How to assess in vivo anticoagulant effect of Rivaroxaban

D. Bertaggia Calderara1, D. Kröll2, C. Gerschheimer1, N. Nicolas1, G. Stirnimann2, L. Alberio1 (1Lausanne, Switzerland, 2Bern, Switzerland)

Antithrombotic treatment
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Rivaroxaban (RVX), an orally active direct FXa inhibitor, does not require monitoring. Nevertheless, in some clinical circumstances it is helpful to estimate its in vivo anticoagulant effect, in order to assess individual bleeding risk, e.g. during pharmacological or surgical interventions. Aim of this study was to assess ex vivo and in vivo anticoagulant effect of RVX in patients undergoing bariatric surgery.

Methods: Blood was collected during 24 hours from patients receiving a single dose of 10 mg RVX before surgery. We determined the anticoagulant effect of various RVX concentrations, in vivo by monitoring thrombin-antithrombin complexes (TAT) and prothrombin fragments 1+2 (F1+2), and ex vivo by thrombin generation assay (CAT) in patients’ platelet poor plasma (PPP), using PPP-reagent normal (5pM tissue factor) and high (20 pM tissue factor).

Results: RVX Cmax was observed 1h after ingestion (120 ng/ml). RVX concentration was stable between 2h and 4h (80-90 ng/ml), decreased between 6h and 8h (from 60 to 50 ng/ml), declined to 30 ng/ml at 12h, and was close to baseline at 24h (15 ng/ml). In vivo: TAT and F1-2 values significantly decreased at Cmax. During RVX plateau (80-90 ng/ml), a further significant decrease for both activation markers was observed. At drug concentrations of 60-50 ng/ml the anticoagulant effect reached a steady state and when RVX concentration dropped below 50 ng/ml TAT and F1+2 significantly increased. Ex vivo: CAT parameters (lag time, time to peak, peak, velocity index) were all statistically significantly altered at every time point except for the peak at 24 hours (reagent PPP high).

Conclusion: The pattern of ex vivo inhibition of thrombin generation (TG) observed with PPP reagent normal or high is very similar. Both reagents show that the thrombin generation profile strongly differs between RVX concentrations of 80-120 ng/ml, 50-60 ng/ml, 30 ng/ml, and 15 ng/ml. For the first time, we demonstrate that in obese individuals the degree of in vivo anticoagulation is not the same as assessed ex vivo by CAT: at concentrations <60 ng/ml, RVX is still able to inhibit TG ex vivo but not in vivo. Our data suggest that a relative inhibition of <60% in velocity index with PPP normal and <30 % with PPP high are the best indicators of a RVX concentration which does not exert an in vivo anticoagulant effect in obese patients.