An Ex Vivo Analysis of Thrombin Generation and Thromboelastometry in Patients Undergoing Treatment with Rivaroxaban Demonstrates Sustained Anticoagulant Effect and High Inter-Individual Variability

Abstract

Background : Rivaroxaban, 20 mg orally administered once daily, is widely used for secondary prevention of venous thromboembolism (VTE) without the need for routine laboratory monitoring. It is licensed for the prevention of VTE after major orthopedic surgery, for the treatment of acute symptomatic VTE, the secondary prevention of VTE and for prevention of stroke in patients with non-valvular atrial fibrillation. Rivaroxaban selectively and competitively inhibits free factor Xa (FXa) and prothrombinase/clot-associated FXa through reversible interactions thereby inhibiting thrombin generation and decreasing fibrin clot formation. The need of laboratory evaluation of rivaroxaban is actually questioned.Aim : In patients treated for secondary prevention of VTE, we evaluated ex vivo the anticoagulant potency of rivaroxaban treatment at different times after drug intake.Methods : 97 patients (39 males, 58 females; median age: 59 years) with idiopathic VTE were treated with rivaroxaban (20 mg/day) for a period longer than 6 months and compared to 30 controls age and sex-matched. Rivaroxaban concentrations (STA®-Liquid Anti-Xa), thrombin generation (PPP-reagent 5 pM TF; calibrated automated thrombogram, Stago France) and whole blood thromboelastometry (5 pM tissue factor; ROTEM® Werfen) were assessed. The interval between drug intake and blood sampling was registered.Results : Treatment with rivaroxaban significantly inhibited thrombin generation (TG) and prolonged clotting time (CT): 93% of patients had TG inferior to the lower normal limit and 77% had CT longer than the upper normal limit. This effect in both assays, was not correlated to its plasma concentrations, it was significant from the 1st hour after drug intake and persisted at similar levels during the daily therapeutic cycle even at low concentrations (30 ng/ml). Rivaroxaban had no effect on clot firmness. The inter-individual coefficient of variation of rivaroxaban concentrations and TG/ROTEM alterations after drug intake ranged from 50% to 100%.Conclusion : Once daily administration of rivaroxaban induces sustained daily anticoagulant effect, detected by TG and ROTEM assays, with no significant changes related to drug concentration reduction. This profile could explain the wide therapeutic window and the favorable benefit risk ratio of the treatment with rivaroxaban. Due to the high variability the identification of patients with extreme values of TG could be useful strategy for treatment optimization on individual basis. DisclosuresNo relevant conflicts of interest to declare.