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Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH12-12-0907
Issue: 2013: 110/1 (July) pp. 1-204
Pages: 162-172

Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

See also Insight by Eikelboom, Weitz

Online Supplementary Material

E. Perzborn (1), A. Gruber (2), H. Tinel (1), U. M. Marzec (2), U. Buetehorn (3), A. Buchmueller (1), S. Heitmeier (1), V. Laux (1)

(1) Global Drug Discovery, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany; (2) Department of Biomedical Engineering, Oregon Health and Science University, School of Medicine, Portland, Oregon, USA; (3) Bioanalytics, Bayer HealthCare Pharmaceuticals AG, Wuppertal, Germany

Keywords

recombinant factor VIIa, rivaroxaban, rats, Baboons, prothrombin complex concentrate

Summary

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.

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