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Reversal of apixaban anticoagulation by four‐factor prothrombin complex concentrates in healthy subjects: a randomized three‐period crossover study
Author(s) -
Song Y.,
Wang Z.,
Perlstein I.,
Wang J.,
LaCreta F.,
Frost R. J. A.,
Frost C.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13815
Subject(s) - apixaban , medicine , crossover study , prothrombin complex concentrate , randomized controlled trial , cardiology , warfarin , atrial fibrillation , rivaroxaban , pathology , placebo , alternative medicine
Essentials Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors. We conducted an open‐label, randomized, placebo‐controlled, three‐period crossover study in 15 subjects. Both PCCs rapidly reversed apixaban‐mediated decreases in mean endogenous thrombin potential. Four‐factor PCC administration had no effect on apixaban pharmacokinetics or anti‐FXa activity.Summary Background Currently, there is no approved reversal agent for direct activated factor Xa ( FX a) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates ( PCC s). Objective This open‐label, randomized, placebo‐controlled, three‐period crossover study assessed the effect of two four‐factor PCC s on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects. Methods Subjects received apixaban 10 mg twice daily for 3 days. On day 4, 3 h after apixaban, subjects received a 30‐min infusion of 50 IU kg −1 Cofact, Beriplex P/N (Beriplex), or saline. Change in endogenous thrombin potential ( ETP ), measured with 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‐ FX a activity, apixaban pharmacokinetics, and safety. Results Apixaban‐related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCC s reversed apixaban's effect on ETP ; the differences in adjusted mean change from pre‐ PCC baseline to end of infusion were 425 n m min (95% confidence interval [ CI ] 219.8–630.7 n m min; P < 0.001) for Cofact, and 91 n m min (95% CI − 31.3 to 212.4 n m min; P > 0.05) for Beriplex. Both PCC s returned ETP to pre‐apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCC s, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCC s reversed apixaban's effect on TGA peak height, PT , and INR . Apixaban pharmacokinetic and anti‐ FX a profiles were consistent across treatments. Conclusions Cofact and Beriplex reversed apixaban's steady‐state effects on several coagulation assessments.