The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban. Issue 4 (October 2015)

• Record Type: Journal Article
• Authors: Brown, Karen S.; Wickremasingha, Prachi; Parasrampuria, Dolly A.; Weiss, Daniel; Kochan, Jarema; Dishy, Victor; He, Ling; Shi, Minggao
• Is Part Of: Thrombosis research. Volume 136:Issue 4(2015)
• Page Start: 825
• Page End: 831
• Publication Date: 2015-10
• Subjects: Coagulation -- Pharmacokinetics -- Thrombin -- Edoxaban -- 3F-PCC -- Pharmacodynamics; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2015.07.012
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Background: Edoxaban, a direct factor Xa inhibitor, is a once-daily, non-vitamin K antagonist oral anticoagulant. There is no established method to reverse the activity of non-vitamin K oral anticoagulants in cases of hemorrhage or urgent surgery. This study evaluated the ability of a 3-factor prothrombin complex concentrate (3F-PCC) to reverse the anticoagulatory effects of edoxaban. Methods: In this phase 1 study, 24 healthy subjects were randomly assigned to receive a single dose of 60 or 180 mg edoxaban, followed by placebo, 25 IU/kg 3F-PCC, or 50 IU/kg 3F-PCC. Edoxaban pharmacokinetics and pharmacodynamics, including the primary endpoint of prothrombin time (PT) and endogenous thrombin potential (ETP), were assessed. D-dimer and prothrombin fragment 1 and 2 (F1+2) were also measured. Results: Overall, there were no apparent consistent effects of 3F-PCC on edoxaban pharmacokinetics. Administration of 3F-PCC 25 or 50 IU/kg with edoxaban 60 or 180 mg did not substantially accelerate the return of PT to baseline levels. However, infusion of 3F-PCC 25 and 50 IU/kg did substantially accelerate return to baseline of ETP compared with placebo. D-dimer and F1+2 data did not indicate any lasting procoagulant effects of 3F-PCC infusion, although a transient increase in F1+2 was noted during and after 3F-PCC infusion. Edoxaban and 3F-PCC co-administration was well tolerated in normal healthy subjects. Conclusions: There was no apparent reversal of PT prolongation with 3F-PCC following edoxaban infusion, but ETP was completely reversed. Co-administration of 3F-PCC was well tolerated, but a dose-dependent increase in F1+2 may reflect a procoagulant risk. Highlights: Edoxaban is a once-daily non-vitamin K antagonist oral anticoagulant Edoxaban 60 or 180 mg effects on prothrombin time were not reversed by 3-factor PCC Effects on endogenous thrombin potential were completely reversed by 3-factor PCC Co-administration of edoxaban and 3-factor PCC was well tolerated The best method for assessing NOAC reversal has still not been determined