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

Reversal of drug‐induced anticoagulation: old solutions and new problems

“…A 2008 abstract (never published in full manuscript form) studied the potential for FEIBA or rFVIIa to reverse rivaroxaban in a baboon model. 36 After baseline bleeding time and PT were measured, juvenile baboons (n = 7) were given rivaroxaban over 60 minutes and then given an infusion of FEIBA (50 IU/kg). After giving rivaroxaban, the median bleeding time (relative to baseline) increased to 2.02, and 20 minutes after FEIBA was 1.65.…”

New oral anticoagulants: An emergency department overview

“…29 Reversal of bleeding time and PT in baboons, 210 mcg/kg. 30 240 mcg/kg NovoSeven shortened PT and bleeding time, but did not correct ETP or reduce blood loss in a rabbit model. 26 Activated PCC FEIBA 100 U/kg reduced bleeding time but did not reduce blood loss or correct coagulopathy in a mouse tail injury model.…”

“…FEIBA 50 U/kg dose. 30 Partial correction of ETP with FEIBA 160U/kg. 24 FEIBA 75 U/kg partially corrected TGT parameters in human plasma in vitro.…”

“…29 rFVIIa appears to shorten Xa inhibitor-related prolongation of prothrombin and bleeding times, but might not have an effect on blood loss. 26,30 Overall, rFVIIa appears to have minor activity as a reversal agent, and should only be used when other therapies have failed. The dose required for efficacy (100-8000 mcg/kg) is greatly in excess of the usual therapeutic dosing (30-120 mcg/kg depending on indication).…”

Rivaroxaban: Practical Considerations for Ensuring Safety and Efficacy

“…In a rat model, however, no inhibition of FXa activity was evident after rFVIIa was administered. 65,66 In a rabbit model, rFVIIa administered after rivaroxaban decreased ear bleeding but did not reduce blood loss as compared with rivaroxaban alone. 67 Four-factor PCCs reversed bleeding time and partially reversed PT prolongation induced by high-dose rivaroxaban in rats but did not reduce bleeding in a rabbit model.…”