Factor Xa inhibition by rivaroxaban in the trough steady state can significantly reduce thrombin generation

• Published in: British journal of clinical pharmacology 2018-01, Vol.84 (1), p.79-87
• Main Authors: Horinaka, Shigeo, Sugawara, Rie, Yonezawa, Yutaka, Ishimitsu, Toshihiko
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Atrial Fibrillation - blood; Atrial Fibrillation - drug therapy; Blood Coagulation Tests; Chromatography, High Pressure Liquid - methods; Factor Xa - metabolism; Factor Xa Inhibitors - blood; Factor Xa Inhibitors - pharmacology; Factor Xa Inhibitors - therapeutic use; Female; Humans; Lipoproteins - metabolism; Male; Middle Aged; nonvalvular atrial fibrillation; Pharmacokinetic Dynamic Relationships; plasma concentration; Prospective Studies; rivaroxaban; Rivaroxaban - blood; Rivaroxaban - pharmacology; Rivaroxaban - therapeutic use; Tandem Mass Spectrometry - methods; Thrombin - metabolism; tissue factor pathway inhibitor; trough steady state
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13429

Aims The aim of the present study was to demonstrate evidence of reduced thrombin generation at the trough plasma rivaroxaban concentration. Methods A single‐centre, prospective, nonrandomized, drug‐intervention, self‐controlled study was conducted in 51 anticoagulation therapy‐naïve patients with nonvalvular atrial fibrillation. Plasma rivaroxaban concentration was measured by liquid chromatography tandem mass spectrometry (LC–MS/MS) and the anti‐factor Xa chromogenic assay. Partial thrombin time (PT), protein C activity, and protein S antigen, prothrombin fragment 1 + 2 (F1 + 2), D‐dimer, thrombomodulin (TM), thrombin–antithrombin complex (TAT), plasminogen activator inhibitor‐1 (PAI‐1) and tissue factor pathway inhibitor (TFPI) levels were also measured at the trough steady state after 4 weeks of rivaroxaban treatment and compared with baseline. Results Plasma concentrations obtained by the LC–MS/MS and anti‐Xa assays were correlated (r = 0.841, P < 0.001). The mean concentration of rivaroxaban at the trough steady state was 23.6 ng ml–1, at which F1 + 2, TAT and D‐dimer had decreased from the baseline values (P < 0.0001, P = 0.029 and P < 0.005, respectively). PT was prolonged (+0.59 s, P < 0.0001). TFPI increased from baseline to the trough steady state in the first to third quartile groups (+0.79 pg ml–1, P = 0.048). By contrast, PAI‐1, protein C activity, protein S antigen and TM remained within the normal range at the trough steady state. Conclusions Residual plasma rivaroxaban at the trough steady state may explain the antithrombin effect of rivaroxaban in patients with nonvalvular atrial fibrillation. What is Already Known about this Subject The preventive effect of once‐daily rivaroxaban, which has a short half‐life, on stroke and/or systemic embolism is equal or superior to that of warfarin. What this Study Adds Residual plasma rivaroxaban at the trough steady state can be traced. Factor Xa inhibition by rivaroxaban in the trough steady state can downregulate and reduce thrombin generation. Rivaroxaban's antithrombin effect at the trough steady state may play a role in the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation.