Supporting the use of a coagulometric method for rivaroxaban control: a hypothesis-generating study to define the safety cut-offs

AIMS: Although quantitative anti-FXa assays can be used to measure rivaroxaban plasma levels, they are not widely performed or available. We aimed to tentatively determine the cut-off for thromboembolism and bleeding prevention based on the clotting effect of non-rivaroxaban conjugate-activated FX plasma levels in patients with rivaroxaban using a coagulometric method. METHODS AND RESULTS: Rivaroxaban was added in vitro to normal plasma at a range of 0 to 241 μg/L to cover expected peak and trough levels. Rivaroxaban chromogenic (μg/L) and RVV-confirm as a ratio were determined. Patient plasma samples were assayed with the RVV-confirm reagent. The appropriate rivaroxaban plasma concentration to inhibit clotting mechanisms was based on the remaining FXa in plasma, which was expressed as the ratio of patients/normal, R-C. There is a high correlation between R-C in vitro and spiked normal plasma rivaroxaban concentration (R-Square 0.910, linear equation; 0.971 quadratic equation, p < 0.0001 for both) but not with plasma rivaroxaban chromogenic assays. We propose a cut-off R-C value of 1.65 and 4.5 for safety. Based on the proposed therapeutic range, in 158 assays performed in 58 patients, 6.3 % assays were above the level of bleeding tendency at the peak (R-C 5.39 ± 1.01, median 5.13) and 42 % assays were below the prevention cut-off at the trough (R-C 1.31 ± 0.18, median 1.35). CONCLUSIONS: RVVconfirm® is fast and sensitive to measure the effect of rivaroxaban. Clinical studies are needed to establish whether this cut-off is useful for identifying patients at increased risk of hemorrhage or those who exhibit a low level of anticoagulation.