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

Summary

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, non-randomised, drug intervention, self-controlled study was conducted in 51 anticoagulation therapy-naïve patients with non-valvular atrial fibrillation. Plasma rivaroxaban concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and 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) were also measured at the trough steady state after 4 weeks of rivaroxaban treatment and compared with baseline.

Results

Plasma concentrations obtained by LC-MS/MS and anti-Xa assay were correlated (r = 0.841, P < 0.001). The mean concentration of rivaroxaban at the trough steady state was 23.6 ng/ml, 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 seconds, P < 0.0001). TFPI increased from baseline to the trough steady state in the first to third quartile groups (+0.79 pg/ml, P = 0.048). In 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 non-valvular atrial fibrillation.

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