Abstract
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.