Current evidence of oral anticoagulant reversal: A systematic review

Published:December 06, 2017DOI:https://doi.org/10.1016/j.thromres.2017.12.003

      Highlights

      • The use of PCC for VKA-associated INR elevation is effective and well-studied.
      • Use of Four factor-PCC is superior to FFP for reversal of VKA-associated INR elevation.
      • There are no studies on clinical efficacy of non-specific agents for DOAC reversal.

      Abstract

      Introduction

      Approximately 4–6% of patients treated with oral anticoagulants (OAC) will suffer from major hemorrhage or be in need of urgent surgery necessitating anticoagulant reversal therapy. Several new oral anticoagulants and reversal agents have been introduced that make it difficult for physicians to stay updated on the current evidence of reversal management. This study aims to review the recent literature on oral anticoagulation reversal therapy and to present the current evidence in an easily approachable manner.

      Materials and methods

      A systematic literature search was conducted using PubMed and EMBASE to identify the latest publications on both vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC) reversal strategies. All studies on humans who received any acute reversal management of VKA treatment were included, except case studies. Since only two studies on acute reversal of DOAC treatment have been published, clinical trials on healthy volunteers were also included.

      Results

      Twenty-one studies with a total of 4783 VKA treated patients, and 12 studies with a total of 529 DOAC treated patients were included. Elevated INR values due to VKA treatment could be reversed (INR ≤ 1.5) in 63.1% (95% CI: 61.0–65.2) of study subjects after treatment with 4F-PCC, as compared with 12.2% (95% CI: 8.2–16.2) after treatment with fresh frozen plasma (FFP), (p < 0.001). Thromboembolism occurred in 1.6% (95% CI: 1.2–2.1) of VKA-patients treated with 4F-PCC, and in 4.5% (95% CI: 2.3–6.7) of FFP-treated patients. To date, reversal of laboratory parameters has been demonstrated for two reversal agents specific to DOACs: idarucizumab for dabigatran reversal and andexanet-alfa for factor Xa-inhibitor reversal.

      Conclusions

      This review supports the use of PCC for VKA reversal, specifically for 4F-PCC over FFP for laboratory reversal. There are no studies on clinical efficacy of non-specific agents for DOAC reversal and the evidence for laboratory reversal is not consistent.

      Abbreviations:

      OAC (Oral anticoagulant), VKA (Vitamin K antagonist), DOAC (Direct oral anticoagulant), PCC (Prothrombin complex concentrate), 4F-PCC (Four factor PCC), 3F-PCC (Three factor PCC), aPCC (Activated PCC), FFP (Fresh frozen plasma), AF (Atrial fibrillation), TE (Thromboembolism), VTE (Venous thromboembolism), FIIa (Activated factor II), FXa (Activated factor X), rFVIIa (Recombinant activated factor VII), TTR (Time in therapeutic range), PT (Prothrombin time), INR (International Normalized Ratio), aPTT (Activated partial thromboplastin time), ECT (Ecarin clotting time), ETP (Endogenous thrombin potential), dTT (Diluted thrombin time), ICH (Intracranial hemorrhage), SBU (Statens beredning för medicinsk och social utvärdering (Swedish Agency for Health Technology Assessment and Assessment of Social Services)), SEK (Swedish kronor)

      Keywords

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      References

        • Yates S.
        • Sarode R.
        Reversal of anticoagulant effects in patients with intracerebral hemorrhage.
        Curr. Neurol. Neurosci. Rep. 2015; 15: 504
        • Barnes G.D.
        • Lucas E.
        • Alexander G.C.
        • Goldberger Z.D.
        National Trends in Ambulatory Oral Anticoagulant Use.
        Am. J. Med. 2015; 128 (e2): 1300-1305
        • Auricula
        Årsrapport 2014.
        (Available from)
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6e1000097
        • Haidich A.B.
        Meta-analysis in medical research.
        Hippokratia. 2010; 14: 29-37
        • SBU
        Mall för kvalitetsgranskning av observatuionsstudier.
        2014
        • NIH
        Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.
        (Available from)
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat. Med. 2002; 21: 1539-1558
        • Graphpad
        Analyze a 2x2 contingency table 2016.
        ([cited 2016 5/12]. Available from)
        • Altorjay A.
        • Szabo E.
        • Boda Z.
        • Kramer L.
        • Ngo L.Y.
        • Engl W.
        • et al.
        An international, multicenter, prospective study of a prothrombin complex concentrate, Prothromplex Total(R), in anticoagulant reversal.
        Thromb. Res. 2015; 135: 485-491
        • Goldstein J.N.
        • Refaai M.A.
        • Milling Jr., T.J.
        • Lewis B.
        • Goldberg-Alberts R.
        • Hug B.A.
        • 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 (London, England): 2077-2087
        • Jones G.M.
        • Erdman M.J.
        • Smetana K.S.
        • Mohrien K.M.
        • Vandigo J.E.
        • Elijovich L.
        3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal in severe bleeding: a multicenter, retrospective, propensity-matched pilot study.
        J. Thromb. Thrombolysis. 2015; : 1-8
        • Riess H.B.
        • Meier-Hellmann A.
        • Motsch J.
        • Elias M.
        • Kursten F.W.
        • Dempfle C.E.
        Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation.
        Thromb. Res. 2007; 121: 9-16
        • Sarode R.
        • Milling Jr., 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
        • Desmettre T.
        • Dehours E.
        • Samama C.M.
        • Jhundoo S.
        • Pujeau F.
        • Guillaudin C.
        • et al.
        Reversal of vitamin K antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of prothrombin complex concentrate (PCC) in current clinical practice.
        Crit. Care. 2012; 16: R185
        • Desmettre T.
        • Dubart A.E.
        • Capellier G.
        • Fanara B.
        • Puyraveau M.
        • Kepka S.
        • et al.
        Emergency reversal of anticoagulation: the real use of prothrombin complex concentrates: a prospective multicenter two year French study from 2006 to 2008.
        Thromb. Res. 2012; 130: e178-83
        • Hickey M.
        • Gatien M.
        • Taljaard M.
        • Aujnarain A.
        • Giulivi A.
        • Perry J.J.
        Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department.
        Circulation. 2013; 128: 360-364
        • Karaca M.A.
        • Erbil B.
        • Ozmen M.M.
        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: 660-664
        • Kerebel D.
        • Joly L.M.
        • Honnart D.
        • Schmidt J.
        • Galanaud D.
        • Negrier C.
        • et al.
        A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal.
        Crit. Care. 2013; 17: R4
        • Khorsand N.
        • Veeger N.J.
        • van Hest R.M.
        • Ypma P.F.
        • Heidt J.
        • Meijer K.
        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
        • Tazarourte K.
        • Riou B.
        • Tremey B.
        • Samama C.M.
        • Vicaut E.
        • Vigue B.
        Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study).
        Crit. Care. 2014; 18: R81
        • Voils S.A.
        • Martin E.J.
        • Mohammed B.M.
        • Bayrlee A.
        • Brophy D.F.
        Laboratory assessment of warfarin reversal with global coagulation tests versus international normalized ratio in patients with intracranial bleeding.
        Blood Coagul. Fibrinolysis. 2015; 26: 443-447
        • Demeyere R.
        • Gillardin S.
        • Arnout J.
        • Strengers P.F.
        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: 251-260
        • Majeed A.
        • Eelde A.
        • Agren A.
        • Schulman S.
        • Holmstrom M.
        Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy.
        Thromb. Res. 2012; 129: 146-151
        • Connolly S.J.
        • Milling T.J.J.
        • Eikelboom J.W.
        • Gibson C.M.
        • Curnutte J.T.
        • Gold A.
        • et al.
        Andexanet alfa for acute major bleeding associated with factor Xa inhibitors.
        N. Engl. J. Med. 2016; 375: 1131-1141
        • Pollack Jr., C.V.
        • Reilly P.A.
        • Eikelboom J.
        • Glund S.
        • Verhamme P.
        • Bernstein R.A.
        • et al.
        Idarucizumab for Dabigatran Reversal.
        N. Engl. J. Med. 2015; 373: 511-520
        • Arellano-Rodrigo E.
        • Lopez-Vilchez I.
        • Galan A.M.
        • Molina P.
        • Reverter J.C.
        • Carne X.
        • et al.
        Coagulation factor concentrates fail to restore alterations in fibrin formation caused by rivaroxaban or dabigatran in studies with flowing blood from treated healthy volunteers.
        Transfus. Med. Rev. 2015; 29: 242-249
        • Barco S.
        • Whitney Cheung Y.
        • Coppens M.
        • Hutten B.A.
        • Meijers J.C.M.
        • Middeldorp S.
        In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate.
        Br. J. Haematol. 2016; 172: 255-261
        • Brown K.S.
        • Wickremasingha P.
        • Parasrampuria D.A.
        • Weiss D.
        • Kochan J.
        • Dishy V.
        • et al.
        The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban.
        Thromb. Res. 2015; 136: 825-831
        • Cheung Y.W.
        • Barco S.
        • Hutten B.A.
        • Meijers J.C.M.
        • Middeldorp S.
        • Coppens M.
        In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers.
        J. Thromb. Haemost. 2015; 13: 1799-1805
        • Eerenberg E.S.
        • Kamphuisen P.W.
        • Sijpkens M.K.
        • Meijers J.C.
        • Buller H.R.
        • Levi M.
        Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.
        Circulation. 2011; 124: 1573-1579
        • Glund S.
        • Stangier J.
        • Schmohl M.
        • Gansser D.
        • Norris S.
        • van Ryn J.
        • et al.
        Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial.
        Lancet (London, England). 2015; 386: 680-690
        • Levi M.
        • Moore K.T.
        • Castillejos C.F.
        • Kubitza D.
        • Berkowitz S.D.
        • Goldhaber S.Z.
        • et al.
        Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers.
        J. Thromb. Haemost. 2014; 12: 1428-1436
        • Marlu R.
        • Hodaj E.
        • Paris A.
        • Albaladejo P.
        • Cracowski J.L.
        • Pernod G.
        Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers.
        Thromb. Haemost. 2012; 108: 217-224
        • Siegal D.M.
        • Curnutte J.T.
        • Connolly S.J.
        • Lu G.
        • Conley P.B.
        • Wiens B.L.
        • et al.
        Andexanet alfa for the reversal of factor Xa inhibitor activity.
        N. Engl. J. Med. 2015; 373: 2413-2424
        • Zahir H.
        • Brown K.S.
        • Vandell A.G.
        • Desai M.
        • Maa J.F.
        • Dishy V.
        • et al.
        Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate.
        Circulation. 2015; 131: 82-90
        • Vang M.L.
        • Hvas A.M.
        • Ravn H.B.
        Urgent reversal of vitamin K antagonist therapy.
        Acta Anaesthesiol. Scand. 2011; 55: 507-516
        • 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; 7
        • Dentali F.
        • Marchesi C.
        • Giorgi Pierfranceschi M.
        • Crowther M.
        • Garcia D.
        • Hylek E.
        • et al.
        Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis.
        Thromb. Haemost. 2011; 106: 429-438
        • Voils S.A.
        • Holder M.C.
        • Premraj S.
        • Catlin J.R.
        • Allen B.R.
        Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal.
        Thromb. Res. 2015; 136: 595-598
        • Läkemedelsverket
        Profylax mot och reversering av blödning orsakad av antivitamin-K (AVK)-läkemedel- Bakgrundsdokumentation2006.
        (Available from)
        • Ohwaki K.
        • Yano E.
        • Nagashima H.
        • Hirata M.
        • Nakagomi T.
        • Tamura A.
        Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement.
        Stroke. 2004; 35: 1364-1367
        • Broderick J.P.
        • Brott T.G.
        • Duldner J.E.
        • Tomsick T.
        • Huster G.
        Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality.
        Stroke. 1993; 24: 987-993
        • Hart R.G.
        • Diener H.C.
        • Yang S.
        • Connolly S.J.
        • Wallentin L.
        • Reilly P.A.
        • et al.
        Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial.
        Stroke. 2012; 43: 1511-1517
        • Hoffman M.
        • Monroe D.M.
        Reversing targeted oral anticoagulants. Hematology/the education program of the American Society of Hematology American Society of Hematology education.
        Program. 2014; 2014: 518-523
        • Appleby N.
        • Groarke E.
        • Crowley M.
        • Wahab F.A.
        • McCann A.M.
        • Egan L.
        • et al.
        Reversal of warfarin anticoagulation using prothrombin complex concentrate at 25 IU kg1: results of the RAPID study.
        Transfus. Med. 2017; 27: 66-71
        • Laible M.
        • Beynon C.
        • Sander P.
        • Purrucker J.
        • Muller O.J.
        • Mohlenbruch M.
        • et al.
        Treatment with prothrombin complex concentrate to enable emergency lumbar puncture in patients receiving vitamin K antagonists.
        Ann. Emerg. Med. 2016; 68: 340-344
        • Parry-Jones A.R.
        • Di Napoli M.
        • Goldstein J.N.
        • Schreuder F.H.
        • Tetri S.
        • Tatlisumak T.
        • et al.
        Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage.
        Ann. Neurol. 2015; 78: 54-62
        • Yanamadala V.
        • Walcott B.P.
        • Fecci P.E.
        • Rozman P.
        • Kumar J.I.
        • Nahed B.V.
        • et al.
        Reversal of warfarin associated coagulopathy with 4-factor prothrombin complex concentrate in traumatic brain injury and intracranial hemorrhage.
        J. Clin. Neurosci. 2014; 21: 1881-1884
        • Frontera J.A.
        • Gordon E.
        • Zach V.
        • Jovine M.
        • Uchino K.
        • Hussain M.S.
        • 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: 397-406
        • Imberti D.
        • Magnacavallo A.
        • Dentali F.
        • Condoleo E.
        • Gallerani M.
        • Benedetti R.
        • et al.
        Emergency reversal of anticoagulation with vitamin K antagonists with 3-factor prothrombin complex concentrates in patients with major bleeding.
        Biomed. Res. Int. 2013; 36: 102-108