Abstract
Background
Urgent reversal of vitamin K antagonists (VKAs) is required for major bleeding or urgent surgery by intravenous vitamin K with either prothrombin complex concentrates (PCCs) or fresh frozen plasma (FFP). However, there is lack of consensus regarding the superiority of either reversal agent. We sought to compare the performance of PCC and FFP in urgent reversal of VKA.
Methods
A meta-analysis was conducted up to November 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model.
Results
Seventeen studies comprising 2606 participants met the inclusion criteria. Compared with FFP treatment, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.60, 95% CI 0.40–0.90, p = 0.01), better reversal of INR (OR 7.36, 95% CI 4.18–12.98; p < 0.00001) and lower risk of at least one treatment-related adverse event (OR 0.45, 95% CI 0.26–0.80, p = 0.006). Among patients with VKA-associated intracranial haemorrhage, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.58, 95% CI 0.35–0.94, p = 0.03) and better reversal of INR (OR 6.52, 95% CI 1.66–25.59, p = 0.007). There were no differences between these two agents in thrombogenicity, requirement for and quantity of red blood cell transfusions, all adverse events, fluid overload or disability on discharge or at 90 days.
Conclusions
As an agent for urgent reversal of VKA, PCC outperforms FFP in 90-day all-cause mortality including those with VKA-related intracranial haemorrhage, INR reversal and treatment-related adverse events.
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References
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines. Chest J. 2008;133(6_suppl):160S–198S.
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: A prevalent adverse effect resulting in regulatory action. Arch Internal Med. 2007;167(13):1414-1519-1419.
Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115(1):145–9.
Holbrook A, Schulman S, Witt DM, 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;141(2 Suppl):e152S–84S.
Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transf. 2010;8(3):149-150-154.
Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin–fourth edition. Br J Haematol. 2011;154(3):311–24.
Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. 2008;83(2):137–43.
Chai-Adisaksopha C, Hillis C, Siegal DM, Movilla R, Heddle N, Iorio A, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. Thromb Haemost. 2016;116(5):879–90.
Johansen M, Wikkelsø A, Lunde J, Wetterslev J, Afshari A. Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients. Cochrane Database Syst Rev; 2015. https://doi.org/10.1002/14651858.CD010555.pub2.
Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45(5):1113–8.
Moher D, Liberati A, Tetzlaff J, Altman DG, Prisma Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS med 2009;6(7):e1000097.
van Tulder M, Furlan A, Bombardier C, Bouter L, Editorial Board of the Cochrane Collaboration Back Review Group. Updated method guidelines for systematic reviews in the cochrane collaboration back review group. Spine (Phila Pa 1976). 2003;28(12):1290–1299.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;18(343):d5928.
Parry-Jones AR, Di Napoli M, Goldstein JN, Schreuder FH, Tetri S, Tatlisumak T, et al. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage. Ann Neurol. 2015;78(1):54–62.
Goldstein JN, Refaai MA, Milling TJ, Lewis B, Goldberg-Alberts R, Hug BA, et al. 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. 2015;385(9982):2077–87.
Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15(6):566–73.
Frontera JA, Gordon E, Zach V, Jovine M, Uchino K, Hussain MS, et al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care. 2014;21(3):397–406.
Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry JJ. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation. 2013;128(4):360–4.
Majeed A, Meijer K, Larrazabal R, Arnberg F, Luijckx GJ, Roberts RS, et al. Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate. Thromb Haemost. 2014;111(2):233–9.
Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, 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(11):1234–43.
Takahashi A, Kato TS, Oda N, Komamura K, Kanzaki H, Asakura M, et al. Prothrombin complex concentrate for rapid reversal of warfarin-induced anticoagulation and intracerebral hemorrhage in patients supported by a left ventricular assist device. Int J Gerontol. 2010;4(3):143–7.
Wu DW, Xia Y, Uelinger J, Forest S, Szymanski J, Mohandas K, et al. Impact of prothrombin complex concentrate on blood use, cost, and outcomes in heart transplantation. Ann Thorac Surg. 2018;105(4):1152–1157.
Cartmill, G. Dolan, JL Byrne, PO Byrne, M. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg. 2000;14(5):458–461.
Karaca MA, Erbil B, Ozmen MM. Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED. Am J Emerg Med. 2014;32(6):660–4.
Rowe AS, Mahbubani PS, Bucklin MH, Clark CT, Hamilton LA. Activated prothrombin complex concentrate versus plasma for reversal of warfarin-associated hemorrhage. Pharmacotherapy. 2016;36(11):1132–1137.
Demeyere R, Gillardin S, Arnout J, Strengers PF. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99(3):251–60.
Farsad BF, Golpira R, Najafi H, Totonchi Z, Salajegheh S, Bakhshandeh H, et al. Comparison between prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) for the urgent reversal of warfarin in patients with mechanical heart valves in a tertiary care cardiac center. Iranian J Pharm Res. 2015;14(3):877–85.
Carothers C, Giancarelli A, Ibrahim J, Hobbs B. Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage. J Surg Res. 2018;2018(223):183–7.
Agarwal P, Abdullah KG, Nayak NR, Ramayya AG, Lucas TH. A retrospective propensity score-matched early thromboembolic event analysis of prothrombin complex concentrate vs fresh frozen plasma for warfarin reversal prior to emergency neurosurgical procedures. Neurosurgery. 2018;82(6):877–86.
Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke. 1992;23(7):972–7.
O’shaughnessy D, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol. 2004;126(1):11–28.
Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke. 2006;37(1):151-152-155.
Felton D, Foley EM, Traub SJ, Vodonos A, Ganetsky M. Risk of venous thromboembolism after receiving prothrombin complex concentrate for warfarin-associated intracranial hemorrhage. J Emerg Med. 2016;50(1):1–6.
Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63(6):1059-1060-1064.
Huttner HB, Schellinger PD, Hartmann M, Köhrmann M, Juettler E, Wikner J, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy. Stroke. 2006;37(6):1465-1466-1470.
Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7(5):391–399.
Beyer-Westendorf J, Förster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014;124(6):955–62.
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PS and PB created the study concept and analysis design. RH performed the data collection and wrote the first draft, and analysed and interpreted the data. TSH further edited the draft. PS, PB, NM and IL edited and TSH revised the manuscript. All authors checked, interpreted results and approved the final version.
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Hill, R., Han, T.S., Lubomirova, I. et al. Prothrombin Complex Concentrates are Superior to Fresh Frozen Plasma for Emergency Reversal of Vitamin K Antagonists: A Meta-Analysis in 2606 Subjects. Drugs 79, 1557–1565 (2019). https://doi.org/10.1007/s40265-019-01179-w
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DOI: https://doi.org/10.1007/s40265-019-01179-w