Reversal of apixaban anticoagulation by 4-factor prothrombin complex concentrates in healthy subjects: a randomized 3-period crossover study.
J Thromb Haemost. 2017 Aug 28;:
Authors: Song Y, Wang Z, Perlstein I, Wang J, LaCreta F, Frost RJA, Frost C
Abstract
BACKGROUND: Currently, there is no approved reversal agent for direct factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs).
OBJECTIVE: This open-label, randomized, placebo-controlled, 3-period crossover study assessed the effect of two 4-factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects.
METHODS: Subjects received apixaban 10 mg twice daily for 3 days. On Day 4, 3 hours after apixaban, subjects received a 30-minute infusion of 50 IU/kg Cofact(®) , Beriplex(®) P/N (Beriplex(®) ), or saline. Change in endogenous thrombin potential (ETP), measured by a thrombin generation assay (TGA), was the primary endpoint. Secondary endpoints included changes in other TGA parameters, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time, anti-FXa activity, apixaban pharmacokinetics, and safety.
RESULTS: Apixaban-related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; difference of adjusted mean change from pre-PCC baseline to end of infusion was 425 (95% confidence interval [CI]: 219.8, 630.7) nM*min for Cofact(®) and 91 (95% CI: -31.3, 212.4) nM*min for Beriplex(®) . Both PCCs returned ETP to pre-apixaban baseline levels 4 hours after PCC infusion, versus 45 hours for placebo. For both PCCs, mean ETP peaked 21 hours after PCC initiation, then slowly decreased over the following 48 hours. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti-FXa profiles were consistent across treatments.
CONCLUSIONS: Cofact(®) and Beriplex(®) reversed apixaban's steady-state effect on several coagulation assessments. This article is protected by copyright. All rights reserved.
PMID: 28846831 [PubMed - as supplied by publisher]