Neurocrit Care DOI 10.1007/s12028-015-0222-x REVIEW ARTICLE Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine 1 2 3 Jennifer A. Frontera • John J. Lewin III • Alejandro A. Rabinstein • 4 5,6 7 8 Imo P. Aisiku • Anne W. Alexandrov • Aaron M. Cook • Gregory J. del Zoppo • 9 10 11 Monisha A. Kumar • Ellinor I. B. Peerschke • Michael F. Stiefel • 12 13 14 Jeanne S Teitelbaum • Katja E. Wartenberg • Cindy L. Zerfoss Ó Springer Science+Business Media New York 2015 Abstract Methods The Neurocritical Care Society, in conjunction Background The use of antithrombotic agents, including with the Society of Critical Care Medicine, organized an anticoagulants, antiplatelet agents, and thrombolytics has international, multi-institutional committee with expertise increased over the last decade and is expected to continue in neurocritical care, neurology, neurosurgery, stroke, to rise. Although antithrombotic-associated intracranial hematology, hemato-pathology, emergency medicine, hemorrhage can be devastating, rapid reversal of coagu- pharmacy, nursing, and guideline development to evaluate lopathy may help limit hematoma expansion and improve the literature and develop an evidence-based practice outcomes. guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the com- mittee were evaluated. The Neurocritical Care Society and Society of Critical Care Medicine Results Utilizing the GRADE methodology, the com- affirm the value of this guideline as an educational tool for clinicians. mittee developed recommendations for reversal of vitamin Jennifer A. Frontera and John J. Lewin III are guideline co-chairs. K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight Jennifer A. Frontera and John J. Lewin III have contributed equally to heparin, heparinoids, pentasaccharides, thrombolytics, and the manuscript. antiplatelet agents in the setting of intracranial hemorrhage. Electronic supplementary material The online version of this Conclusions This guideline provides timely, evidence- article (doi:10.1007/s12028-015-0222-x) contains supplementary based reversal strategies to assist practitioners in the care of material, which is available to authorized users. 6 & Jennifer A. Frontera Australian Catholic University, Sydney, Australia [email protected] 7 Department of Pharmacy (UK Healthcare) & Department of Pharmacy Practice & Science (UK College of Pharmacy), 1 The Cerebrovascular Center, Neurological Institute, University of Kentucky, Lexington, KY, USA Cleveland Clinic and Case Western Reserve University, 9500 8 Euclid Ave. S80, Cleveland, OH 44195, USA The Departments of Medicine (Hematology) and Neurology, University of Washington School of Medicine, Seattle, WA, 2 The Departments of Pharmacy and Anesthesiology & Critical USA Care Medicine, The Johns Hopkins Hospital and Johns 9 Hopkins University School of Medicine, Baltimore, MD, The Departments of Neurology, Neurosurgery, USA Anesthesiology & Critical Care, Perelman School of Medicine, Hospital of the University of Pennsylvania, 3 The Department of Neurology, Mayo Clinic, Rochester, MN, Philadelphia, PA, USA USA 10 The Department of Laboratory Medicine and Pathology, 4 Harvard Medical School, Brigham and Women’s Hospital, Memorial Sloan Kettering Cancer Center and Weill Cornell Boston, MA, USA Medical School, New York, NY, USA 5 The University of Tennessee Health Science Center, Memphis, TN, USA 123 Neurocrit Care patients with antithrombotic-associated intracranial commonly available antithrombotic agents in the setting of hemorrhage. intracranial hemorrhage. Keywords Anticoagulant Á Antiplatelet Á Antithrombotic Á Intracranial hemorrhage Á Methodology Intracerebral hemorrhage Á Intraparenchymal hemorrhage Á ICH Á Subarachnoid hemorrhage Á SAH Á The Neurocritical Care Society along with the Society of Subdural hematoma Á SDH Á Reversal Á Antidote Á Critical Care Medicine assembled a 13-person, interna- Vitamin K antagonist Á VKA Á Warfarin Á Coumadin Á tional, multi-institutional committee with expertise in Direct thrombin inhibitor Á DTI Á Dabigatran Á neurocritical care, neurology, neurosurgery, stroke, hema- Factor Xa inhibitor Á Apixaban Á Rivaroxaban Á Edoxaban Á tology, emergency medicine, pharmacy, nursing, hemato- Low-molecular weight heparin Á Heparin Á Heparinoid Á pathology, and guideline development. The target popula- Pentasaccharide Á Fondaparinux Á TPA Á rtPA Á Alteplase Á tion was adult patients with intracranial hemorrhage Thrombolytic Á Plasminogen activator Á Aspirin Á including subarachnoid hemorrhage (traumatic or sponta- Clopidogrel Á Prothrombin complex concentrates Á neous), intraparenchymal hemorrhage (traumatic or PCC Á aPCC Á FEIBA Á spontaneous), intraventricular hemorrhage, subdural Activated prothrombin complex concentrates Á FFP Á hematoma, epidural hematoma, or traumatic contusion. Fresh frozen plasma Á Recombinant factor VIIa Á Committee members were assigned one or more of the rFVIIa Á Protamine Á Platelets Á DDAVP Á Desmopressin Á following sub-topic areas: vitamin K antagonists, direct Cryoprecipitate Á Guideline Á GRADE criteria factor Xa antagonists, direct thrombin inhibitors, unfrac- tionated heparin, low-molecular weight heparin, pentasaccharides, thrombolytics, and antiplatelet agents. Introduction The group did not address reversal of intrinsic coagu- lopathies such as those due to inherited hemophilia, liver, Antithrombotics, including anticoagulants, antiplatelet or renal disease. agents, and thrombolytics are used to treat or decrease the The committee developed a comprehensive list of key risk of thrombotic or embolic events in a wide variety of search words including the generic and commercial names medical conditions. With the introduction of new of the aforementioned antithrombotic agents, intracranial antithrombotics to the market, an aging patient population, hemorrhage, subarachnoid hemorrhage, intracerebral and the increasing prevalence of atrial fibrillation, the use hemorrhage, intraparenchymal hemorrhage, subdural of antithrombotics is expected to continue to rise in future hematoma, subdural hemorrhage, intraventricular hemor- years [1, 2]. As compared to patients experiencing spon- rhage, epidural hemorrhage, epidural hematoma, and taneous intracranial hemorrhage without anticoagulation, traumatic brain injury. A professional librarian organized those on antithrombotics have a higher likelihood of sec- this list of key words, developed medical subject heading ondary hematoma expansion, and an increased risk of (MeSH) terms, searched relevant clinical databases (in- death, or poor functional outcome [3–5]. cluding PubMed/Medline, Library of Science, the Because of the controversial literature regarding the Cochrane database, EMBASE, and CINAHL), and created optimal antithrombotic reversal strategies in patients with a database using EndnoteTM software. The original search intracranial hemorrhage, the Neurocritical Care Society/ included articles published through January 2013, and was Society of Critical Care Medicine Antithrombotic Reversal limited to articles describing human subjects that were in Intracranial Hemorrhage Guideline Writing Committee published in the English language. As guideline develop- was established in October 2012. Its aim was to develop ment progressed, committee members were responsible for evidence-based guidelines for counteracting the effects of updating the search intermittently to identify the more recent literature for inclusion (through November 2015). 11 Clinical trials, meta-analyses, case series, preclinical The Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA studies and practice guidelines were all eligible for inclu- sion. Results were supplemented with the literature 12 Hoˆpital du Sacre´-Coeur and University of Montreal and Montreal Neurological Institute and McGill University, recommended by the committee or identified from refer- Montreal, Quebec, Canada ence lists. 13 Klinik fu¨r Neurologie, Martin-Luther-Universita¨t Halle- The writing committee reviewed articles selected from Wittenberg, Halle, Germany this database for inclusion in the treatment recommenda- 14 The Neuroscience and Neurosurgery Departments, Centra tions. The quality of evidence was analyzed, and treatment Lynchburg General Hospital, Lynchburg, VA, USA recommendations were drafted based on the Grading of 123 Neurocrit Care Recommendations Assessment, Development, and Evalua- Anticoagulant Agents tion (GRADE) system [6]. The system allows for two grades of recommendations: ‘‘strong’’ and ‘‘conditional’’ (weak). Vitamin K Antagonists Definitions for the quality of evidence are asshown in Table 1. In certain circumstances, a strong recommendation can Vitamin K antagonists (VKA) include warfarin, aceno- be made using low- or very low-quality evidence such as in coumarol, phenprocoumon, dicoumarol, tecarfarin, and the following five paradigms [7]: fluindione (Table 2). Their use more than doubles the risk of spontaneous intraparenchymal hemorrhage [11] and is asso- 1. A life-threatening clinical situation in which the ciated with 12–14 % of all intraparenchymal hemorrhages [1, intervention may reduce mortality and the adverse 12]. Overall, intraparenchymal hemorrhage occurs in effects are not prohibitive. 0.3–1.1 % of patients on VKA therapy