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A review of guidelines on anticoagulation reversal across different clinical scenarios – Is there a general consensus?

Open AccessPublished:May 27, 2020DOI:https://doi.org/10.1016/j.ajem.2020.05.086

      Abstract

      Anticoagulation is key to the treatment/prevention of thromboembolic events. The primary complication of anticoagulation is serious or life-threatening hemorrhage, which may necessitate prompt anticoagulation reversal; this could also be required for nonbleeding patients requiring urgent/emergent invasive procedures. The decision to reverse anticoagulation should weigh the benefit–risk ratio of supporting hemostasis versus post-reversal thrombosis. We appraise the available guidelines/recommendations for vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC) reversal in the management of major bleeding, and also assess recent clinical data that may not yet be reflected in official guidance. In general, available guidelines are consistent in their recommendations, advocating administration of vitamin K and 4-factor prothrombin complex concentrates (4F-PCCs) rather than fresh frozen plasma to patients with VKA-associated intracranial hemorrhage and life-threatening bleeding, and specific reversal agents as essential therapy for DOAC reversal in those same severe conditions. However, guidelines also recommend off-label use of PCCs for DOAC reversal when specific reversal agents are unavailable. Limited recent evidence generally support the latter recommendation, but guidelines are likely to evolve as more data become available.

      Keywords

      1. Introduction

      Anticoagulant therapy is fundamental for the prevention and treatment of thromboembolic diseases [
      • Marano G.
      • Vaglio S.
      • Pupella S.
      • Liumbruno G.M.
      • Franchini M.
      How we treat bleeding associated with direct oral anticoagulants.
      ]. With an aging population, the number of people requiring chronic oral anticoagulation to manage conditions such as atrial fibrillation is increasing [
      • Milling Jr., T.J.
      • Ziebell C.M.
      A review of reversal of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery.
      ]. Options for anticoagulation have been increasing – currently available options include vitamin K antagonists (VKAs, primarily warfarin) and the newer direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban) [
      • Marano G.
      • Vaglio S.
      • Pupella S.
      • Liumbruno G.M.
      • Franchini M.
      How we treat bleeding associated with direct oral anticoagulants.
      ,
      • Milling Jr., T.J.
      • Ziebell C.M.
      A review of reversal of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery.
      ]. However, several studies describe the risk of hemorrhage in patients taking anticoagulants. VKA use has been associated with more than double the risk of intracerebral hemorrhage (ICH) versus non-use [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ], while patients receiving DOAC therapy have a lower or comparable risk of ICH or major bleeding compared with VKA therapy [
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      ]. While DOACs have significantly changed the anticoagulation therapy landscape, DOAC-treated patients remain at some risk of major bleeding (up to 5% of patients, based on clinical trial data) [
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      ].
      Prompt anticoagulation reversal during severe/life-threatening bleeding events is a key component of multimodal therapy in these complex and fortunately rare clinical scenarios [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. However, the decision to reverse anticoagulation should weigh the benefit–risk ratio of supporting hemostasis and potentially promoting post-reversal thrombosis. The advisability of administering reversal agents depends upon several clinical factors, including patient stability, timing of last anticoagulant dose, baseline coagulation assays (particularly international normalized ratio [INR] in the case of VKA-related hemorrhage), and product availability [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ]. Reversal and other management strategies are often administered sequentially if required to obtain adequate control of bleeding.
      VKA reversal can be achieved by various treatment approaches including fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs; including 3- or 4-factor PCC [3F-PCC or 4F-PCC] and activated PCC [aPCC]) [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ,
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ]. Historically, clinicians used FFP for VKA reversal, but PCCs have taken precedence in this setting [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. In contrast to FFP, PCCs require a lower infusion volume and shorter infusion time, are associated with a lower risk of pathogen transmission, and have a more rapid impact on INR [
      • Holbrook A.
      • Schulman S.
      • Witt D.M.
      • 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.
      ]. Several clinical trials have found 4F-PCCs to be effective agents for urgent VKA reversal in patients with major bleeding or prior to emergency surgery [
      • Eichinger S.
      Reversing vitamin K antagonists: making the old new again.
      ,
      • Levy J.H.
      • Douketis J.
      • Steiner T.
      • Goldstein J.N.
      • Milling T.J.
      Prothrombin complex concentrates for perioperative vitamin K antagonist and non-vitamin K anticoagulant reversal.
      ,
      • Chai-Adisaksopha C.
      • Hillis C.
      • Siegal D.M.
      • et al.
      Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis.
      ]. The potential for increased post-treatment risk of thromboembolic events (TEEs) with 4F-PCCs is a concern, though several studies have shown this risk to be similar to that with FFP [
      • Eichinger S.
      Reversing vitamin K antagonists: making the old new again.
      ,
      • Chai-Adisaksopha C.
      • Hillis C.
      • Siegal D.M.
      • et al.
      Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis.
      ].
      Since DOACs have shorter half-lives compared with warfarin, many non-life-threatening bleeding events are adequately controlled through supportive care (e.g. temporarily withholding DOAC therapy, blood product transfusion, etc) [
      • Peacock W.F.
      • Gearhart M.M.
      • Mills R.M.
      Emergency management of bleeding associated with old and new oral anticoagulants.
      ]. However, during a life-threatening bleed, DOAC reversal may become necessary in addition to supportive therapy and, in the recently dosed patient, oral activated charcoal administration. Vigorous resuscitation encompasses surgical control of bleeding when direct pressure cannot be applied, along with other stabilizing measures, such as FFP, 3F- or 4F-PCCs, and aPCCs [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ,
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ,
      • Almegren M.
      Reversal of direct oral anticoagulants.
      ]. Emergency hemodialysis may remove dabigatran from the circulation but is often logistically challenging or not available; dialysis is not effective for anti-FXa anticoagulants [
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ,
      • Erdoes G.
      • Martinez Lopez De Arroyabe B.
      • Bolliger D.
      • et al.
      International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
      ].
      Unlike VKA reversal, DOAC reversal has, until recently, been a clinical challenge due to limited availability of/access to specific reversal agents [
      • Dickneite G.
      • Hoffman M.
      Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?.
      ]. Two specific reversal agents are now available: idarucizumab for dabigatran [], and andexanet alfa for apixaban and rivaroxaban [
      • Portola Pharmaceuticals Inc
      Andexxa prescribing information.
      ]. Idarucizumab was approved in 2015 (US and Europe) [
      • Boehringer Ingelheim
      FDA provides full approval to Praxbind, specific reversal agent for pradaxa.
      ,
      • European Medicines Agency (EMA)
      ]. Data from a large clinical study show that idarucizumab was associated with cessation of bleeding and normal periprocedural hemostasis in the majority of patients with major bleeding/requirement for urgent surgery, respectively [
      • Pollack Jr., C.V.
      • Reilly P.A.
      • van Ryn J.
      • et al.
      Idarucizumab for Dabigatran reversal - full cohort analysis.
      ]. Andexanet alfa (approved in the US in 2018 [

      Portola Pharmaceuticals Inc. U.S. Food and Drug Administration approves Portola Pharmaceuticals' prior approval supplement for Andexxa® generation 2 manufacturing process, 2018. https://www.pharmaceutical-business-review.com/news/portola-secures-fda-approval-for-andexxa-generation-2-manufacturing-process/.

      ] and approved conditionally in Europe in 2019 [
      • European Medicines Agency (EMA)
      First antidote for reversal of anticoagulation with factor Xa inhibitors apixaban and rivaroxaban.
      ]) is a relatively recent addition to the reversal agent armamentarium and is not mentioned in a majority of current guidelines. Limited availability and high cost may have constrained its use in clinical practice [
      • Frontera J.J.
      • Danielle
      • Lalchan Rebecca
      • Ahuja Tania
      • Papadopoulis John
      Cost comparison of andexanet versus PCC for direct factor Xa inhibitor reversal after hemorrhage.
      ]. Clinical trial evidence suggests that andexanet alfa reduces anti-factor Xa activity by >90% in patients with major bleeding events [
      • Connolly S.J.
      • Crowther M.
      • Eikelboom J.W.
      • et al.
      Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.
      ].
      In this narrative review, we appraise available guidelines and recommendations on bleeding management for VKA and DOAC reversal, and examine recent efficacy and safety data supporting use of reversal agents in this setting.

      2. Methodology

      This is a narrative review based on relevant US and international anticoagulation management and reversal guidelines published prior to April 2020; these were identified through PubMed and Internet searches, using the search terms “(anticoagulant reversal guidelines) OR anticoagulation reversal guidelines”. Where appropriate, the authors supplemented the searches according to their own understanding of the subject area. Clinical studies and reviews/meta-analyses published after January 1, 2018 were identified using similar search terms in PubMed: ((anticoagulant reversal) OR anticoagulation reversal) AND (“2018/01/01”[Date - Publication]: “3000”[Date - Publication]). Clinical studies and key reviews/meta-analyses focusing on the efficacy/safety of non-specific anticoagulation reversal agents in VKA and DOAC reversal were included, as were articles focusing on the efficacy/safety of idarucizumab in dabigatran reversal and the efficacy/safety of andexanet alfa in rivaroxaban/apixaban reversal. We selected the Jan. 1, 2018 cut-off, to capture recent important studies reported after the guidelines were published and thus not considered by those panels.

      3. Consensus and divergence between the recommendations

      3.1 Methodology of guideline development

      Methodologies employed by guideline authors to generate recommendations on anticoagulant reversal strategies are summarized in Table 1. Most recommendations are based on a systematic review of the literature and acknowledge the lack of irrefutable evidence to fully support their recommendations, as specific reversal agents were either still in development or only recently approved at the time the guidance was developed. While clinical trial data support recommendations for PCC use in VKA reversal, recommendations for PCC use in DOAC reversal were mainly based on expert opinion extrapolated from a small evidence base primarily in animal and in vitro models, healthy volunteers, and two small prospective cohorts of bleeding patients [
      • Johansen M.
      • Wikkelso A.
      • Lunde J.
      • Wetterslev J.
      • Afshari A.
      Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients.
      ,
      • Majeed A.
      • Agren A.
      • Holmstrom M.
      • et al.
      Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study.
      ,
      • Schulman S.
      • Gross P.L.
      • Ritchie B.
      • et al.
      Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study.
      ].
      Table 1General overview of the guidelines and their development
      Society/group (citation)AimsEvidence used and grading systemFormat of guidelines
      ICH
      European Stroke Organisation

      (Christensen et al. 2019) [
      • Christensen H.
      • Cordonnier C.
      • Korv J.
      • et al.
      European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral hemorrhage.
      ]
      To provide clinically useful evidence-based recommendation on reversal of anticoagulant activity VKA, direct factor II (thrombin) inhibitors (dabigatran etexilat) and factor-Xa-inhibitors (apixaban, edoxaban and rivaroxaban) in patients with acute intracerebral hemorrhage.The guideline was prepared following the Standard Operational Procedure for an ESO guideline document and according to GRADE methodology.Recommendations separated into level of evidence (very low, low, moderate, high and very high) and strength of recommendation (weak versus strong)
      American Heart Association (Raval et al. 2017) [
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ]
      Review the literature and offer practical suggestions for providers who manage patients who are actively bleeding in the acute care and periprocedural setting, with specific clinical scenarios including ICHInterprets available data rather than providing specific management recommendations in under-studied populations



      A systematic search of the literature was performed



      The group did not assign formal classes of recommendation/level of evidence
      Practical suggestions are given by indication, including serious bleeding on DOAC protocol



      The strength of the recommendations and/or evidence quality are not indicated
      Neurocritical Care Society; Society of Critical Care Medicine (Frontera et al. 2015) [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]
      The aim was to develop evidence-based guidelines for counteracting the effects of commonly available antithrombotic agents in the setting of ICHFormalized literature searches were conducted to end of November 2015



      The writing committee reviewed articles selected from this database for inclusion in the treatment recommendations. The quality of evidence was analyzed and utilized the GRADE methodology; the committee developed recommendations VKA reversal, direct factor Xa antagonists, direct thrombin inhibitors, etc.
      Evidence is appraised, followed by a list of recommendations for each antithrombotic agent, indicating the strength of the recommendation and quality of evidence supporting the recommendation
      American Heart Association; American Stroke Association (Hemphill et al. 2015) [
      • Franchini M.
      • Lippi G.
      Prothrombin complex concentrates: an update.
      ]
      To present current and comprehensive recommendations for the diagnosis and treatment of spontaneous ICH. An update of the 2010 guidelinesLiterature search of PubMed was performed to end of August 2013



      Recommendations follow the American Heart Association/American Stroke's Association's method of classifying the level of certainty of the treatment effect and the class of evidence
      The guidelines consist of 10 sections (e.g. Emergency Diagnosis and Assessment, Hemostasis and Coagulopathy, Antiplatelet Agents, and DVT Prophylaxis, Blood Pressure), with classified recommendations and graded by level of evidence
      Trauma
      Pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma (Spahn et al. 2019) [
      • Pernod G.
      • Albaladejo P.
      • Godier A.
      • et al.
      Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
      ]
      This update is the fifth edition of a guideline first published in 2007 and updated in 2010, 2013 and 2016, with the aim of providing guidance for the management of bleeding following severe injuryRecommendations were generated using a structured, evidence-based consensus approach using the GRADE hierarchy of evidence and based on a systematic review of published literature (RCTs and non-RCTs, existing systematic reviews and guidelines) and expert opinion/current clinical practiceRecommendations for managing bleeding following severe injury are given step by step in numerical order, with each recommendation graded on the strength of evidence supporting it
      Severe or life-threatening bleeding
      Anticoagulation Forum, a North American organisation of anticoagulation providers (Cuker et al. 2019) [
      • Andrade J.G.
      • Verma A.
      • Mitchell L.B.
      • et al.
      2018 focused update of the Canadian Cardiovascular Society guidelines for the Management of Atrial Fibrillation.
      ]
      Guidance on how the individual reversal agents should be administered, and to offer suggestions for stewardship at the health system levelGrade of evidence not mentioned; includes key questions regarding DOAC reversal through discussion and consensus among the authors. For each question, a summary of the evidence is provided, followed by

      guidance representing unanimous consensus of the authors
      Guidelines are split into multiple questions, and an evidence summary is provided for each question
      CHEST guideline and expert panel report (Lip et al. 2018) [
      • Hemphill 3rd, J.C.
      • Greenberg S.M.
      • Anderson C.S.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ]
      To provide guidance on stroke prevention and antithrombotic therapy, including management of bleedingElectronic databases were searched systematically to identify relevant articles. The quality of the evidence was assessed using the GRADE approach. Graded recommendations and ungraded consensus-based statements were revised until consensus was reachedThe guideline is split into multiple sections, with the evidence discussed followed by a set of recommendations for each section
      American Society of Hematology (Witt et al. 2018) [
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ]
      To provide evidence-based recommendations on the optimal management of anticoagulants for the prevention and treatment of VTE, including recommendations covering excessive anticoagulation and bleeding managementGuidance is based on reviews of evidence developed under the direction of the McMaster University GRADE Centre. This GRADE approach was used by the panel to assess evidence and make recommendationsGuideline includes 25 recommendations and two good practice statements



      Recommendations are presented, section by section along with supporting evidence, benefits, harms/burdens, other considerations and research needs
      American College of Cardiology (Tomaselli et al. 2017) [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ]
      To provide guidance on the management of bleeding in patients treated with anticoagulants (both DOACs and VKAs) used for any indicationGuidance is based on the scientific evidence presented and expert opinions considered during the Anticoagulation Consortium Roundtable, and by subsequent review and deliberation on available evidence by the expert consensus writing committeeProvides guidance for temporary or permanent interruption of therapy, general approaches to bleeding management, decision support for treatment with a reversal agent, and indications and timing for reinstituting anticoagulant treatment



      Guidance is summarized by a series of decision pathway flow diagrams
      Anticoagulation Forum (Burnett et al. 2016) [
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ]
      To provide guidance on the practical VTE management of DOACs by answering a number of pivotal practical questions that apply to DOACs in real-world clinical scenarios, including managing bleeding complications in emergent situationsA literature search from the previous

      10 years was conducted utilizing key words



      Guidance is based on the best available evidence wherever possible



      Guidance statements represent consensus opinion
      Guidance statements around general DOAC management, including the management of DOAC-associated bleeding among other clinical scenarios are included
      The Task Force for the management of atrial fibrillation of the European Society of Cardiology (Kirchhof et al. 2016) [
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ]
      The second edition of the ESC guidelines on atrial fibrillation, developed to meet the growing need for effective care of patients with atrial fibrillation based on current state-of-the-art evidence. Specific guidance on the management of bleeding events is providedExternal systematic reviews were commissioned to answer three Population, Intervention, Comparison, Outcome, Time (PICOT) questions on relevant topics, and these reviews informed specific recommendations



      Recommendations supported by >75% of the Task Force members were included in the guidelines. The level of evidence and the strength of the recommendations were weighed and graded according to predefined scales
      Guidelines are split into multiple sections, one of which is the management of bleeding events in anticoagulated patients with atrial fibrillation. Sections provide a summary of the evidence with recommendations summarized in tables or decision pathway flow diagrams
      Association of Anaesthetists of Great Britain and Ireland (Thomas et al. 2010) [
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016.
      ]
      Guidelines developed to improve management of massive hemorrhageGrade of evidence not mentioned in the text, but the Working Party believe the advice is consistent with European guidelines and current evidence published at the timeConsensus document
      Surgery
      European Association of Cardiothoracic Anaesthesiology (Erdoes et al. 2018) [
      • Erdoes G.
      • Martinez Lopez De Arroyabe B.
      • Bolliger D.
      • et al.
      International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
      ]
      To provide guidance for the monitoring and perioperative management of cardiac surgery patients on DOACs based on currently available literature and expert knowledgeConsensus statement developed based on an independent systematic review of peer-reviewed original research, review articles and case reports



      Recommendation/level of evidence was not graded
      A series of 10 recommendations for best clinical practice are made, followed by a narrative review of the supporting literature
      American College of Cardiology (Doherty et al. 2017) [
      • Lippi G.
      • Mattiuzzi C.
      • Cervellin G.
      • Favaloro E.J.
      Direct oral anticoagulants: analysis of worldwide use and popularity using Google trends.
      ]
      To provide guidance on the management of anticoagulation in patients with nonvalvular atrial fibrillation



      The guidance is primarily for elective planned procedures (the section on postprocedural anticoagulant management is also relevant for urgent/emergent procedures)
      Narrative review of the literature to offer direct guidance where available. Areas in which clinical judgement is needed are highlightedGuidance is in the form of statements and algorithms covering the decision of whether and how to interrupt anticoagulation; whether and how anticoagulant bridging should be performed; and when and how anticoagulant therapy should be restarted
      European Society of Anaesthesiology (Kozek-Langenecker et al. 2017) [

      Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257–3291.

      ]
      An update of the 2013 ESA evidence-based guidelines on the management of severe perioperative bleeding to aid physicians to prepare for potential bleeding risks, plan for any intraoperative bleeding and take any necessary actionElectronic databases were searched from 2011 to 2015. The GRADE system was utilizedThe report includes general recommendations, as well as specific recommendations in various fields of surgical intervention
      British Society for Hematology (Keeling et al. 2016) [
      • Doherty J.U.
      • Gluckman T.J.
      • Hucker W.J.
      • et al.
      2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force.
      ]
      The guideline considers whether and when anticoagulants and antiplatelet agents should be stopped before elective surgery and invasive procedures, when agents can be restarted and how to manage patients on these drugs who require emergency surgeryElectronic databases were searched up to 2015. The GRADE system was used to evaluate levels of evidence and assess the strength of recommendationsGuidelines are broken down into sections with a review of the literature followed by a series of recommendations for each section
      ‘Groupe d'Intérêt en Hémostase Périopératoire’ (GIHP, working group on perioperative hemostasis; Faraoni et al. 2015) [
      • Albaladejo P.
      • Pernod G.
      • Godier A.
      • et al.
      Management of bleeding and emergency invasive procedures in patients on dabigatran: updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.
      ]
      Updates to the management of DOACs. The article briefly reviews current evidence and proposes an algorithm based on published information for the perioperative management of patients treated with DOACsNarrative review of literature of preoperative, intraoperative, and postoperative management of DOACs up to 2015Recommendations on the perioperative management of patients treated with DOACs are formatted as an algorithm, largely based on expert opinion due to lack of good clinical studies available at the time
      General
      American College of Cardiology/American Heart Association Task Force on

      Clinical Practice Guidelines and the Heart Rhythm Society (January et al. 2019) [
      • Keeling D.
      • Tait R.C.
      • Watson H.
      British Committee of Standards for Haematology. Peri-operative management of anticoagulation and antiplatelet therapy.
      ]
      This is an update of the 2014 guideline for the management of patients with atrial fibrillationThis guideline reviews, updates, and modifies guideline methodology on the basis of published standards from organizations, including the Institute of Medicine and on the basis of internal re-evaluationThis guideline follows Class of Recommendation and Level of Evidence
      ‘Groupe d'Intérêt en Hémostase Périopératoire’ (GIHP, working group on perioperative hemostasis; Albaladejo et al. 2018) [
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • et al.
      The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ]
      This update of the 2013 guideline on the management of severe hemorrhages and emergency surgery applies to patients treated with dabigatran, with a bleeding complication or undergoing an urgent invasive procedureNarrative review of literature covering management of hemorrhages and management of emergency invasive procedures in patients treated with dabigatran



      Guidance/recommendations/level of evidence are not graded
      Recommendations are described within the text and summarized as algorithms displayed as figures
      Canadian Cardiovascular Society (Andrade et al. 2018) [
      • Smith M.N.
      • Deloney L.
      • Carter C.
      • Weant K.A.
      • Eriksson E.A.
      Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.
      ]
      The guidelines committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation management



      The 2018 update includes a section on the use of specific DOAC reversal agents
      Recommendations were developed using the GRADE system. Individual studies and literature were reviewed for quality and biasDetails of the updated recommendations are presented, along with their background and rationale
      European Heart Rhythm Association (Steffel et al. 2018) [

      Association of Anaesthetists of Great B, Ireland, Thomas D, et al. Blood transfusion and the anaesthetist: management of massive haemorrhage. Anaesthesia. 2010;65:1153–1161.

      ]
      The third version of the original Practical Guide, published in June 2013 to unify a way of informing physicians on the use of the different DOACs in patients with atrial fibrillationEvidence discussed narratively in the context of recommendations. Evidence includes in vitro, in vivo, and clinical studiesA total of 20 clinical scenarios are listed with practical answers based on available evidence



      One of the 20 topics focuses on the management of bleeding under DOAC therapy
      Australasian Society of Thrombosis and Hemostasis (Tran et al. 2014) [
      • Spahn D.R.
      • Bouillon B.
      • Cerny V.
      • et al.
      The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.
      ]
      Development of local guidelines to manage patients receiving DOAC who present with bleeding or require urgent surgeryRecommendations on the administration of hemostatic agents are given based on the limited evidence



      General principles were drawn from existing guidelines
      The practical guide comprises three sections:

      (1) selection of the most suitable patient groups to receive DOAC;

      (2) laboratory measurements of DOAC in appropriate circumstances;

      (3) management of patients taking DOAC in the peri-operative period, and strategies to manage bleeding complications or reverse the anticoagulant effects for urgent invasive procedures
      ‘Groupe d'Intérêt en Hémostase Périopératoire’ (GIHP, working group on perioperative hemostasis; Pernod et al. 2013) [
      • Olivera P.
      • Gabilondo M.
      • Constans M.
      • et al.
      [email protected] Working Group recommendations for management in patients receiving direct oral anticoagulants.
      ]
      The guidelines were considered by the group to define the management basis around the management of major bleeding complications and emergency surgery that need to be evaluated and not an absolute guide for prescriptionThe method used was based on analysis of the literature reporting on the pharmacokinetic properties of the DOACs and their use in a surgical context



      Due to the limited data available, the working group made extrapolations from existing data



      Members of the GIHP critically appraised the proposals until a consensus was reached
      General recommendations are made, which consist of expert opinion



      The working group recognize that the recommendations are of limited use for the ‘specialized’ centers
      Thrombosis and Hemostasis Summit of North America (Kaatz et al. 2012) [
      • January C.T.
      • Wann L.S.
      • Calkins H.
      • et al.
      2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation.
      ]
      To develop guidance to help clinicians manage the reversal of DOACs in patients who are bleeding or require emergent surgery until more definitive and evidence-based guidelines became availableNarrative review of the evidence base, including in vitro, in vivo, and clinical studiesDifferent reversal strategies for DOACs, specifically dabigatran and rivaroxaban, are appraised based on the existing evidence base



      Recommendations are drawn from a final consensus among the authors
      Grupo Catalán de Trombosis ([email protected] Working Group) (Olivera et al. 2018) [
      • Heidbuchel H.
      • Verhamme P.
      • Alings M.
      • et al.
      Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ]
      Guidelines developed to establish clear recommendations for management of patients receiving DOAC treatment; includes advice on dabigatran reversal in cases of major or life-threatening hemorrhage or surgery OR urgent invasive proceduresA literature search was conducted using published literature (human studies only) in the EMBASE and MEDLINE databases from 2007 to 2016; published abstracts from the 2016 meeting of the American Society of Hematology were also searched using the same strategy.



      Bibliographic references were classified according to the level of evidence, following the criteria established by the US Agency for Health Research and Quality. The Working Group evaluated all compiled evidence and established recommendations based on the evidence; in cases where no evidence was found, consensus recommendations were made based on their clinical experience.
      Consensus document
      DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; ICH, intracranial hemorrhage; RCT, randomized controlled trial; VKA, vitamin K antagonist; VTE, venous thromboembolism.

      3.2 Anticoagulant reversal recommendations

      3.2.1 Vitamin K antagonists

      All guidelines recommend or suggest administering PCCs for VKA reversal only in cases of severe and life-threatening bleeding or prior to emergency surgery (Table 2).
      Table 2Summary of guidelines for the reversal of vitamin K antagonists
      GuidelinesIndicationPCCFFPrFVIIaPlus Vitamin K
      ICH
      European Stroke Organisation

      (Christensen et al. 2019) [
      • Christensen H.
      • Cordonnier C.
      • Korv J.
      • et al.
      European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral hemorrhage.
      ]
      ICHPCC (30 IU/kg) in adults with ICH during use of VKA over no treatment to decrease mortality and normalise INR.

      Very low/Strong
      PCC (30 IU/kg) in patients with ICH during use of VKA over FFP (20 mL/kg) to decrease mortality and normalise INR.

      Moderate/Strong
      Recommend against using rFVIIa to improve outcome, decrease haematoma expansion or increase normalisation of INR.

      Very Low/Strong
      Vitamin K (10 mg IV) in addition to fast reversal strategies including PCC to prevent re-increase of INR to decrease haematoma expansion and decrease mortality.

      Very low/Strong
      Neurocritical Care Society; Society of Critical Care Medicine (Frontera et al. 2015) [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]
      ICH

      3F-PCC or 4F-PCC

      PCC to patients with ICH and INR ≥1.4. Proposed initial reversal with PCC alone rather than combined with FFP or rVIIa



      4F-PCC recommended over 3F-PCC


      FFP may be considered in patients over no treatment when PCCs are unavailable or when PCCs are contraindicated



      Patients who have already received a full dose of PCC but do not have adequate INR correction may also receive FFP as re-dosing of 4F-PCCs (i.e. Kcentra®) is not recommended


      Low-quality evidence


      One dose of vitamin K 10 mg IV as soon as possible to ensure durable INR reversal
      American Heart Association; American Stroke Association (Hemphill et al. 2015) [
      • Franchini M.
      • Lippi G.
      Prothrombin complex concentrates: an update.
      ]
      ICH

      PCCs might be considered over FFP, as the former may have fewer complications and correct the INR more rapidly than FFP


      Guidelines acknowledge that FFP and vitamin K have been the mainstay of anticoagulation reversal but PCCs may be considered over FFP


      rFVIIa does not replenish all the vitamin K-dependent factors and may not restore thrombin generation as effectively as PCCs


      Intravenous vitamin K
      Trauma
      Pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma (Spahn et al. 2019) [
      • Pernod G.
      • Albaladejo P.
      • Godier A.
      • et al.
      Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
      ]
      Trauma

      Recommend early use of

      PCC for emergency VKA reversal (Grade 1A)



      Thromboprophylaxis as early as possible is prudent in patients who have received PCC


      5 mg IV phytomenadione (vitamin K1)

      (Grade 1A)
      Severe or life-threatening bleeding
      CHEST guideline and expert panel report (Lip 2018) [
      • Hemphill 3rd, J.C.
      • Greenberg S.M.
      • Anderson C.S.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ]
      Severe or life-threatening bleeding

      PCCs preferred over FFP
      American Society of Hematology (Witt et al. 2018) [
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ]
      Life-threatening bleeding

      In patients with elevated INR, 4F-PCCs suggested



      Guidelines state 4F-PCC preferred over FFP


      4F-PCC preferred over FFP


      IV vitamin K supplemented by 4F-PCC
      American College of Cardiology (Tomaselli et al. 2017) [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ]
      Major bleeding

      Only 4F-PCC are licensed for rapid VKA reversal (aPCC not indicated)



      PCC preferred over FFP



      Dosed based on INR and body weight (INR 2–4

      25 U/kg; INR 4–6 35 U/kg; INR >6 50 U/kg; max dose 5000 U capped at 100 kg body weight). Or low fixed-dose option, 1000 U for any major bleed; 1500 U for ICH


      10–15 mL/kg recommended but only if 4F-PCC unavailable


      1–10 mg by slow IV administration (in 25–50 mL normal saline over 15–30 min)



      Must be supplemented by PCC/FFP for major bleed
      The Task Force for the management of atrial fibrillation of the European Society of Cardiology (Kirchhof et al. 2016) [
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ]
      Moderate-severe and severe or life-threatening bleeding

      Consider for severe or life-threatening bleeding (restores coagulation quicker than FFP)


      Consider for severe or life-threatening bleeding (restores coagulation quicker than

      vitamin K)


      Vitamin K 1–10 mg IV for moderate-severe bleed
      Association of Anaesthetists of Great Britain and Ireland (Thomas et al. 2010) [
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016.
      ]
      Massive hemorrhage

      PCC recommended



      Dose based on INR: 2–3.9 25 U/kg; 4–5.9 35 U/kg;

      >6 50 U/kg


      IV vitamin K (5–10 mg) coadministered with PCC
      Surgery
      European Society of Anaesthesiology (Kozek-Langenecker et al. 2017) [

      Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257–3291.

      ]
      Severe perioperative bleeding

      4F-PCC 25–50 IU/kg recommended
      If PCC unavailable, plasma 15–20 mL/kg (plus IV vitamin K 5–10 mg) recommended-

      IV vitamin K (5–10 mg) coadministered with PCC
      British Society for Hematology (Keeling et al. 2016) [
      • Doherty J.U.
      • Gluckman T.J.
      • Hucker W.J.
      • et al.
      2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force.
      ]
      Emergency surgery

      If surgery cannot wait

      6–8 h, reverse warfarin with 25–50 U/kg 4F-PCC, with a preference for a lower dose and checking INR


      If surgery can wait

      6–8 h, reverse warfarin with 5 mg IV vitamin K
      ✓ Recommended; ✗ Not recommended; − Not mentioned in guidelines.
      3F-PCC, three-factor prothrombin complex concentrate; 4F-PCC, four-factor prothrombin complex concentrate; aPCC, activated prothrombin complex concentrate; DOAC, direct oral anticoagulant; DTI, direct thrombin inhibitors; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; INR, international normalized ratio; IU, international unit; IV, intravenous; PCC, prothrombin complex concentrate; rVIIa, recombinant factor VIIa; unit; VKA, vitamin K antagonist.

      3.2.1.1 Intracranial hemorrhage (ICH)

      The European Stroke Organisation guideline recommends PCC at 30 IU/kg (along with vitamin K) for VKA reversal in ICH without distinguishing between 3- and 4-factor products [
      • Christensen H.
      • Cordonnier C.
      • Korv J.
      • et al.
      European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral hemorrhage.
      ]. The Neurocritical Care Society and the Society of Critical Care Medicine (NCS/SCCM), recommend discontinuation of VKAs and administration of vitamin K at a dose of 10 mg intravenously (IV) in cases of ICH [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. Furthermore, these guidelines indicate the limited utility of FFP-based strategies in ICH due to the prolonged time to INR reversal, and acknowledge the low cost of FFP and its use in circumstances where PCCs are contraindicated (e.g. allergies or known adverse reaction to PCCs or their components) [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ,
      • Franchini M.
      • Lippi G.
      Prothrombin complex concentrates: an update.
      ]. Treatment with FFP and vitamin K is recommended only if no other treatments are available. FFP should be administered at 10–20 mL/kg IV in combination with one dose of vitamin K 10 mg IV. The NCS/SCCM guidelines recommend 4F-PCC over 3F-PCC [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ], with co-administration of vitamin K generally advised to ensure durable INR reversal. Initial reversal with PCCs alone rather than use in combination with FFP or recombinant Factor VIIa (rFVIIa) is also recommended. The dose of PCC should be weight-based and vary according to admission INR and type of PCC used.
      Due to low-quality evidence and its association with thrombosis, rFVIIa is currently not recommended for VKA reversal in patients presenting with ICH (Table 2). Furthermore, American Heart Association/American Stroke Association (AHA/ASA) guidelines state that although rFVIIa administration rapidly reduces INR, it may not restore thrombin generation effectively as it does not replenish all of the vitamin-K dependent factors [
      • Hemphill 3rd, J.C.
      • Greenberg S.M.
      • Anderson C.S.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ].

      3.2.1.2 Life-threatening bleeding/surgery

      PCCs (primarily 4F-PCCs) are recommended or preferred for VKA reversal (Table 2), and several guidelines support usage of FFP for VKA reversal in life-threatening bleeding only if PCCs are unavailable [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ,
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ,
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ,

      Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257–3291.

      ]. The majority of guidelines also recommend co-administration of vitamin K. The European Society of Anaesthesiology (ESA) guideline recommends that patients on oral anticoagulant therapy should be given PCCs and vitamin K before any other coagulation management steps for severe perioperative bleeding. This guideline specifies 4F-PCC administration at a dose of 20–40 IU/kg for VKA reversal. Due to their thrombogenic profile, aPCCs are not indicated for VKA reversal, even in emergency bleeding situations [
      • Kozek-Langenecker S.A.
      • Ahmed A.B.
      • Afshari A.
      • et al.
      Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: first update 2016.
      ]. Guidelines from the Association of Anaesthetists of Great Britain and Ireland also recommend against administration of rFVIIa in this setting (Table 2) [

      Association of Anaesthetists of Great B, Ireland, Thomas D, et al. Blood transfusion and the anaesthetist: management of massive haemorrhage. Anaesthesia. 2010;65:1153–1161.

      ].

      3.2.2 Direct-acting oral anticoagulants

      Most guidelines advocate using specific reversal agents as treatment, where available, and particularly in life-threatening situations. Several guidelines recommend the use of PCCs for non-specific DOAC reversal when specific reversal agents are not available (Table 3).
      Table 3Summary of guidelines for the reversal of the effects of direct oral anticoagulants
      GuidelinesIndicationSpecific reversal agentsPCCFFPrFVIIaVitamin KAdjunctive therapy
      Oral activated charcoalHemodialysisHemoperfusion with activated charcoal
      ICH
      European Stroke Organisation

      (Christensen et al. 2019) [
      • Christensen H.
      • Cordonnier C.
      • Korv J.
      • et al.
      European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral hemorrhage.
      ]
      ICHandexanet alfa for (FXaI).

      Low/Weak

      idarucizumab

      for dabigatran.

      Low/Strong
      For FXaIs 4-factor PCC (37.5–50 IU/kg)

      Very Low/Weak
      Secondary to PCC_____
      American Heart Association (Raval et al. 2017) [
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ]
      ICHIdarucizumab for dabigatran

      With rivaroxaban, apixaban, or edoxaban, should receive PCC until more specific reversal agents become available
      Neurocritical Care Society; Society of Critical Care Medicine (Frontera et al. 2015) [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]
      ICHDTI:

      recommend administering idarucizumab

      (5 g IV in two divided doses) to reverse dabigatran


      Xa inhibitors:

      4F-PCC (50 U/kg) or activated PCC (50 U/kg) if ICH occurred within 3–5 terminal half-lives of drug exposure or in the context of liver failure



      DTI: for dabigatran if idarucizumab is unavailable


      4F-PCC or aPCC is recommended over rFVIIa because of the lower risk of thrombotic events


      50 g of activated charcoal to intubated ICH patients with enteral access and/or those at low risk of aspiration who present within 2 h of dosing


      DTI:

      if idarucizumab is not available and the patient has renal insufficiency or overdosed on dabigatran

      OR

      clinically significant bleed apparent despite idarucizumab or PCC treatment
      American Heart Association; American Stroke Association (Hemphill et al. 2015) [
      • Franchini M.
      • Lippi G.
      Prothrombin complex concentrates: an update.
      ]
      ICH

      In development at the time


      Consider FEIBA/PCCs

      for dabigatran, rivaroxaban, or apixaban on an individual basis in cases with elevated INR


      Unclear utility


      Consider on an individual basis in cases with elevated INR


      May be used if the most recent dose of dabigatran, apixaban, or rivaroxaban was taken <2 h earlier


      May be considered for dabigatran reversal
      Trauma
      Pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma (Spahn et al. 2019) [
      • Pernod G.
      • Albaladejo P.
      • Godier A.
      • et al.
      Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
      ]
      TraumaFor life-threatening bleeding in patients on dabigatran, idarucizumab 5 g IV (Grade 1B)

      and suggest TXA (15 mg/kg [or 1 g] IV) (Grade 2C)


      Factor Xa inhibitors:



      For life-threatening bleeding, suggest TXA (15 mg/kg [or 1 g] IV) and consider use of PCC

      (25–50 U/kg) until specific reversal agents are available (Grade 2C)
      Severe or life-threatening bleeding
      Anticoagulation Forum (Cuker et al. 2019) [
      • Andrade J.G.
      • Verma A.
      • Mitchell L.B.
      • et al.
      2018 focused update of the Canadian Cardiovascular Society guidelines for the Management of Atrial Fibrillation.
      ]
      Major and life-threatening bleedingDabigatran: consider idarucizumab 5 g IV



      Rivaroxaban or apixaban: consider andexanet alfa (dosing according to US FDA label)



      Edoxaban: consider high-dose andexanet alfa (800 mg bolus followed by a continuous infusion of 8 mg/min for up to 120 min)


      Dabigatran:

      If idarucizumab is unavailable, consider aPCC 50 U/kg IV



      Rivaroxaban or apixaban:

      If andexanet alfa unvailable, consider 4F-PCC (2000 U)



      Edoxaban: 4F-PCC (2000 U)


      DOAC overdose along with bleeding
      American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society (January et al. 2019) [
      • Keeling D.
      • Tait R.C.
      • Watson H.
      British Committee of Standards for Haematology. Peri-operative management of anticoagulation and antiplatelet therapy.
      ]
      Life-threatening bleeding



      Surgery


      Life-threatening bleeding or surgery



      For dabigatran:

      Consider idarucizumab



      Life-threatening or uncontrolled bleeding



      Rivaroxaban and apixaban: Consider andexanet alfa
      CHEST guideline and expert panel report (Lip et al. 2018) [
      • Hemphill 3rd, J.C.
      • Greenberg S.M.
      • Anderson C.S.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ]
      Severe or life-threatening bleedingSpecific reversal agent recommended first-line if available

      PCCs are the preferred non-specific reversal agent if a specific reversal agent is unavailable, but data are limited


      For overdose or if last dose within 2–4 h
      American Society of Hematology (Witt et al. 2018) [
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ]
      Life-threatening bleedingDabigatran: idarucizumab



      FXa inhibitors: andexanet alfa


      FXa inhibitors: 4F-PCC (guideline does not recommend either 4F-PCC or andexanet alfa over the other)
      American College of Cardiology (Tomaselli et al. 2017) [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ]
      Major bleedingDabigatran: idarucizumab 5 g IV



      Apixaban and rivaroxaban: andexanet alfa (according to DOAC dose and timing of last administration)


      Dabigatran: 4F-PCC or aPCC 50 U/kg IV (if idarucizumab unavailable)



      Edoxaban: 4F-PCC

      50 U/kg IV; consider aPCC 50 U/kg IV (if 4F-PCC unavailable)



      Apixaban and rivaroxaban:

      4F-PCC or aPCC 50 U/kg (if andexanet alfa unavailable)


      If DOAC ingestion was within the last 2–4 h
      Anticoagulation Forum (Burnett et al. 2016) [
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ]
      Major bleeding

      4F-PCC (KCentra®)

      50 U/kg or aPCC

      80 U/kg for Xa inhibitors and direct thrombin inhibitors, respectively


      Not as a

      first-line reversal agent





      In the event of PCC failure to restore hemostasis


      If DOAC ingestion was within the last 6 h


      For dabigatran patients, especially if renally impaired
      The Task Force for the management of atrial fibrillation of the

      European Society of Cardiology (Kirchhof et al. 2016) [
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ]
      Moderate-severe and severe or life-threatening bleedingDabigatran: idarucizumab



      FXa inhibitors: andexanet alfa


      For severe/life-threatening bleeding, consider PCC if no specific reversal agent available


      For moderate-severe bleeding, consider if DOAC recently ingested (<2–4 h)


      Dialysis clears dabigatran but less effective for other DOACs
      Surgery
      European Association of Cardiothoracic Anaesthesiology (Erdoes et al. 2018) [
      • Erdoes G.
      • Martinez Lopez De Arroyabe B.
      • Bolliger D.
      • et al.
      International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
      ]
      Moderate or severe bleeding during cardiac surgeryDabigatran: idarucizumab IV two doses of 2.5 g



      Rivaroxaban, apixaban, edoxaban: andexanet alfa


      PCC (25–50 U/kg)/aPCC (50 U/kg)




      Consider for moderate/severe bleeding


      Consider for severe bleeding


      May not be applicable in the hemodynamically unstable bleeding patient
      American College of Cardiology (Doherty et al. 2017) [
      • Lippi G.
      • Mattiuzzi C.
      • Cervellin G.
      • Favaloro E.J.
      Direct oral anticoagulants: analysis of worldwide use and popularity using Google trends.
      ]
      Urgent/emergent procedure with high bleeding riskDabigatran: idarucizumab
      European Society of Anaesthesiology (Kozek-Langenecker et al. 2017) [

      Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257–3291.

      ]
      Severe perioperative bleedingDabigatran: idarucizumab

      There is limited evidence that 4F-PCC and aPCC provide clinical benefit and there is a lack of evidence regarding optimal dosing and possible thrombotic risk


      There is limited evidence that rFVIIa provides clinical benefit and there is a lack of evidence regarding optimal dosing and possible thrombotic risk


      For apixaban 20 mg


      For dabigatran
      British Society for Hematology (Keeling et al. 2016) [
      • Doherty J.U.
      • Gluckman T.J.
      • Hucker W.J.
      • et al.
      2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force.
      ]
      Emergency surgeryDabigatran: idarucizumab



      FXa inhibitors: andexanet alfa


      PCCs should not be routinely used prior to emergency surgery but could be considered in the event of diffuse coagulopathic bleeding


      For dabigatran (but rarely practical)
      Groupe d'Intérêt en Hémostase Périopératoire’ (GIHP, working group on perioperative hemostasis; Faraoni et al. 2015) [
      • Albaladejo P.
      • Pernod G.
      • Godier A.
      • et al.
      Management of bleeding and emergency invasive procedures in patients on dabigatran: updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.
      ]
      Major intraoperative bleeding

      4F-PCCs 25–50 U/kg

      FEIBA 30–50 U/kg (maximum 200 U/kg) in case of life-threatening bleeding
      Limited evidence to support its use
      General
      ‘Groupe d'Intérêt en Hémostase Périopératoire’ (GIHP, working group on perioperative hemostasis; Albaladejo et al. 2018) [
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • et al.
      The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ]
      Severe or life-threatening bleeding or ICH (patients on dabigatran)Dabigatran:

      idarucizumab administered according to the SmPC


      Second-line if idarucizumab unavailable,

      PCC (50 U/kg) or aPCC (30–50 U/kg)


      Usually only in rare clinical cases of overdose


      Not clearly established in the management of hemorrhages and emergency invasive procedures
      Canadian Cardiovascular Society (Andrade et al. 2018) [
      • Smith M.N.
      • Deloney L.
      • Carter C.
      • Weant K.A.
      • Eriksson E.A.
      Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.
      ]
      Uncontrollable or life-threatening bleeding/urgent surgeryDabigatran: idarucizumab 5 g IV as soon as possible



      FXa inhibitors: insufficient data to recommend andexanet alfa at this time
      Grupo Catalán de Trombosis ([email protected] Working Group) (Olivera et al. 2018) [
      • Heidbuchel H.
      • Verhamme P.
      • Alings M.
      • et al.
      Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ]
      Major or life-threatening hemorrhage or surgery OR urgent invasive proceduresDabigatran: idarucizumab if available (2 × 2.5 g vials)

      Dabigatran:

      PCC 25–50 IU/kg (if idarucizumab unavailable)
      European Heart Rhythm Association (Steffel et al. 2018) [

      Association of Anaesthetists of Great B, Ireland, Thomas D, et al. Blood transfusion and the anaesthetist: management of massive haemorrhage. Anaesthesia. 2010;65:1153–1161.

      ]
      Severe, life-threatening bleeding, surgeryFor non-life-threatening major bleeding



      Dabigatran: consider idarucizumab (see below)



      First-line for life-threatening bleeding (or immediate surgical procedures – dabigatran)



      Dabigatran: idarucizumab 5 g IV in two doses of 2.5 g IV no >15 min apart



      FXa inhibitors: andexanet alfa if available and approved (dose based on FXa inhibitor and timing of last administration)


      May be considered second-line for life-threatening bleeding (and first-line for immediate surgical procedures for patients on FXa inhibitors)



      PCC 50 U/kg (with additional 25 U/kg if clinically needed)



      aPCC 50 U/kg;

      max 200 U/kg/day): no strong data about additional benefit over PCC. Can be considered before PCC, if available


      Not as reversal agent but may be considered as plasma expander


      PCCs are preferred given the absence of outcome data and pro-coagulant effect


      Dabigatran: consider for severe but non-life-threatening bleeding
      Australasian Society of Thrombosis and Hemostasis (Tran et al. 2014) [
      • Spahn D.R.
      • Bouillon B.
      • Cerny V.
      • et al.
      The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.
      ]
      Life-threatening bleeding or urgent surgery
      No published data were available at the time; therefore, specific advice was not given on managing bleeding in patients on this agent.


      3F-PCC 25–50 IU/kg



      aPCC 25–100 IU/kg


      Administration of rFVIIa

      90 μ/kg every 2 h


      Patients with moderate and severe bleeding who present within 4 h of the last dose of dabigatran or rivaroxaban


      For dabigatran users, especially if renally impaired or dabigatran is present in excess



      No role for dialysis in rivaroxaban and apixaban-related basis as they are highly protein bound
      ‘Groupe d'Intérêt en Hémostase Périopératoire’ (GIHP, working group on perioperative hemostasis; Pernod et al. 2013) [
      • Olivera P.
      • Gabilondo M.
      • Constans M.
      • et al.
      [email protected] Working Group recommendations for management in patients receiving direct oral anticoagulants.
      ]
      Urgent surgery/

      severe bleeding or ICH


      Urgent surgery (for rivaroxaban and dabigatran): PCC

      25–50 U/kg or FEIBA 30–50 U/kg

      [applies primarily to emergency situations where you cannot wait]



      ICH or severe bleeding (for rivaroxaban and dabigatran): PCC 25–50 U/kg (severe bleeding); 50 U/kg (ICH) or FEIBA 30–50 U/kg


      Not considered first line
      Thrombosis and Hemostasis Summit of North America (Kaatz et al. 2012) [
      • January C.T.
      • Wann L.S.
      • Calkins H.
      • et al.
      2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation.
      ]
      Critical bleeding or emergency surgery

      Consensus was not reached regarding PCC due to absence of data


      No role in reversing the effect of DOACs


      If DOAC intake was within ~2 h of presentation


      To be considered in patients with impaired renal function in dabigratan users



      Use of dialysis is not likely effective for apixaban or rivaroxaban users
      ✓ Recommended; ✗ Not recommended; − Not mentioned in guidelines.
      3F-PCC, three-factor prothrombin complex concentrate; 4F-PCC, four-factor prothrombin complex concentrate; aPCC, activated prothrombin complex concentrate; DOAC, direct oral anticoagulant; DTI, direct thrombin inhibitors; FFP, fresh frozen plasma; ICH, intracranial hemorrhage; INR, international normalized ratio; IU, international unit; IV, intravenous; PCC, prothrombin complex concentrate; rVIIa, recombinant factor VIIa; TXA, tranexamic acid; U, unit.
      a No published data were available at the time; therefore, specific advice was not given on managing bleeding in patients on this agent.

      3.2.2.1 ICH

      In patients with dabigatran-associated ICH and renal insufficiency, or dabigatran overdose, NCS/SCCM guidelines state that hemodialysis can be considered if idarucizumab is not available [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. Hemodialysis is postulated to be ineffective for rivaroxaban and apixaban because of their high degree of protein binding, which can result in lower dialysis clearance. Charcoal can be considered as an option to diminish the effects of all DOACs in patients who present within 2 h of dosing (Table 3) [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. The AHA and European Stroke Organisation guidelines describe FFP as having no clear utility for DOAC reversal in ICH [
      • Christensen H.
      • Cordonnier C.
      • Korv J.
      • et al.
      European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral hemorrhage.
      ,
      • Hemphill 3rd, J.C.
      • Greenberg S.M.
      • Anderson C.S.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ]. The NCS/SCCM guidelines recommend administration of aPCC (50 IU/kg) or 4F-PCC (50 IU/kg) in patients with dabigatran- and direct factor Xa inhibitor-associated ICH [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. These guidelines do not currently recommend rFVIIa for dabigatran-related ICH, but do recommend administering idarucizumab (5 g IV in two divided doses) with redosing of idarucizumab and/or hemodialysis during clinically significant bleeding [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]. Idarucizumab is generally recommended for dabigatran reversal in patients presenting with an ICH (Table 3). There are no recommendations in the NCS/SCCM guidelines regarding andexanet alfa use, as these documents were developed before its approval [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ]; other guidelines have been appropriately updated to include these agents and are listed further on.

      3.2.2.2 Life-threatening bleeding/surgery

      Similar to ICH management, hemodialysis may have a role for patients receiving dabigatran. Charcoal is generally recommended if the timing of the last DOAC dose is known (i.e. within ~2 h of last dose; Table 3), while FFP is not recommended for DOAC reversal by any of the guidelines included in this report. The Anticoagulation Forum (ACF) states that the volume of FFP required for the inhibition of thrombin or Factor Xa would likely cause adverse effects such as fluid overload, and states that the time taken to administer the high volume required would preclude its use in emergency/urgent settings [
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ]. If the patient needs volume support in the management of hemorrhagic shock, however, FFP can still be employed, though not explicitly as a reversal agent [
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • et al.
      The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ]. In the absence of a vitamin K deficiency or VKA treatment, none of the guidelines included here indicate a role for vitamin K administration in the management of DOAC-associated bleeding.
      Despite being off-label, most guidelines suggest (or propose consideration of) aPCC or 3-/4F-PCC administration at doses 25–50 IU/kg in cases of serious or life-threatening bleeding when specific reversal agents are not available [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ,
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ,
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ,
      • Erdoes G.
      • Martinez Lopez De Arroyabe B.
      • Bolliger D.
      • et al.
      International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
      ,
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ,
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • et al.
      The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ,
      • Albaladejo P.
      • Pernod G.
      • Godier A.
      • et al.
      Management of bleeding and emergency invasive procedures in patients on dabigatran: updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.
      ,
      • Faraoni D.
      • Levy J.H.
      • Albaladejo P.
      • Samama C.M.
      Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants.
      ,
      • Heidbuchel H.
      • Verhamme P.
      • Alings M.
      • et al.
      Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
      ,
      • Olivera P.
      • Gabilondo M.
      • Constans M.
      • et al.
      [email protected] Working Group recommendations for management in patients receiving direct oral anticoagulants.
      ,
      • Pernod G.
      • Albaladejo P.
      • Godier A.
      • et al.
      Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
      ,
      • Spahn D.R.
      • Bouillon B.
      • Cerny V.
      • et al.
      The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.
      ,
      • Tran H.
      • Joseph J.
      • Young L.
      • et al.
      New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis.
      ]. The mechanism of PCCs in DOAC reversal is not well understood, and studies of the effectiveness of PCCs in DOAC reversal have largely included healthy volunteers. However, recent clinical studies show that treatment with 4F-PCCs is associated with a low risk of TEEs and has similar efficacy to that shown for VKA reversal [
      • Tran H.
      • Joseph J.
      • Young L.
      • et al.
      New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis.
      ,
      • Muller M.
      • Eastline J.
      • Nagler M.
      • Exadaktylos A.K.
      • Sauter T.C.
      Application of prothrombin complex concentrate for reversal of direct oral anticoagulants in clinical practice: indications, patient characteristics and clinical outcomes compared to reversal of vitamin K antagonists.
      ]. Some guidelines recommend the administration of rFVIIa for DOAC reversal; however, they note that rFVIIa should only be considered if other hemostatic measures have been ineffective, due to its relatively high risk of thrombosis [
      • Frontera J.A.
      • Lewin Iii J.J.
      • Rabinstein A.A.
      • et al.
      Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine.
      ,
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ,
      • Erdoes G.
      • Martinez Lopez De Arroyabe B.
      • Bolliger D.
      • et al.
      International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
      ,
      • Pernod G.
      • Albaladejo P.
      • Godier A.
      • et al.
      Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.
      ].
      Following the approval of idarucizumab and andexanet alfa, most guidelines recommend the use of these reversal agents in patients with severe or life-threatening bleeding events, or prior to emergency surgery (Table 3). For dabigatran reversal, idarucizumab 5 g IV is recommended [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ,
      • Erdoes G.
      • Martinez Lopez De Arroyabe B.
      • Bolliger D.
      • et al.
      International consensus statement on the peri-operative management of direct oral anticoagulants in cardiac surgery.
      ,

      Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257–3291.

      ,
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • et al.
      The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ,
      • Albaladejo P.
      • Pernod G.
      • Godier A.
      • et al.
      Management of bleeding and emergency invasive procedures in patients on dabigatran: updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.
      ,
      • Olivera P.
      • Gabilondo M.
      • Constans M.
      • et al.
      [email protected] Working Group recommendations for management in patients receiving direct oral anticoagulants.
      ,
      • Spahn D.R.
      • Bouillon B.
      • Cerny V.
      • et al.
      The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition.
      ,
      • Andrade J.G.
      • Verma A.
      • Mitchell L.B.
      • et al.
      2018 focused update of the Canadian Cardiovascular Society guidelines for the Management of Atrial Fibrillation.
      ,
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ]. Less guidance is available for andexanet alfa, but the American College of Cardiology recommends its usage in rivaroxaban/apixaban reversal and suggests the dose (high versus low) should be based on FXa inhibitor dose and time since last administration of FXa inhibitor [
      • Tomaselli G.F.
      • Mahaffey K.W.
      • Cuker A.
      • 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.
      ]. This is supported by guidance from the ACF, which suggests treatment with andexanet alfa in patients with rivaroxaban- or apixaban-associated major bleeding, or prior to surgery in patients receiving these agents [
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ]; however, it should be noted that the FDA/Europe labels for andexanet alfa do not currently specify pre-surgical use [
      • Portola Pharmaceuticals Inc
      Andexxa prescribing information.
      ]. There are significant uncertainties with andexanet alfa in periprocedural populations as it has not yet been extensively studied in urgent surgery, and optimal andexanet alfa infusion times during longer procedures are unknown [
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ]. As andexanet alfa is not indicated for edoxaban reversal, several guidelines still recommend using PCCs for this purpose [
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • et al.
      The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      ,
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ,
      • Raval A.N.
      • Cigarroa J.E.
      • Chung M.K.
      • et al.
      Management of Patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association.
      ]. However, the ACF recommends off-label treatment with either high-dose andexanet alfa or 4F-PCC in patients with edoxaban-associated major bleeding, or prior to surgery in patients receiving edoxaban [
      • Cuker A.
      • Burnett A.
      • Triller D.
      • et al.
      Reversal of direct oral anticoagulants: guidance from the anticoagulation forum.
      ].

      4. Recent evidence for anticoagulant reversal

      To identify any gaps between the available guidelines and currently available clinical evidence, we conducted a search to identify key clinical studies and reviews/metanalyses, focusing on efficacy/safety of non-specific and specific anticoagulation reversal agents for VKAs and DOACs. Key data for all articles are provided in Supplementary Table 1. There is recent evidence that 4F-PCCs effectively reduce INR in patients with VKA-associated bleeding, with TEE rates ranging from 1.8 to 6.5% [
      • Holt T.
      • Taylor S.
      • Abraham P.
      • et al.
      Three-versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding.
      ,
      • Barton C.A.
      • Hom M.
      • Johnson N.B.
      • Case J.
      • Ran R.
      • Schreiber M.
      Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa.
      ] data from a meta-analysis of PCC use in VKA-associated ICH support these findings [
      • Pan R.
      • Cheng J.
      • Lai K.
      • Huang Q.
      • Wu H.
      • Tang Y.
      Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis.
      ]. 4F-PCC was shown to reduce INR more effectively compared with 3F-PCC alone [
      • Holt T.
      • Taylor S.
      • Abraham P.
      • et al.
      Three-versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding.
      ], but not compared with 3F-PCC + rFVIIa [
      • Barton C.A.
      • Hom M.
      • Johnson N.B.
      • Case J.
      • Ran R.
      • Schreiber M.
      Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa.
      ]; however, 4F-PCC has also been associated with a significantly lower rate of TEEs compared with 3F-PCC + rFVIIa [
      • Barton C.A.
      • Hom M.
      • Johnson N.B.
      • Case J.
      • Ran R.
      • Schreiber M.
      Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor prothrombin complex concentrate with recombinant factor VIIa.
      ]. In contrast, one recent retrospective study of emergency department data reported an increased rate of TEEs in patients on warfarin who received 4F-PCC compared with FFP [
      • Maguire M.
      • Fuh L.
      • Goldstein J.N.
      • et al.
      Thromboembolic risk of 4-factor prothrombin complex concentrate versus fresh frozen plasma for urgent warfarin reversal in the emergency department.
      ]. aPCC appears to be similarly effective to 4F-PCC [
      • Rowe A.S.
      • Dietrich S.K.
      • Phillips J.W.
      • Foster K.E.
      • Canter J.R.
      Activated prothrombin complex concentrate versus 4-factor prothrombin complex concentrate for vitamin K-antagonist reversal.
      ], and more effective than FFP [
      • Carothers C.
      • Giancarelli A.
      • Ibrahim J.
      • Hobbs B.
      Activated prothrombin complex concentrate for warfarin reversal in traumatic intracranial hemorrhage.
      ], in reversing INR in patients with hemorrhage and traumatic ICH, respectively, with no significant different in TEE rate between treatments. One meta-analysis assessed the use of vitamin K for VKA reversal in patients with elevated INR (4.5–10) but no bleeding, concluding that vitamin K administration was not significantly associated with achieving the goal of timely INR reduction in this population [
      • Khatib R.
      • Ludwikowska M.
      • Witt D.M.
      • et al.
      Vitamin K for reversal of excessive vitamin K antagonist anticoagulation: a systematic review and meta-analysis.
      ].
      Various studies have evaluated the safety and efficacy of 4F-PCCs in DOAC reversal, in settings including major bleeding and requirement for urgent surgery [
      • Schulman S.
      • Gross P.L.
      • Ritchie B.
      • et al.
      Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study.
      ,
      • Smith M.N.
      • Deloney L.
      • Carter C.
      • Weant K.A.
      • Eriksson E.A.
      Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.
      ,
      • Arachchillage D.R.J.
      • Alavian S.
      • Griffin J.
      • et al.
      Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding.
      ,
      • Sheikh-Taha M.
      Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate.
      ,
      • Allison T.A.
      • Lin P.J.
      • Gass J.A.
      • et al.
      Evaluation of the use of low-dose 4-factor prothrombin complex concentrate in the reversal of direct oral anticoagulants in bleeding patients.
      ,
      • Tao J.
      • Bukanova E.N.
      • Akhtar S.
      Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors.
      ,
      • Tellor K.B.
      • Barasch N.S.
      • Lee B.M.
      Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital.
      ,
      • Harrison S.K.
      • Garrett J.S.
      • Kohman K.N.
      • Kline J.A.
      Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate.
      ,
      • Dybdahl D.
      • Walliser G.
      • Chance Spalding M.
      • Pershing M.
      • Kincaid M.
      Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage.
      ]. 4F-PCC was generally effective in achieving hemostasis in patients with major bleeding, with TEE rates ranging from 0% to 8% [
      • Schulman S.
      • Gross P.L.
      • Ritchie B.
      • et al.
      Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study.
      ,
      • Smith M.N.
      • Deloney L.
      • Carter C.
      • Weant K.A.
      • Eriksson E.A.
      Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.
      ,
      • Sheikh-Taha M.
      Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate.
      ,
      • Allison T.A.
      • Lin P.J.
      • Gass J.A.
      • et al.
      Evaluation of the use of low-dose 4-factor prothrombin complex concentrate in the reversal of direct oral anticoagulants in bleeding patients.
      ,
      • Tao J.
      • Bukanova E.N.
      • Akhtar S.
      Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors.
      ,
      • Tellor K.B.
      • Barasch N.S.
      • Lee B.M.
      Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital.
      ,
      • Harrison S.K.
      • Garrett J.S.
      • Kohman K.N.
      • Kline J.A.
      Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate.
      ,
      • Hoffman M.
      • Goldstein J.N.
      • Levy J.H.
      The impact of prothrombin complex concentrates when treating DOAC-associated bleeding: a review.
      ], and appeared to be associated with a mortality benefit versus no reversal treatment in patients with traumatic ICH [
      • Dybdahl D.
      • Walliser G.
      • Chance Spalding M.
      • Pershing M.
      • Kincaid M.
      Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage.
      ]. However, one meta-analysis (including 10 case series) reported that it was difficult to assess whether the addition of 4F-PCCs was more effective in managing major bleeding compared with cessation of DOAC therapy alone [
      • Piran S.
      • Khatib R.
      • Schulman S.
      • et al.
      Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis.
      ]. Another meta-analysis compared anticoagulant reversal rates for non-specific and specific reversal agents, reporting that patients on Factor Xa inhibitors generally experienced higher reversal rates compared with patients on dabigatran; reversal rates were highest in each case when a specific reversal agent was used [
      • Udayachalerm S.
      • Rattanasiri S.
      • Angkananard T.
      • Attia J.
      • Sansanayudh N.
      • Thakkinstian A.
      The reversal of bleeding caused by new Oral anticoagulants (NOACs): a systematic review and meta-analysis.
      ]. Activated PCC was also shown to be effective in reversing DOAC anticoagulation due to bleeding or requirement for urgent surgical intervention, with TEE rates ranging from 8 to 10% [
      • Engelbart J.M.
      • Zepeski A.
      • Galet C.
      • Policeni B.
      • Skeete D.A.
      • Faine B.A.
      Safety and effectiveness of factor eight inhibitor bypassing activity for direct oral anticoagulant-related hemorrhage reversal.
      ,
      • Dager W.E.
      • Roberts A.J.
      • Nishijima D.K.
      Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants.
      ].
      A retrospective study investigated the safety and efficacy of 4F-PCC in patients with major bleeding, comparing outcomes according to baseline anticoagulation therapy (warfarin, rivaroxaban, or apixaban). Here, 4F-PCC effectively reversed warfarin, rivaroxaban, and apixaban anticoagulation, with <6% of patients experiencing TEEs; no between-group difference was observed in terms of either efficacy or safety for any treatment [
      • Arachchillage D.R.J.
      • Alavian S.
      • Griffin J.
      • et al.
      Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding.
      ]. Another retrospective study of 4F-PCC in patients on warfarin or DOAC therapy with major bleeding/requiring emergent surgery supported these results, but reported a higher overall TEE rate (10.4%) [
      • Santibanez M.
      • Lesch C.A.
      • Lin L.
      • Berger K.
      Tolerability and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) for warfarin and non-warfarin reversals.
      ]. Findings from a systematic review of studies including patients on VKA or DOAC therapy who received acute reversal management favored the use of PCC (particularly 4F-PCC) for VKA reversal, noting that TEE rates were higher in VKA patients receiving FFP versus those who received 4F-PCC; the authors did not recommend any particular therapy for DOAC reversal [
      • Tornkvist M.
      • Smith J.G.
      • Labaf A.
      Current evidence of oral anticoagulant reversal: a systematic review.
      ].
      The safety and effectiveness of the specific reversal agents idarucizumab and andexanet alfa have been evaluated in several studies. The largest study (RE-VERSE AD; n = 503) reported that the majority of patients with uncontrollable/life-threatening bleeding experienced bleeding cessation within 24 h of idarucizumab administration, while >90% of patients requiring surgery reported normal hemostasis following idarucizumab administration [
      • Pollack Jr., C.V.
      • Reilly P.A.
      • van Ryn J.
      • et al.
      Idarucizumab for Dabigatran reversal - full cohort analysis.
      ]. These findings are supported by results from smaller studies in patients with bleeding or a requirement for urgent surgical procedure(s), along with a systematic literature review [
      • Brennan Y.
      • Favaloro E.J.
      • Pasalic L.
      • Keenan H.
      • Curnow J.
      Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran.
      ,
      • Thibault N.
      • Morrill A.M.
      • Willett K.C.
      Idarucizumab for reversing Dabigatran-induced anticoagulation: a systematic review.
      ]. Other studies assessed the use of idarucizumab following acute ischemic stroke and immediately prior to thrombolysis treatment, reporting that idarucizumab effectively reversed the effects of dabigatran in this population [
      • Fang C.W.
      • Tsai Y.T.
      • Chou P.C.
      • et al.
      Intravenous thrombolysis in acute ischemic stroke after Idarucizumab reversal of Dabigatran effect: analysis of the cases from Taiwan.
      ,
      • Giannandrea D.
      • Caponi C.
      • Mengoni A.
      • et al.
      Intravenous thrombolysis in stroke after dabigatran reversal with idarucizumab: case series and systematic review.
      ].
      The ANNEXA-4 study, which assessed the use of andexanet alfa in 352 patients with acute major bleeding within 18 h of rivaroxaban or apixaban administration, supported FDA and EMA approval of this reversal agent [
      • Connolly S.J.
      • Crowther M.
      • Eikelboom J.W.
      • et al.
      Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.
      ]. Treatment with andexanet alfa markedly reduced anti-factor Xa activity and was associated with good or excellent clinical hemostasis in 82% of cases with a 30-day TEE rate of 9.7% [
      • Connolly S.J.
      • Crowther M.
      • Eikelboom J.W.
      • et al.
      Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.
      ].

      5. Discussion/summary

      While VKAs have traditionally been the mainstay for anticoagulation, DOACs represent a major development in treating and preventing venous thromboembolic disease and in suppressing stroke risk in atrial fibrillation. Interest in DOAC therapy has increased significantly over time, with prescription claims rising from 15.4% to 31.0% of all oral anticoagulant claims between 2013 and 2015, according to US Medicare data [
      • Ziakas P.D.
      • Kourbeti I.S.
      • Poulou L.S.
      • Vlachogeorgos G.S.
      • Mylonakis E.
      Medicare part D prescribing for direct oral anticoagulants in the United States: cost, use and the “rubber effect”.
      ]. Google Trend data also indicate an increasing global interest in DOAC therapy; the greatest number of searches for dabigatran, rivaroxaban, and apixaban between 2012 and 2017 were conducted in North America, central/eastern Europe, and Australia. Interest in edoxaban was less pronounced and restricted to Germany, Japan, and the USA. Interest in warfarin therapy, in contrast to DOAC therapy, has decreased significantly over time [
      • Lippi G.
      • Mattiuzzi C.
      • Cervellin G.
      • Favaloro E.J.
      Direct oral anticoagulants: analysis of worldwide use and popularity using Google trends.
      ].
      A key issue with guidelines is that they become out of date as soon as they are published, due to the continuous publication of new clinical data. This is especially relevant for DOAC reversal, with several current guidelines published prior to the approval of andexanet alfa. Attempts are being made to update guidelines to address use of this agent. Recent clinical data support the use of 4F-PCC in VKA reversal and also DOAC reversal if specific agents are not available, while currently available clinical data on idarucizumab and andexanet alfa supports their use in specific DOAC reversal. It is likely that anticoagulation reversal guidelines will continue to evolve, particularly in the case of specific DOAC reversal agents, as more evidence becomes available on their appropriate use.
      The following is the supplementary data related to this article.

      Funding sources

      Editorial assistance with this article was funded by CSL Behring .

      Ethics statement

      TJM and CVP were both involved in conception of the idea for the review, development of the literature search strategy, interpretation of the literature and critical revision of the manuscript. Both authors read and approved the final version of the manuscript.

      Data availability

      All authors had access to the data contained within this review (i.e. guidelines and research articles available online).

      Declaration of competing interest

      TJM has received consulting fees and/or research funding from CSL Behring, Portola, Boehringer Ingelheim and Genentech. His institutional salary is supported by a grant from the National Heart, Lung and Blood Institute. He serves on the executive committee for the ANNEXA4 and ANNEXA-I trials, the steering committee for the Lex-209 trial and the publications committee for the KCentra trials.
      CVP has acted as scientific consultant to Janssen Pharma, Portola Pharma, Boehringer Ingelheim, and received research support from Janssen Pharma, Portola Pharma, Boehringer Ingelheim, Daiichi-Sankyo and CSL Behring.

      Acknowledgements

      Editorial assistance was provided by Hanna Mourad-Agha of Fishawack Communications Ltd., funded by CSL Behring.

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