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Four-factor prothrombin complex concentrate dose response relationship with INR for warfarin reversal

      Abstract

      Introduction

      For reversal of warfarin-induced coagulopathy, FDA labeling of four-factor prothrombin complex concentrate (4F-PCC) endorses a dosing strategy based on body weight and baseline INR. Recent literature suggests lower, fixed doses of 4F-PCC may be equally efficacious. The present evaluation aims to characterize the relationship between 4F-PCC dose and degree of reduction in INR.

      Methods

      This is a retrospective, single-center review of 4F-PCC administrations for warfarin reversal between May 2014 and August 2017. The primary endpoint evaluates the relationship between doses of 4F-PCC and INR measurement after reversal, represented as a linear regression. Exploratory endpoints characterize the relationships of both body weight and baseline INR, the components determining initial 4F-PCC dose, with INR after reversal. Additionally, for records presenting with an INR of 2–3.9, mean INR after reversal was characterized as a function of two 4F-PCC dose cohorts (< 30 and ≥30 IU fIX/kg).

      Results

      A significant linear relationship between 4F-PCC dose and INR after reversal (INR after 4F-PCC = 1.3651–0.00004(4F-PCC Dose), p = 0.0071, R2 = 0.0630) was observed. Body weight and baseline INR were not correlated with INR after reversal. The subgroup analysis of records with presenting INR of 2–3.9 demonstrated no difference in mean INR after reversal with 4F-PCC for those receiving <30 IU fIX/kg and those receiving ≥30 IU fIX/kg.

      Conclusion

      This evaluation found no clinically relevant relationship with 4F-PCC doses and degree of INR reversal. Further prospective study is required to determine optimal dosing schemes of 4F-PCC for warfarin reversal.

      Abbreviations:

      4F-PCC (four-factor prothrombin complex concentrate), IU fIX (international units of Factor IX)

      Keywords

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      References

        • Holbrook A.
        • Schulman S.
        • Witt D.M.
        • Vandvik P.O.
        • Fish J.
        • Kovacs M.J.
        • et al.
        Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141e152S
        • Fitzmaurice D.A.
        • Blann A.D.
        • Lip G.Y.
        Bleeding risks of antithrombotic therapy.
        BMJ. 2002; 325: 828
        • Tomaselli G.F.
        • Mahaffey K.W.
        • Cuker A.
        • Dobesh P.P.
        • Doherty J.U.
        • Eikelboom J.W.
        • et al.
        2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.
        J Am Coll Cardiol. 2017; 70: 30-42
        • Kcentra
        Prothrombin complex concentrate human.
        ([prescribing information]) CSL Behring, Kankakee, IL2013
        • Zemark W.R.
        • Kelley E.
        • Kovacic N.L.
        • Mooney D.M.
        • Morris J.G.
        • MacVane C.Z.
        • et al.
        Thrombotic complications following the administration of high-dose prothrombin complex concentrate for acute warfarin reversal.
        Am J Emerg Med. 2016; 34: 1736.e1-1736.e3
        • Abdoellakhan R.A.
        • Khorsand N.
        • Van Hest R.M.
        • Veeger N.
        • Ter Avest E.
        • Ypma P.F.
        • et al.
        Randomised controlled trial protocol to evaluate a fixed dose prothrombin complex concentrate against the variable dose in vitamin K antagonist related bleeding (PROPER3).
        BMJ Open. 2018; 8e020764
        • Khorsand N.
        • Veeger N.J.
        • van Hest R.M.
        • et al.
        An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies.
        Haematologica. 2012; 97: 1501-1506
        • Klein L.
        • Peters J.
        • Miner J.
        • et al.
        Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal.
        Am J Emerg Med. 2015; 33: 1213-1218
        • Abdoellakhan R.A.
        • Miah I.P.
        • Khorsand N.
        • Ypma P.F.
        • Heidt J.
        • Meijer K.
        Fixed versus variable dosing of prothrombin complex concentrate in vitamin k antagonist-related intracranial hemorrhage: a retrospective analysis.
        Neurocrit Care. 2017; 26: 64-69
        • Astrup F.
        • Sarangarm P.
        • Burnett A.
        Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis.
        J Thromb Thrombolysis. 2018; 45: 300-305
        • Khorsand N.
        • Kooistra H.A.
        • van Hest R.M.
        • Veeger N.J.
        • Meijer K.
        A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy.
        Thromb Res. 2015; 135: 9-19
        • Harris P.A.
        • Taylor R.
        • Thielke R.
        • Payne J.
        • Gonzalez N.
        • Conde J.G.
        Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support.
        J Biomed Inform. 2009; 42: 377-381
      1. The data analysis for this paper was generated using SAS software. Copyright © 2017 SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.

        • Pabinger I.
        • Brenner B.
        • Kalina U.
        • Knaub S.
        • Nagy A.
        • Ostermann H.
        Beriplex P/N Anticoagulation Reversal Study Group. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial.
        J Thromb Haemost. 2008; 6: 622-631
        • Sarode R.
        • Milling T.J.
        • Refaai M.A.
        • Mangione A.
        • Schneider A.
        • Durn B.L.
        • et al.
        Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.
        Circulation. 2013; 128: 1234-1243
        • The Joint Commission
        Specifications manual for joint commission national quality measures: version 2017B2.
        Joint Commission Resources, Oak Brook, IL2017