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Low-dose compared to manufacturer-recommended dose four-factor prothrombin complex concentrate for acute warfarin reversal

  • Wesley ZemrakEmail author
  • Francis Manuel
  • Kathryn E. Smith
  • Stephen Rolfe
  • Timothy Hayes
  • Robert L. Trowbridge
  • Brian Carlone
  • David Seder
Article

Abstract

Background

Four-factor PCC is the recommended standard of care for acute warfarin reversal but optimal dosing is unknown. We aim to show that a low-dose strategy is often adequate and may reduce the risk of thromboembolic events when compared to manufacturer-recommended dosing.

Methods

A weight-based dosing strategy of 15–25 units/kg was established as the institutional standard of care in May 2015. This retrospective, before-and-after cohort analysis included patients receiving 4F-PCC according to a manufacturer-recommended (n = 122) or a low-dose (n = 83) strategy. The primary efficacy outcome was a combination of INR reversal on first check and hemostatic efficacy at 24 h.

Results

Demographics, indications for warfarin, and presenting INR values were similar between the two groups. Patients in the manufacturer-recommended dose group received significantly more 4F-PCC than the low dose group (2110 units vs. 1530 units). More patients in the manufacturer-recommended dose group achieved the primary endpoint (75.4% vs. 61.4%), with more patients achieving the target INR on recheck in the manufacturer-recommended dose group (95.9% vs. 84.3%) and no difference in hemostatic efficacy between groups (79.5% vs. 74.7%). There was no difference in thromboembolic events at 72 h (4.1% vs. 1.2%) or at 30 days (8.2% vs. 4.8%). Significantly more patients in the manufacturer-recommended dose group died or were transferred to hospice care during hospitalization (21.3% vs. 9.6%).

Conclusion

Utilization of a low-dose 4F-PCC strategy resulted in fewer patients achieving target INR reversal, but no difference in hemostatic efficacy, thromboembolic events, or survival.

Keywords

Warfarin Reversal Prothrombin complex concentrate Hemorrhage PCC 

Notes

Funding

No funding was received for this study.

Compliance with ethical standards

Conflict of interest

All authors have no conflict of interest to report in relation to this study.

References

  1. 1.
    Goldstein JN, Refaai MA, Milling TJ, Lewis B, Goldberg-Alberts R, Hug BA, Sarode R (2015) Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 385(9982):2077–2087.  https://doi.org/10.1016/s0140-6736(14)61685-8 CrossRefPubMedGoogle Scholar
  2. 2.
    Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) 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 128(11):1234–1243.  https://doi.org/10.1161/CIRCULATIONAHA.113.002283 CrossRefPubMedGoogle Scholar
  3. 3.
    Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, del Zoppo GJ, Kumar MA, Peerschke EI, Stiefel MF, Teitelbaum JS, Wartenberg KE, Zerfoss CL (2016) Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the neurocritical care society and society of critical care medicine. Neurocrit Care 24(1):6–46.  https://doi.org/10.1007/s12028-015-0222-x CrossRefPubMedGoogle Scholar
  4. 4.
    Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH, American College of Chest Physicians (2012) 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 141(2 Suppl):e152S–e184S.  https://doi.org/10.1378/chest.11-2295 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, Florido R, Hucker W, Mehran R, Messe SR, Pollack CV Jr, Rodriguez F, Sarode R, Siegal D, Wiggins BS (2017) 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 70(24):3042–3067.  https://doi.org/10.1016/j.jacc.2017.09.1085 CrossRefPubMedGoogle Scholar
  6. 6.
    Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K (2012) 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 97(10):1501–1506.  https://doi.org/10.3324/haematol.2012.063701 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Varga C, Al-Touri S, Papadoukakis S, Caplan S, Kahn S, Blostein M (2013) The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin. Transfusion 53(7):1451–1458, quiz 1450.  https://doi.org/10.1111/j.1537-2995.2012.03924.x CrossRefPubMedGoogle Scholar
  8. 8.
    Yasaka M, Sakata T, Naritomi H, Minematsu K (2005) Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res 115(6):455–459.  https://doi.org/10.1016/j.thromres.2004.09.002 CrossRefPubMedGoogle Scholar
  9. 9.
    Khorsand N, Veeger NJ, Muller M, Overdiek JW, Huisman W, van Hest RM, Meijer K (2011) Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med 21(2):116–123.  https://doi.org/10.1111/j.1365-3148.2010.01050.x CrossRefPubMedGoogle Scholar
  10. 10.
    Zemrak WR, Kelley E, Kovacic NL, Mooney DM, Morris JG, MacVane CZ, Rosenblatt JA (2016) Thrombotic complications following the administration of high-dose prothrombin complex concentrate for acute warfarin reversal. Am J Emerg Med 34(8):1736 e1731–e1733.  https://doi.org/10.1016/j.ajem.2015.12.069 CrossRefGoogle Scholar
  11. 11.
    Zemrak WR, Smith KE, Rolfe SS, May T, Trowbridge RL, Hayes TL, Grindlinger GA, Seder DB (2017) Low-dose prothrombin complex concentrate for warfarin-associated intracranial hemorrhage with INR less than 2.0. Neurocrit Care 27(3):334–340.  https://doi.org/10.1007/s12028-017-0422-7 CrossRefPubMedGoogle Scholar
  12. 12.
    Khorsand N, Majeed A, Sarode R, Beyer-Westendorf J, Schulman S, Meijer K, Subcommittee on Control of A (2016) Assessment of effectiveness of major bleeding management: proposed definitions for effective hemostasis: communication from the SSC of the ISTH. J Thromb Haemost 14(1):211–214.  https://doi.org/10.1111/jth.13148 CrossRefPubMedGoogle Scholar
  13. 13.
    Khan M, Baird GL, Elias R, Rodriguez-Srednicki J, Yaghi S, Yan S, Collins S, Thompson BB, Wendell LC, Potter NS, Fehnel C, Saad A, Silver B (2017) Comparison of intracerebral hemorrhage volume calculation methods and their impact on scoring tools. J Neuroimaging 27(1):144–148.  https://doi.org/10.1111/jon.12370 CrossRefPubMedGoogle Scholar
  14. 14.
    Astrup G, Sarangarm P, Burnett A (2018) Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. J Thromb Thrombolysis 45(2):300–305.  https://doi.org/10.1007/s11239-017-1586-x CrossRefPubMedGoogle Scholar
  15. 15.
    van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF (2006) Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 118(3):313–320.  https://doi.org/10.1016/j.thromres.2005.08.005 CrossRefPubMedGoogle Scholar
  16. 16.
    Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K (2017) Fixed versus variable dosing of prothrombin complex concentrate in vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocrit Care 26(1):64–69.  https://doi.org/10.1007/s12028-016-0248-8 CrossRefPubMedGoogle Scholar
  17. 17.
    Junagade P, Grace R, Gover P (2007) Fixed dose prothrombin complex concentrate for the reversal of oral anticoagulation therapy. Hematology 12(5):439–440.  https://doi.org/10.1080/10245330701448529 CrossRefPubMedGoogle Scholar
  18. 18.
    Majeed A, Meijer K, Larrazabal R, Arnberg F, Luijckx GJ, Roberts RS, Schulman S (2014) Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate. Thromb Haemost 111(2):233–239.  https://doi.org/10.1160/TH13-07-0536 CrossRefPubMedGoogle Scholar
  19. 19.
    Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Juttler E, Grau A, Palm F, Rother J, Michels P, Hamann GF, Huwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bazner H, Roth A, Wohrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Mullges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Gunther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dorfler A, Kohrmann M, Schwab S, Huttner HB (2015) Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 313(8):824–836.  https://doi.org/10.1001/jama.2015.0846 CrossRefPubMedGoogle Scholar
  20. 20.
    Steiner T, Poli S, Griebe M, Husing J, Hajda J, Freiberger A, Bendszus M, Bosel J, Christensen H, Dohmen C, Hennerici MG, Kollmer J, Stetefeld H, Wartenberg KE, Weimar C, Hacke W, Veltkamp R (2016) Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 15(6):566–573.  https://doi.org/10.1016/S1474-4422(16)00110-1 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacyMaine Medical CenterPortlandUSA
  2. 2.Department of PharmacyMayo ClinicRochesterUSA
  3. 3.Department of PathologyMaine Medical CenterPortlandUSA
  4. 4.Department of MedicineMaine Medical CenterPortlandUSA
  5. 5.Department of Critical Care ServicesMaine Medical CenterPortlandUSA

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