Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate

Abstract

Background-Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results-In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (nϭ6) or dabigatran 150 mg twice daily (nϭ6) for 2 1 ⁄2 days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8Ϯ1.3 versus 12.3Ϯ0.7 seconds at baseline; PϽ0.001) that was immediately and completely reversed by PCC (12.8Ϯ1.0; PϽ0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51Ϯ22%; baseline, 92Ϯ22%; Pϭ0.002) and normalized with PCC (114Ϯ26%; PϽ0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Conclusion-Prothrombin

Neurosurgery in a patient at peak levels of rivaroxaban: taking into account all factors

“…PCCs were effective in reducing bleeding in animal models of severe trauma during NOAC treatment 12. In healthy volunteers who received rivaroxaban or apixaban, PCCs (50 U/kg) reversed the effects on coagulation tests and biopsy‐induced bleeding 13, 14. Therefore, PCCs are recommended as a prohemostatic agent in patients treated with a factor Xa inhibitor who present with severe or life‐threatening bleeds not responding to conservative measures 15.…”

Selecting antithrombotic therapy for patients with atrial fibrillation

“…The anticoagulant effect of rivaroxaban has been shown to be reversed by prothrombin complex concentrate in vitro; clinical effect has not been demonstrated. 58 PRT06445 (andexanet alfa), a recombinant protein antidote specific for factor Xa inhibitors, has entered clinical studies, with a phase 2 trial reporting high reversing capability for apixaban. 59 …”

Gestion péri-opératoire des patients traités par antithrombotiques en chirurgie orale. Argumentaire

“…En l'absence d'antidote spécifique, les réversions possibles sont les concentrés de facteurs du complexe prothrombique non activés (ex : CPP) et activés (ex : FEIBA®) [131], mais les données d'efficacité (arrêt de l'hémorragie) et de sécurité (risque thrombotique) sont très faibles et fonction de la molécule (dabigatran, rivaroxaban) [90]. L'idarucizumab, un anticorps humanisé dirigé contre le dabigatran est actuellement en phase III d'étude clinique [295].…”