Reversal Guidelines
Bleeding Management and Reversal
European Society of Cardiology (ESC): 2020 ESC Guidelines for the Diagnosis and Management of Atrial Fibrillation Developed in Collaboration with the European Association of Cardio-Thoracic Surgery (EACTS): The Task Force for the Diagnosis and Management of Atrial Fibrillation of the European Society of Cardiology (ESC) Developed with the Special Contribution of the European Heart Rhythm Association (EHRA) of the ESC (Hindricks et al, Eur Heart J 2020 and SUPPL)
The ESC, in collaboration with the EACTS and developed with the EHRA, updated its 2016 guidelines for the screening, diagnosis, assessment, and management of atrial fibrillation (AF) in patients with or without comorbid cardiovascular disease (CVD), including valvular heart disease (direct oral anticoagulants [DOACs] are not indicated for use in patients with mechanical heart valves). Options for rate and rhythm control are described. Strategies for minimizing bleeding risk and managing bleeding episodes (including reversal options) are included, as are recommendations for periprocedural management of anticoagulation, including in patients undergoing ablation or cardioversion. Risks and benefits of DOACs and vitamin K antagonists (VKAs) are highlighted. Sample pathways to help guide decision-making are included for various clinical scenarios. These guidelines also include quality and performance indicators that may be used to evaluate the level of implementation of the guidelines and identify opportunities for improvement.
Canadian Cardiovascular Society (CSC): The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation (Andrade et al, Can J Cardiol [CJC] 2020 and SUPPL)
The Canadian Cardiovascular Society, in collaboration with the Canadian Heart Rhythm Society, provides comprehensive evidence-based recommendations for the use of vitamin K antagonists and direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF), including those with chronic kidney disease (CKD), end-stage renal disease (ESRD), coronary artery disease, liver disease, advanced age, frailty, or increased body mass index (BMI), and in those undergoing cardioversion, catheter ablation, or other invasive procedures. The guidelines also provide recommendations on the prevention and management of DOAC-associated bleeding events. Several clinical pathways to help guide anticoagulation therapy decision-making in various clinical scenarios are provided.
American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS): 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation (January et al, Circulation 2019)
These updated guidelines for the management of AF, published by the AHA/ACC/HRS in 2019 and developed in collaboration with the Society of Thoracic Surgeons (STS), outline risk-based initiation of anticoagulation therapy using the CHADS2, CHA2DS2-VASc, and HAS-BLED risk assessment tools and describe options for rate and rhythm control, including ablation and cardioversion. Management of anticoagulation in specific patient populations, including those with renal impairment and those undergoing ablation, cardioversion, or other invasive procedures, is also addressed. An overview of the risks and benefits of vitamin K antagonists and direct oral anticoagulants (DOACs) is provided.
American College of Chest Physicians (ACCP): Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report (Lip et al, Chest 2018)
The ACCP guidelines describe risk-based antithrombotic therapy for prevention of thrombosis in patients with AF using the CHA2DS2-VASc score to help guide choice of therapy. Considerations for management of anticoagulation in patients undergoing urgent or elective cardioversion, catheter ablation, or other invasive procedure or in patients with AF and concomitant chronic kidney disease (CKD) are provided. Strategies for bleeding management, including use of reversal agents, are described. Sample pathways for determining eligibility for anticoagulation therapy in various clinical scenarios and links to patient education resources are included.
Canadian Cardiovascular Society (CCS): Society Guidelines: 2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation (Andrade et al, Can J Cardiol [CJC] 2018 and SUPPL)
This updated guidance, published by the EHRA in 2018, provides evidence-based recommendations for the use of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF), including eligibility assessment; monitoring; transitioning between vitamin K antagonists and DOACs; possible drug-drug interactions (DDIs); dosing adjustments in the elderly, in patients with hepatic or renal impairment, or based on body weight; management of DOAC-associated bleeding (including use of reversal agents); and periprocedural management considerations for elective or emergency procedures (including ablation and cardioversion). Sample pathways to help guide decision making are included for various clinical scenarios.
Supplemental Material
European Society of Cardiology (ESC): 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS (Kirchhof et al, Eur Heart J [EHJ] 2016)
The 2016 ESC guidelines outline management strategies for patients with AF (with or without comorbid cardiovascular disease [CVD], including valvular heart disease [direct oral anticoagulants (DOACs) are not indicated for use in patients with mechanical heart valves]). Options for rate and rhythm control are described. Anticoagulant dosing adjustments in patients with renal impairment are provided. Strategies for minimizing bleeding risk and managing bleeding episodes (including reversal options) are included, as are recommendations for periprocedural management of anticoagulation, including in patients undergoing ablation or cardioversion. Risks and benefits of vitamin K antagonists and DOACs are highlighted. Sample pathways to help guide decision making are included for various clinical scenarios.
International Society on Thrombosis and Haemostasis (ISTH): When and How to Use Antidotes for the Reversal of Direct Oral Anticoagulants: Guidance From the SSC of the ISTH (Levy et al, J Thromb Haemost [JTH] 2016)
This article from the Scientific and Standardization Committee of the ISTH describes the mechanism of action, risks and benefits, and use of reversal antidotes in the management of DOAC-associated bleeding or prior to emergency procedural interventions.
American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS): 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society (January et al, Circulation 2014)
These guidelines for the management of AF, published by the AHA/ACC/HRS in 2014 and developed in collaboration with the Society of Thoracic Surgeons (STS), outline risk-based initiation of anticoagulation therapy using the CHADS2, CHA2DS2-VASc, and HAS-BLED risk assessment tools and describe options for rate and rhythm control, including ablation and cardioversion. Management of anticoagulation in specific patient populations, including those with renal impairment and those undergoing ablation, cardioversion, or other invasive procedures, is also addressed. An overview of the risks and benefits of vitamin K antagonists and direct oral anticoagulants (DOACs) is provided.
Consensus Statements
Expert Consensus Decision Pathway of the American College of Cardiology on Management of Bleeding in Patients With Oral Anticoagulants: A Review of the 2020 Update for Perioperative Physicians (Navas-Blanco et al, J Cardiothorac Vasc Anesth 2021)
This is an update to the American College of Cardiology's 2017 Expert Consensus Decision Pathway (ECDP) and focuses on bleeding in patients on DOACs, including point-of-care testing devices, lab monitoring of anticoagulation status, novel reversal agents, and reversal strategies. This ECDP has updates that are relevant for perioperative physicians, who often encounter bleeding patients taking DOACs. An algorithm for the ECDP for bleeding management in patients taking DOACs is presented to guide decisions regarding discontinuation of DOACs, reinitiation of anticoagulation, and administration of reversal or hemostatic agents. Overall, the consensus panel emphasizes that reinitiation of DOAC therapy provides an overall benefit.
European Heart Rhythm Association (EHRA): 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation (Steffel et al, EP Europace 2021)
This updated guidance, published by the EHRA in 2021, provides evidence-based recommendations for the use of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF), including eligibility assessment; monitoring; transitioning between other anticoagulants and DOACs; possible drug-drug interactions (DDIs); dosing adjustments in the elderly, in patients with hepatic or renal impairment, or based on body weight; management of DOAC-associated bleeding (including use of reversal agents); and periprocedural management considerations for elective or emergency procedures (including ablation and cardioversion). Special considerations for DOAC use during the COVID-19 pandemic are also included. Sample pathways to help guide decision-making are included for various clinical scenarios.
American College of Cardiology (ACC): 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee (Tomaselli et al, J Am Coll Cardiol [JACC] 2020)
This updated consensus statement offers evidence-based recommendations for management of major and nonmajor bleeding in patients taking oral anticoagulants for any indication. A decision pathway that accounts for bleeding severity, presence of comorbidities and/or concomitant medications that may contribute to bleeding, need for procedural intervention to control the bleed, and need for reversal is provided, along with guidance on whether and when to restart anticoagulation. This article supplements the 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With NVAF by Doherty et al.
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American College of Emergency Physicians (ACEP): Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel (Baugh et al, Ann Emerg Med 2019)
This consensus statement on the evaluation and management of anticoagulant-related bleeding and nonbleeding anticoagulated patients who require emergency invasive procedures reviews the mechanisms of action, pharmacokinetics, and corresponding reversal agents of available oral anticoagulants. An anticoagulation reversal or replacement decision tree is provided.
Reversal of Direct Oral Anticoagulants: Guidance From the Anticoagulation Forum (Cuker et al, Am J Hematol 2019)
This article provides guidance from the Anticoagulation Forum on the use of direct oral anticoagulant (DOAC) reversal agents, including indications for reversal and recommendations on how the individual reversal agents should be administered (sample pathway included).
Management of Severe Bleeding in Patients Treated With Oral Anticoagulants: Proceedings Monograph From the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Severe Bleeding Consensus Panel October 20, 2018 (Gibler et al, Crit Pathw Cardiol 2019)
This monograph from the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Consensus Panel reviews current guidelines for the management of patients requiring oral anticoagulation, reversal of anticoagulation in patients with severe anticoagulant-associated bleeding, including intracranial hemorrhage, and resumption of anticoagulation therapy after resolution of the bleeding episode. A sample algorithm for the management of patients with life-threatening oral anticoagulant-associated bleeding is provided.
American College of Cardiology (ACC): 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation (Doherty et al, J Am Coll Cardiol [JACC] 2017)
This consensus statement offers insights into periprocedural management of anticoagulation in patients with NVAF, including assessment of procedure- and patient-specific bleeding risks, guidance on whether and when to interrupt vitamin K antagonists or DOACs and whether and how to bridge with a parenteral anticoagulant, and, finally, information on reinitiating oral anticoagulation post-procedure. A simple clinical decision pathway is included.
American Heart Association (AHA): 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 (Raval et al, Circulation 2017)
This scientific statement from the AHA describes the management of direct oral anticoagulants (DOACs) in patients needing interruption or reversal of anticoagulation because of an acute bleed or procedural intervention, including in patients undergoing cardioversion or ablation. Sample pathways for these scenarios are provided. The pharmacology, potential drug-drug interactions (DDIs), and reversal of individual DOACs are compared, and guidance on transitioning between oral anticoagulants, based on the prescribing information of individual DOACs, is included.
North American Thrombosis Forum (NATF): North American Thrombosis Forum, AF Action Initiative Consensus Document (Ruff et al, Am J Med [AJM] 2016)
The NATF consensus document describes considerations for stroke and bleeding risk assessment using the CHA2DS2-VASc and HAS-BLED, respectively, and gives recommendations for anticoagulation therapy in patients with atrial fibrillation. The risks, benefits, and cost-effectiveness of direct oral anticoagulants (DOACs) are outlined. Strategies for management of anticoagulation-related bleeding and use of reversal agents are described, as are approaches to periprocedural management of DOACs in patients undergoing ablation, cardioversion, or other surgeries. Considerations are also provided for treating AF in elderly patients, patients with impaired renal function, patients with concomitant coronary artery disease (CAD), patients who are naïve to or experienced with vitamin K antagonists (VKAs), and patients with subclinical AF, along with strategies for optimizing patient safety and adherence to therapy.
American College of Cardiology (ACC): Practical Management of Anticoagulation in Patients With Atrial Fibrillation; (Kovacs et al, J Am Coll Cardiol [JACC] 2015)
Includes considerations for the management of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF) that are based on the consensus recommendations of experts from multiple specialties as part of the ACC’s Anticoagulation Initiative. Topics include initiation and interruption of anticoagulation, quality of anticoagulation care, management of major and minor bleeding (including when and how to use reversal agents [sample pathway included]), and treatment of special populations, such as those with various comorbid cardiovascular diseases (including those with stents) and those undergoing ablation or cardioversion. Comparisons of the risks and benefits of DOACs, dosing considerations in patients with hepatic or renal impairment, and potential drug-drug interactions are provided, along with periprocedural considerations and guidance on transitioning between anticoagulants. A list of topics to cover in patient education encounters is also provided.
Reversal Review Articles
Novel Bleeding Risk Score for Patients With Atrial Fibrillation on Oral Anticoagulants, Including Direct Oral Anticoagulants (Adam et al, J Thromb Haemostat 2021 and SUPPL)
This article describes the development and internal validation of a novel bleeding risk prediction model for AF patients taking oral anticoagulants, including DOACs and vitamin K antagonists. The model was derived from a large, prospective, population-based cohort study of AF patients, the majority of whom were using DOACs. The patients were at low risk of bleeding and could safely use and benefit from anticoagulants. Also included were patients at high risk of bleeding after controlling for known bleeding risk factors. The model may also be useful in identifying patients who would benefit from more frequent clinical monitoring for signs of occult bleeding or DOAC dose adaptation.
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Anticoagulation in Atrial Fibrillation (Barra and Providência, Heart 2020)
In this narrative review, the authors provide an algorithm for selecting the appropriate anticoagulant according to age, renal or hepatic impairment, bleeding risk, and other characteristics. The article also presents recommendations on how to adjust DOAC dosage in patients with renal impairment. The article includes a flowchart to guide the clinician in the management of active bleeding events, categorized by bleeding severity, in AF anticoagulated patients.
Non-vitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Safety Issues in the Elderly (Ajam et al, Expert Rev Clin Pharmacol 2020)
This article reviews the use of direct oral anticoagulants (DOACs) in elderly patients with atrial fibrillation (AF), high risk of stroke and bleeding, and comorbidities requiring polypharmacy. The safety, efficacy, pharmacokinetics, pharmacodynamics, drug-drug interactions, and drug-food interactions of DOACs are described. Clinical studies, guidelines for the management of AF, and expert consensus statements of US and European societies of cardiovascular diseases and cardiac electrophysiology are also reviewed. The article addresses specific challenges with the use of DOACs, including bleeding management and reversal, switching between anticoagulants (vitamin K antagonists and DOACs), and use of DOACs in patients with AF and renal impairment.
A Review of Guidelines on Anticoagulation Reversal Across Different Clinical Scenarios - Is There a General Consensus? (Milling and Pollack, Am J Emergency Med 2020)
This narrative review provides a comprehensive overview of available guidelines and recommendations for reversal of vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) in the management of major bleeding, including intracranial hemorrhage, and summarizes recent clinical efficacy and safety data for reversal agents that may not yet be reflected in available guidelines.
An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants (Mujer et al, Adv Hematol 2020)
This narrative review describes approved specific and nonspecific reversal agents for direct oral anticoagulants (DOACs), as well as investigational reversal agents for the management of bleeding episodes with DOACs. Strategies are proposed for anticoagulation reversal and resumption. Specific laboratory parameters to determine DOAC concentration are suggested as part of point-of-care testing in patients who have acute bleeding, suspected anticoagulant overdose, emergent surgery, or intravenous thrombolysis.
Anesthesiologists Guide to the 2019 AHA/ACC/HRS Focused Update for the Management of Patients With Atrial Fibrillation (Dalia et al, J Cardiothorac Vasc Anesth 2019)
This narrative review summarizes the 2019 American Heart Association/American College of Cardiologists/Heart Rhythm Society guidelines for the perioperative management of anticoagulation in patients with atrial fibrillation, with emphasis on the elements most applicable to anesthesiologists.
To Maintain or Cease Non–Vitamin K Antagonist Oral Anticoagulants Prior to Minimal Bleeding Risk Procedures: A Review of Evidence and Recommendations (Brennan et al, Semin Thromb Hemost 2019)
This article reviews recommendations and supporting evidence for management of direct oral anticoagulants (DOACs) in patients undergoing procedures associated with minimal risk of bleeding, such as minor dental, dermatologic, ophthalmologic, gastrointestinal, urological, gynecological, and interventional radiology procedures, as well as arthrocentesis and atrial fibrillation catheter ablation.
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Insight Into the Perioperative Management of Direct Oral Anticoagulants: Concerns and Considerations (Ibrahim et al, Expert Opin Pharmacother 2019)
This article reviews the indications, mechanism of action, and pharmacokinetics of DOACs and their management in different perioperative settings based on current guidelines and practices. The role of reversal agents is also discussed.
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Pharmacological Reversal of the Direct Oral Anticoagulants—A Comprehensive Review of the Literature (Shaw and Siegal, Res Pract Thromb Haemost [RPTH] 2018)
This review outlines strategies for reversing anticoagulation.
Direct Oral Anticoagulant Agents: Pharmacologic Profile, Indications, Coagulation Monitoring, and Reversal Agents (Rose and Bar, J Stroke Cerebrovasc Dis 2018)
This article reviews the pharmacology of and coagulation monitoring assays for DOACs, as well as clinical study data for reversal agents used in the management of DOAC-associated bleeding.
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Decision Algorithms for Direct Oral Anticoagulant Use in Patients With Nonvalvular Atrial Fibrillation: A Practical Guide for Neurologists (Canavero et al, Clin Appl Thromb Hemost [CATH] 2018)
This narrative review provides an overview of current international guidelines for reduction of stroke risk in patients with NVAF, including the elderly, and offers neurologists guidance on the use of DOACs. The CHA2DS2-VASc and HAS-BLED risk assessment tools, possible drug-drug interactions (DDIs) with DOACs, and reversal strategies for DOAC-associated bleeding are described. Sample pathways for initiation of a DOAC after an acute ischemic stroke or resumption of DOAC therapy after an intracranial hemorrhage (ICH) are included.
American Society of PeriAnesthesia Nurses (2018): Periprocedural Considerations for Anticoagulated Atrial Fibrillation Patients (Collins-Yoder and Collins, J Perianesth Nurs [JPN] 2018)
This review describes assessment of stroke and bleeding risks, highlights current guidelines for periprocedural anticoagulation in patients with atrial fibrillation, and outlines the roles of various perianesthesia health care providers in creating periprocedural anticoagulation protocols and patient care plans.
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Reversal in Patients with Intracranial Hemorrahage
Antithrombotics in Intracerebral Hemorrhage in the Era of Novel Agents and Antidotes: A Review (Giakoumettis, J Popul Ther Clin Pharmacol 2020)
The use of oral anticoagulants (OACs) for atrial fibrillation is linked to an increased risk of intracerebral hemorrhage (ICH). OAC discontinuation and reversal are important if ICH occurs. However, consensus guidelines for post-ICH resumption of OAC therapy are needed. This review presents published evidence on the risk of ICH during OAC therapy and restarting OAC therapy after ICH. The role of multidisciplinary involvement in individualizing the withdrawal, reversal, and resumption of post-ICH antithrombotic treatment is also explored.
Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage (Bower et al, Stroke 2019)
This article reviews the safety, efficacy, and cost of available reversal options for vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) for patients with intracerebral hemorrhage (ICH) in need of reversal of coagulopathy (sample pathway included).
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European Stroke Organisation Guideline on Reversal of Oral Anticoagulants in Acute Intracerebral Haemorrhage (Christensen et al, Eur Stroke J 2019 and SUPPL)
These evidence-based recommendations provide guidance on acute treatments to reverse coagulopathy and normalize coagulation caused by vitamin K antagonists, direct factor II inhibitors, and factor Xa inhibitors in patients with acute intracerebral hemorrhage (ICH). An anticoagulant reversal algorithm is provided.
Reversal of Oral Anticoagulation in Patients With Acute Intracerebral Hemorrhage (Kuramatsu et al, Critical Care 2019)
This article reviews the risk of intracranial hemorrhage (ICH) overall and with use of various oral anticoagulants (OACs) and the challenges of coagulation measurement. Various reversal agents are described, including their pharmacology, efficacy, and safety from clinical studies, and dosing strategies. A sample algorithm for the acute management of OAC-associated ICH is provided.
IPRO: Management of Anticoagulation in the Peri-Procedural Period
The MAPPP app is an interactive tool that may assist clinicians in assessing risk of procedure-related bleeding and help guide periprocedural anticoagulation management decisions.
Neurocritical Care Society and Society of Critical Care Medicine (2016): Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine (Frontera et al, Neurocrit Care 2016)
This evidence-based guideline from the Neurocritical Care Society and Society of Critical Care Medicine provides recommendations for reversal of oral and injectable anticoagulants, thrombolytics, and antiplatelet agents in patients suffering from antithrombotic-associated ICH.
Developing Guidelines for the Reversal of Anticoagulant and Antithrombotic Agents in the Setting of Intracranial Hemorrhage (Christensen and Cooper, J Neurosci Nurs [JNN] 2016 and SUPPL)
This narrative review describes how the Sutter East Bay Neuroscience Institute in Castro Valley, CA developed evidence-based guidelines for management of anticoagulation-associated intracranial hemorrhage or traumatic brain injury. Clinical pathways specific to the anticoagulant or antiplatelet regimen are provided in the supplemental materials.
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Race Against the Clock: Overcoming Challenges in the Management of Anticoagulant-Associated Intracerebral Hemorrhage (Le Roux et al, J Neurosurg [JNS] 2014)
This narrative review describes strategies for anticoagulant reversal in patients suffering from anticoagulant-associated intracranial hemorrhage. Because there were no direct oral anticoagulant (DOAC) reversal agents available at the time this article was published, the focus is primarily on vitamin K antagonist (VKA) reversal; however, strategies for removing DOACs from the circulation using charcoal, dialysis, or prothrombin complex concentrates (PCCs) are described. The algorithmic pathway for the emergency reversal of VKA in patients with serious or life-threatening bleeding used at Pennsylvania Hospital in Philadelphia, PA, is included.