Potential of Activated Prothrombin Complex Concentrate and Activated Factor VII to Reverse the Anticoagulant Effects of Rivaroxaban in Primates

Abstract Rivaroxaban is an oral, direct Factor Xa (FXa) inhibitor that has been recommended for approval by the Committee for Medicinal Products for Human Use for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Because bleeding is a potential side-effect of accidental rivaroxaban overdose, we evaluated whether activated prothrombin complex concentrate (APCC, FEIBA®) and recombinant activated Factor VII (rFVIIa, NovoSeven®) administration could mitigate the antihemostatic effects of high-dose rivaroxaban in juvenile male baboons. Pharmacologic impairment of hemostasis (3- to 4-fold increase in prothrombin time PT from baseline and ≥2-fold increase in template bleeding time BT) was achieved by an intravenous (i.v.) bolus of rivaroxaban (0.6 mg/kg) followed by continuous infusion (0.6 mg/kg/h) for 60 minutes. At steady-state anticoagulation (30 minutes from bolus), one group of anticoagulated baboons (n=7) received APCC (50 U/kg, over 25 minutes). A second group (n=7) received an i.v. bolus dose of rFVIIa (210 μg/kg) 30 minutes after the start of anticoagulation. Reversal of the antihemostatic effects of supratherapeutic doses of rivaroxaban by APCC and rFVIIa was assessed by measurement of BT and clotting times. In the APCC group, high-dose rivaroxaban prolonged BT to 202% (95% CI±21%; p<0.001) of baseline and PT by 3-fold (Table). On completion of APCC infusion, BT returned to baseline and PT was reduced. In the rFVIIa group, rivaroxaban prolonged BT to 254% (95% CI±30%; p<0.05). Infusion of rFVIIa reduced BT by 34%, and PT was also shortened. Circulating thrombin–antithrombin complex (TAT) levels decreased during rivaroxaban infusion, and this decrease did not change significantly after rFVIIa bolus administration. However, APCC increased baseline plasma TAT levels, suggesting a systemic hypercoagulation. We conclude that administration of APCC or rVIIa can rapidly attenuate hemostasis impairment after rivaroxaban overdose in baboons, thus providing potential antidotes during bleeding emergencies. Table. The effect of activated prothrombin complex concentrate (APCC) and recombinant activated Factor VII (rFVIIa) on bleeding time (BT), prothrombin time (PT), and thrombin–antithrombin complex concentration (TAT) in baboons anticoagulated with high-dose rivaroxaban (n=7 each). Values are given as mean ± standard deviation Time BT (x-fold change from baseline) PT (x-fold change from baseline) TAT (μg/L) APCC Baseline 1.00 1.00 3.51±0.08 30 minutes after rivaroxaban 2.02±0.56 3.04±0.43 3.01±1.37 At end of APCC infusion 1.02±0.33 2.20±0.29 10.35±1.41 20 minutes after end of APCC infusion 1.65±0.94 2.28±0.29 n.d. rFVIIa Baseline 1.00 1.00 7.35±4.17 30 minutes after rivaroxaban 2.54±0.79 3.17±0.42 2.95±0.79 5 minutes after rFVIIa 1.68±0.80 2.38±0.41 2.58±0.52 30 minutes after rFVIIa 1.96±1.26 2.48±0.49 4.00±1.12