Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

Abstract

Rivaroxaban is an oral, direct factor Xa inhibitor for the management of thromboembolic disorders. Despite its short half-life, the ability to reverse rivaroxaban anticoagulation could be beneficial in life-threatening emergencies. The potential of prothrombin complex concentrate (PCC; Beriplex®), activated PCC (aPCC; FEIBA®) or recombinant activated factor VII (rFVIIa; NovoSeven®) to reverse rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous rivaroxaban (2 mg/kg) received intravenous rFVIIa (100/400 μg/kg), PCC (25/50 U/kg) or aPCC (50/100 U/kg) after initiation of bleeding. Clotting times and bleeding times (BTs) were recorded. Rivaroxaban was administered as an intravenous 0.6 mg/kg bolus followed by continuous 0.6 mg/kg/hour infusion in baboons. Animals received intravenous aPCC 50 U/kg (2 U/kg/minute) or rFVIIa 210 μg/kg. BT and clotting parameters were measured. In rats pretreated with high-dose rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIIa 400 μg/kg significantly reduced BT vs rivaroxaban alone (5.4 ± 1.4-fold to 1.5 ± 0.4-fold [p<0.05]; 3.0 ± 0.4-fold to 1.4 ± 0.1-fold [p<0.001]; and 3.5 ± 0.7-fold to 1.7 ± 0.2-fold [p<0.01] vs baseline, respectively). In baboons pre-infused with rivaroxaban and then given aPCC, BT increased by 2.0 ± 0.2-fold and aPCC returned BT to baseline for the duration of its infusion. rFVIIa reduced BT from 2.5 ± 0.3-fold over baseline to 1.7 ± 0.3-fold over baseline. Prolongation of prothrombin time was reduced by PCC, aPCC and rFVIIa in both species. Rivaroxaban reduced thrombin-antithrombin levels; application of PCC and aPCC, but not rFVIIa, increased these levels. In conclusion, PCC, aPCC or rFVIIa have the potential to reverse the anticoagulant and anti-haemostatic effects of rivaroxaban.

Global assays and the management of oral anticoagulation

“…In rivaroxaban-anticoagulated human volunteers, e.g., the PT normalized completely upon treatment with PCC [106]. In contrast, PT correction was only partial in rivaroxaban-anticoagulated animals receiving PCC [107,108]. In PT, extent of reversal is dependent on NOAC concentration, NOAC type, PCC dose and used thromboplastin reagent [32,68].…”

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates

“…The efficacy of recombinant factor VIIa and prothrombin complex concentrates and activated prothrombin concentrates on bleeding was evaluated in rats only. 48 …”

Antidotes for Novel Oral Anticoagulants

“…Reduced tail bleeding time but not blood loss 25,29 Improvement in exogenous thrombin potential and lag time 27,30 rFVIIa Failed to correct abnormal thrombin generation 40 Reduced tail bleeding time but not blood loss 25,29 Improvement in exogenous thrombin potential and lag time 27,30 Apixaban PCC Improved thrombin generation 31 Improved laboratory parameters but no effect on blood loss 32 No evidence aPCC Improved thrombin generation, clotting time, and clot formation time 31 No evidence No evidence rFVIIa Improved thrombin generation, clotting time, clot formation time, and platelet deposition 31 Reduced bleeding time but no effect on blood loss in rabbits 32 No evidence Rivaroxaban PCC Demonstrated some improvement in PT, clotting time, and thrombin potential but not as effective as aPCC or rFVIIa. 33 Different studies demonstrated no change 34 or only improvement in thrombin generation 35 Reduced PT and bleeding time in rats and baboons 36 Improvement in laboratory parameters including PT and thrombin potential 26,27 Four factor concentrate reduces the PT >3 factor but 3 factor improves thrombin generation more …”