title: 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.
authors: Global Clinical Development, Cardiovascular Pharmacology, Pharma RD, Bayer HealthCare, Aprather Weg 18a, D-42096 Wuppertal, Germany. elisabeth.perzborn@bayer.com
authors: Elisabeth
authors: E
authors: Perzborn
authors: András
authors: A
authors: Gruber
authors: Hanna
authors: H
authors: Tinel
authors: Ulla M
authors: UM
authors: Marzec
authors: Ulf
authors: U
authors: Buetehorn
authors: Anja
authors: A
authors: Buchmueller
authors: Stefan
authors: S
authors: Heitmeier
authors: Volker
authors: V
authors: Laux
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000008:administration & dosage; D015942:Factor VIIa / Q000008:administration & dosage; D006801:Humans; D008297:Male; D009025:Morpholines / Q000008:administration & dosage*; D011323:Primates; D011517:Prothrombin Time; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage*; D013923:Thromboembolism / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants; D001779:Blood Coagulation Factors; D009025:Morpholines; D011994:Recombinant Proteins; D013876:Thiophenes; C025667:prothrombin complex concentrates; D000069552:Rivaroxaban; C103587:recombinant FVIIa; C065655:anti-inhibitor coagulant complex; D015942:Factor VIIa