Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

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 con: centrate (PCC; Beriplex (R)), activated PCC (aPCC; FEIBA (R)) or recombinant activated factor VII (rFVIIa; NovoSeven (R)) to reverse rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous rivaroxaban (2 mg/kg) received intravenous rFVIla (100/400 mu g/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 rFVIla 210 pg/kg. BT and clotting parameters were measured. In rats pre-treated with high-dose rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIla 400 pg/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. rFVIla 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 rFVIla in I both species. Rivaroxaban reduced thrombin-antithrombin levels; application of PCC and aPCC, but not rFVI la, increased these levels. In conclusion, PCC, aPCC or rFVIla have the potential to reverse the anticoagulant and anti-haemostatic effects of rivaroxaban.