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• W2747089708 abstract "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.AcknowledgementsMedical writing and editorial assistance was provided by C. Line and D. Fox at Caudex, funded by Bristol‐Myers Squibb and Pfizer. The authors would also like to acknowledge J. Pursely for support with apixaban concentration liquid chromatography–tandem mass spectrometry analysis, B. Bedford for support with clinical study management, M. Chang for support with pharmacokinetic data analysis, and R. Fuhr, the principal investigator, for overseeing the clinical conduct of the study.Bristol‐Myers SquibbPfizerSummaryBackgroundCurrently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs).ObjectiveThis open‐label, randomized, placebo‐controlled, three‐period crossover study assessed the effect of two four‐factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects.MethodsSubjects 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‐FXa activity, apixaban pharmacokinetics, and safety.ResultsApixaban‐related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; the differences in adjusted mean change from pre‐PCC baseline to end of infusion were 425 nm min (95% confidence interval [CI] 219.8–630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI − 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre‐apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti‐FXa profiles were consistent across treatments.ConclusionsCofact and Beriplex reversed apixaban's steady‐state effects on several coagulation assessments. 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.AcknowledgementsMedical writing and editorial assistance was provided by C. Line and D. Fox at Caudex, funded by Bristol‐Myers Squibb and Pfizer. The authors would also like to acknowledge J. Pursely for support with apixaban concentration liquid chromatography–tandem mass spectrometry analysis, B. Bedford for support with clinical study management, M. Chang for support with pharmacokinetic data analysis, and R. Fuhr, the principal investigator, for overseeing the clinical conduct of the study.Bristol‐Myers SquibbPfizer •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. Medical writing and editorial assistance was provided by C. Line and D. Fox at Caudex, funded by Bristol‐Myers Squibb and Pfizer. The authors would also like to acknowledge J. Pursely for support with apixaban concentration liquid chromatography–tandem mass spectrometry analysis, B. Bedford for support with clinical study management, M. Chang for support with pharmacokinetic data analysis, and R. Fuhr, the principal investigator, for overseeing the clinical conduct of the study.Bristol‐Myers SquibbPfizer Background Currently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs). Objective This open‐label, randomized, placebo‐controlled, three‐period crossover study assessed the effect of two four‐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 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‐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; the differences in adjusted mean change from pre‐PCC baseline to end of infusion were 425 nm min (95% confidence interval [CI] 219.8–630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI − 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre‐apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. 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 effects on several coagulation assessments." @default.
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• W2747089708 date "2017-11-01" @default.
• W2747089708 modified "2023-10-17" @default.
• W2747089708 title "Reversal of apixaban anticoagulation by four‐factor prothrombin complex concentrates in healthy subjects: a randomized three‐period crossover study" @default.
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• W2747089708 doi "https://doi.org/10.1111/jth.13815" @default.
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