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

AimsThe aim of the present study was to demonstrate evidence of reduced thrombin generation at the trough plasma rivaroxaban concentration. MethodsA single-centre, prospective, nonrandomized, drug-intervention, self-controlled study was conducted in 51 anticoagulation therapy-naive 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 4weeks of rivaroxaban treatment and compared with baseline. ResultsPlasma 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 23.6ng 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 (+0.59s, P < 0.0001). TFPI increased from baseline to the trough steady state in the first to third quartile groups (+0.79pg 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. ConclusionsResidual plasma rivaroxaban at the trough steady state may explain the antithrombin effect of rivaroxaban in patients with nonvalvular atrial fibrillation.