far, there are only few reports on the pharmacodynamic profiles of edoxaban [11,[13][14][15][16][17] and only three of these present more extensive results based on in vitro effects on routine and more specialized coagulation assays [11,13,15]. All these studies utilized pooled normal plasma spiked with edoxaban.…”

Determination of edoxaban equivalent concentrations in human plasma by an automated anti-factor Xa chromogenic assay

“…Several in vitro studies have assessed the performance of chromogenic assays designed to measure heparin and anti-FXa chromogenic assays with non-edoxaban-specific calibrators and controls for measuring edoxaban concentrations [19,20]. In a previous in vitro study, chromogenic assays without edoxaban-specific calibrators and controls showed good sensitivity to measuring edoxaban levels in edoxabanspiked plasma [19].…”

“…Clotting assays, such as prothrombin time (PT) and activated partial thromboplastin time (aPTT), are more widely available but are not quantitative and direct, oral FXa inhibitors have variable effects on these standard coagulation tests [11,[16][17][18]. Recent studies have suggested that some PT reagents could be useful to measure edoxaban, however, the impact of edoxaban on PT and aPTT depends on the reagents [19,20].…”

“…When used with appropriate calibrators and controls, anti-FXa assays can accurately quantify plasma concentrations for rivaroxaban and apixaban over a wide concentration range with good intra-and inter-laboratory consistency [17,18,[25][26][27][28][29]. For measuring edoxaban levels, several studies have assessed the performance of chromogenic assays designed to measure heparins or anti-FXa chromogenic assays with non-edoxaban-specific calibrators and controls [19,20]. However, the performances of anti-FXa chromogenic assays with edoxaban-specific calibrators and controls have not been reported.…”