Secondary Logo

Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine

Frontera, Jennifer A. MD, FNCS; Lewin, John J. III PharmD, MBA, FASHP, FCCM, FNCS; Rabinstein, Alejandro A. MD, FNCS; Aisiku, Imo P. MD, MBA, FCCP; Alexandrov, Anne W. PhD, RN, ANVP-BC, FAAN; Cook, Aaron M. PharmD, BCPS; del Zoppo, Gregory J. MD, MS; Kumar, Monisha MD; Peerschke, Ellinor I. B. PhD, FAHA; Stiefel, Michael F. MD, PhD; Teitelbaum, Jeanne S. MD; Wartenberg, Katja E. MD; Zerfoss, Cindy L. MSN, RN, ACNP-BC

doi: 10.1097/CCM.0000000000002057
Special Article
Free

1The Cerebrovascular Center, Neurological Institute, Cleveland Clinic and Case Western Reserve University, Cleveland, OH.

2The Departments of Pharmacy and Anesthesiology & Critical Care Medicine, The Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore, MD.

3The Department of Neurology, Mayo Clinic, Rochester, MN.

4Department of Emergency Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA.

5The University of Tennessee Health Science Center, Memphis, TN.

6Australian Catholic University, Sydney, NSW, Australia.

7The Department of Pharmacy, University of Kentucky, Lexington, KY.

8The Departments of Medicine (Hematology) and Neurology, University of Washington School of Medicine, Seattle, WA.

9The Departments of Neurology, Neurosurgery, Anesthesiology & Critical Care, Perelman School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.

10The Department of Laboratory Medicine and Pathology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical School, New York, NY.

11The Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY.

12Hôpital du Sacré-Coeur, Montreal, QC, Canada.

13University of Montreal and Montreal Neurological Institute and McGill University, Montreal, QC, Canada.

14Department of Neurology, Klinik für Neurologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.

15The Neuroscience and Neurosurgery Departments, Centra Lynchburg General Hospital, Lynchburg, VA.

The Neurocritical Care Society and Society of Critical Care Medicine affirm the value of this guideline as an educational tool for clinicians.

The American Association of Neurological Surgeons and Congress of Neurological Surgeons affirm the educational benefit of this document.

Drs. Frontera and Lewin (Guideline cochairs) contributed equally to this article.

Dr. Aisiku serves on the National Advisory Board for the Medicines Company. Dr. Lewin III disclosed other support. He serves as a consultant to the U.S. Department of Defense (Defense Advanced Research Projects Agency [January 2014 to present] for work unrelated to this publication). Dr. Rabinstein disclosed off-label product use (andexanet alfa). Dr. Alexandrov serves on the speaker’s bureau for Genentech. She has lectured for Genentech (Alteplase speakers program; reversal of alteplase, as discussed in this work, is not part of the program content). Dr. del Zoppo has received research funds from the National Institutes of Health, Boehringer Ingelheim, and Novartis. He has served on advisory boards for Boehringer Ingelheim, Daiichi-Sankyo, and Novartis. Dr. Kumar has received support from Haemonetics. Dr. Stiefel serves as a consultant for Medtronic and Penumbra. Dr. Wartenberg received funding from the Martha Maria Hospital Doelau, Halle, Germany (payment for two lectures, all unrelated to the article) and from the City Hospital of Altenburg, Germany (payment for one lecture, all unrelated to the article). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Jennifer A. Frontera, Cleveland Clinic Foundation, Cerebrovascular Center, 9500 Euclid Ave, S80 Cleveland, OH 44195. E-mail: frontej@ccf.org

Back to Top | Article Outline

PRELIMINARY REMARKS

Guideline Limitations

Practice guidelines should be used in the context of individual patient characteristics and may be superseded by clinical judgment or patient preference. The use of practice guidelines does not guarantee specific outcome benefit but rather should serve as an evidence-based tool for clinicians. This guideline addresses commonly encountered antithrombotic-associated intracranial hemorrhage scenarios for which data and experience have been reported. Management of patients with complex situations (e.g., intracerebral hemorrhage with intrinsic coagulopathy, thrombocytopenia, disseminated intravascular coagulopathy [DIC], polytrauma, and/or concomitant ischemia or thrombophilia) will require prioritizing interventions and risk-benefit analyses. For these situations, the information here should serve as a first guide, with reliance upon local and outside experts in a multidisciplinary team to help formulate treatment plans where necessary. This guideline did not specifically address antithrombotic reversal in a pediatric population. For some antithrombotics, the literature is indirect, or focused on laboratory variable outcomes, rather than functional clinical outcomes. The strength of the recommendations takes into account the quality of the evidence, potential harm of the intervention, and cost. The full guidelines are published elsewhere (1).

Back to Top | Article Outline

Periodic Guideline Review and Update

This guideline may be subject to review and revision as new antithrombotics and reversal agents become available for use. The 488 references and 16 tables included in the guideline and three appendices reflect literature queried through November 2015. Of note, our guidelines are in agreement with a recently released guidance document for novel oral anticoagulants from International Society of thrombosis and hemostasis (2).

Back to Top | Article Outline

Target Patient Population for Guidelines

These guidelines are intended for adult patients with intracranial hemorrhage including subarachnoid hemorrhage (traumatic or spontaneous), intraparenchymal hemorrhage (traumatic or spontaneous), intraventricular hemorrhage, subdural hematoma, epidural hematoma, or traumatic contusion.

Back to Top | Article Outline

Target Audience

These guidelines are intended for use by all clinicians providing care to intracranial hemorrhage patients exposed to antithrombotic agents.

Back to Top | Article Outline

Methodology

The Neurocritical Care Society along with the Society of Critical Care Medicine assembled a 13-person, international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, emergency medicine, pharmacy, nursing, hematopathology, and guideline development. Committee members were assigned one or more of the following subtopic areas: vitamin K antagonists (VKAs), direct factor Xa antagonists, direct thrombin inhibitors (DTIs), unfractionated heparin, low molecular weight heparin (LMWH), pentasaccharides, thrombolytics, and antiplatelet agents. The group did not address reversal of intrinsic coagulopathies such as those due to inherited hemophilia and liver or renal disease.

The committee developed a comprehensive list of key search words including the generic and commercial names of the aforementioned antithrombotic agents, intracranial hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage, intraparenchymal hemorrhage, subdural hematoma, subdural hemorrhage, intraventricular hemorrhage, epidural hemorrhage, epidural hematoma, and traumatic brain injury. A professional librarian organized this list of key words, developed medical subject heading terms, searched relevant clinical databases (including PubMed/Medline, Library of Science, the Cochrane database, Excerpta Medica dataBASE, and Cumulative Index of Nursing and Allied Health Literature), and created a database using Endnote software (Thomas Reuters, New York, NY). The original search included articles published through January 2013 and was limited to articles describing human subjects that were published in the English language. As guideline development progressed committee members were responsible for updating the search intermittently to identify more recent literature for inclusion (through November 2015). Clinical trials, meta-analyses, review articles, and practice guidelines were all eligible for inclusion. Results were supplemented with literature recommended by the committee or identified from reference lists.

The writing committee reviewed articles selected from this database for inclusion in the treatment recommendations. The initial article search yielded 5,981 articles, of which 368 were reviewed and 174 used to produce the final recommendations and are abstracted in evidentiary tables. An additional 314 articles were referenced as supporting literature. The quality of evidence was analyzed and treatment recommendations were drafted based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system (3). The system allows for two grades of recommendations: “strong” and “conditional” (weak). Definitions for the quality of evidence are as shown in Table 1.

TABLE 1

TABLE 1

In certain circumstances, a strong recommendation can be made using low or very low quality evidence such as in the following five paradigms (4):

  1. A life-threatening clinical situation in which the intervention may reduce mortality and the adverse effects are not prohibitive.
  2. There is uncertain benefit to an intervention, but substantial established harm.
  3. There is potential equivalence between treatment options, but one is clearly less costly or less risky.
  4. There is high confidence in equivalence between treatment options, but one option is possibly more costly or risky.
  5. The utility of the intervention is unknown, there is the possibility of harm and a high value is placed on avoiding potentially increased harm, which could be catastrophic.

The GRADE criteria also allows for the assignment of “Good Practice” statements. These statements imply high confidence in the estimates of the effect of the intervention but are garnered from indirect evidence that would be challenging to subject to a formalized GRADE evaluation (6–8). Good practice statements should be actionable, necessary, have a large or unequivocal benefit, be based on data that are difficult to collect (or cannot be collected due to ethical or logistical reasons), and be based on a clear rationale (7).

Back to Top | Article Outline

INTRODUCTION

Antithrombotics, including anticoagulants, antiplatelet agents, and thrombolytics are used to treat or decrease the risk of thrombotic or embolic events in a wide variety of medical conditions. With the introduction of new antithrombotics to the market, an aging patient population, and the increasing prevalence of atrial fibrillation, the use of antithrombotics is expected to continue to rise in future years (9, 10). As compared with patients experiencing spontaneous intracranial hemorrhage without anticoagulation, those on antithrombotics have a higher likelihood of secondary hematoma expansion and an increased risk of death or poor functional outcome (5, 11, 12). Though antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes.

Back to Top | Article Outline

RECOMMENDATIONS

A summary of the recommendations from this document can be found in Table 2.

TABLE 2

TABLE 2

Back to Top | Article Outline

VKA Reversal

  • We recommend discontinuing VKAs when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We recommend urgent reversal of VKAs in patients with intracranial hemorrhage (Strong recommendation, moderate quality evidence) with the following considerations:
    • a. We suggest against VKA reversal in patients where there is a high suspicion of intracranial hemorrhage due to cerebral venous thrombosis (Conditional recommendation, very low quality evidence).
    • b. We recommend assessing risks and benefits when considering VKA reversal in intracranial hemorrhage patients with concurrent symptomatic or life-threatening thrombosis, ischemia, heparin-induced thrombocytopenia, or DIC (Good Practice statement).
  • We recommend administration of vitamin K to ensure durable reversal of international normalized ratio (INR) following VKA-associated intracranial hemorrhage. Vitamin K should be dosed as soon as possible or concomitantly with other reversal agents (Strong recommendation, moderate quality evidence).
    • a. We suggest one dose of vitamin K 10 mg IV. Subsequent treatment should be guided by follow-up INR (Good Practice statement).
    • b. If repeat INR is still elevated greater than or equal to 1.4 within the first 24–48 hours after reversal agent administration, we suggest redosing with vitamin K 10 mg IV (Good Practice statement).
  • We recommend administering three-factor or four-factor prothrombin complex concentrates (PCCs) rather than fresh frozen plasma (FFP) to patients with VKA-associated intracranial hemorrhage and INR greater than or equal to 1.4 (Strong recommendation, moderate quality evidence).
    • a. We suggest the use of four-factor PCC over three-factor PCC (Conditional recommendation, low quality evidence).
    • b. We suggest initial reversal with PCC alone (either three- or four-factor) rather combined with FFP or recombinant factor VIIa (rFVIIa) (Conditional recommendation, low quality evidence).
    • c. We recommend that PCC dosing should be weight based and vary according to admission INR and type of PCC used (Strong recommendation, moderate quality evidence).
    • d. We recommend repeating INR testing soon after PCC administration (15–60 min), and serially every 6–8 hours for the next 24–48 hours. Subsequent treatment should be guided by follow-up INR, with consideration given to the fact that repeat PCC dosing may lead to increased thrombotic complications and risk of DIC (Good Practice statement).
    • e. If the repeat INR is still elevated greater than or equal to 1.4 within the first 24–48 hours after initial PCC dosing, we suggest further correction with FFP (Conditional recommendation, low quality evidence).
  • We recommend against administration of rFVIIa for the reversal of VKA (Strong recommendation, low quality evidence).
  • If PCCs are not available or contraindicated, alternative treatment is recommended over no treatment (Strong recommendation, moderate quality evidence). Treatment choice may be guided by available therapies and patient-specific factors (Good Practice statement).
    • a. Treatment with FFP and vitamin K is recommended over no treatment (Strong recommendation, moderate quality evidence).
    • b. We suggest dosing FFP at 10–15 mL/kg IV along with one dose of vitamin K 10 mg IV (Conditional recommendation, low quality evidence).
Back to Top | Article Outline

Oral Direct Factor Xa Inhibitor Reversal

  • We recommend discontinuing factor Xa inhibitors when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We recommend obtaining information on the time elapsed since the last dose of direct factor Xa inhibitor and possible medication interactions to assist in estimating the degree of anticoagulation exposure (Good Practice statement).
  • We suggest that pharmacologic reversal of oral factor Xa inhibitors should be guided primarily by bleeding (major or intracranial) and not primarily by laboratory testing (Conditional recommendation, low quality evidence).
  • We suggest administration of activated charcoal (50 g) to intubated intracranial hemorrhage patients with enteral access and/or those at low risk of aspiration who present within 2 hours of ingestion of an oral direct factor Xa inhibitor (Conditional recommendation, very low quality evidence).
  • We suggest administering a four-factor PCC (50 U/kg) or activated PCC (aPCC; 50 U/kg) if intracranial hemorrhage occurred within 3–5 terminal half-lives of drug exposure or in the context of liver failure (Conditional recommendation, low quality evidence).
  • We suggest administering four-factor PCC or aPCC over rFVIIa because of the lower risk of adverse thrombotic events (Conditional recommendation, low quality evidence).
Back to Top | Article Outline

DTI Reversal

  • We recommend discontinuing DTIs when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We recommend assessing the time and amount of the last ingested dose, renal function, and possible medication interactions to assist in estimating the degree of anticoagulation exposure (Good Practice statement).
  • We suggest that pharmacologic reversal of DTIs should be guided primarily by bleeding (major or intracranial) and not primarily by laboratory testing (Conditional recommendation, low quality evidence).
  • We suggest administering activated charcoal (50 g) to intubated intracranial hemorrhage patients with enteral access and/or those at low risk of aspiration who present within 2 hours of ingestion of an oral DTI (Conditional recommendation, very low quality evidence).
  • We recommend administering idarucizumab (5 g IV in two divided doses) to patients with intracranial hemorrhage associated with dabigatran if
    • a. the dabigatran was administered within a period of 3–5 half-lives and there is no evidence of renal failure (Strong recommendation, moderate quality of evidence) or
    • b. there is renal insufficiency leading to continued drug exposure beyond the normal 3–5 half-lives (Strong recommendation, moderate quality of evidence).
  • We suggest administering aPCC (50 U/kg) or four-factor PCC (50 U/kg) to patients with intracranial hemorrhage associated with DTIs if idarucizumab is not available or if the hemorrhage is associated with a DTI other than dabigatran and if
    • a. the DTI was administered within a period of 3–5 half-lives and there is no evidence of renal failure (Conditional recommendation, low quality evidence) or
    • b. there is renal insufficiency leading to continued drug exposure beyond the normal 3–5 half-lives (Conditional recommendation, low quality evidence).
  • In patients with dabigatran-associated intracranial hemorrhage and renal insufficiency or dabigatran overdose, we suggest hemodialysis if idarucizumab is not available (Conditional recommendation, low quality data).
  • In patients with dabigatran-associated intracranial hemorrhage who have already been treated with idarucizumab, PCC, or aPCC, with ongoing evidence of clinically significant bleeding, we suggest consideration of redosing idarucizumab and/or hemodialysis (Conditional recommendation, low quality evidence).
  • We recommend against administration of rFVIIa or FFP in DTI-related intracranial hemorrhage (Strong recommendation, low quality evidence).
Back to Top | Article Outline

Unfractionated Heparin Reversal

  • We recommend discontinuing heparin infusions when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We recommend urgently reversing anticoagulation in patients when intracranial hemorrhage develops during full-dose heparin infusion (Good Practice statement).
  • We do not recommend routinely reversing prophylactic subcutaneous heparin (Good Practice statement).
    • a. We suggest considering reversal of prophylactic subcutaneous heparin if the activated partial thromboplastin time (aPTT) is significantly prolonged (Good Practice statement).
  • We recommend administering IV protamine sulfate to reverse heparin in the context of intracranial hemorrhage (Strong recommendation, moderate quality evidence).
    • a. We recommend dosing protamine according to the dose of heparin infused over the preceding 2–3 hours (Strong recommendation, high quality evidence).
    • b. We recommend dosing protamine sulfate at 1 mg for every 100 units of heparin given in the previous 2–3 hours with a maximum single dose of 50 mg (Strong recommendation, moderate quality evidence).
    • c. If the aPTT remains elevated, we suggest repeat administration of protamine at a dose of 0.5 mg protamine per 100 units of unfractionated heparin (Conditional recommendation, low quality of evidence).
Back to Top | Article Outline

LMWH Reversal

  • We recommend discontinuing LMWH when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We recommend reversing LMWH in patients with intracranial hemorrhage receiving therapeutic doses of LMWH (Strong recommendation, moderate evidence).
  • We recommend protamine administration by slow IV injection over a period of about 10 minutes according to the following dosing:
    • a. For enoxaparin: If enoxaparin was given within 8 hours, protamine sulfate should be administered at a dose of 1 mg per 1 mg of enoxaparin administered (up to a maximum single dose of 50 mg). If enoxaparin was given within 8–12 hours, a dose of 0.5 mg of protamine per 1 mg of enoxaparin should be administered. After 3–5 half-lives have elapsed, protamine is probably not needed (Strong recommendation, moderate quality evidence).
    • b. For dalteparin, nadroparin, and tinzaparin: Dose protamine at 1 mg per 100 anti-Xa units of LMWH administered in the past 3–5 half-lives of the drug, up to a maximum single dose of 50 mg (Strong recommendation, moderate quality evidence).
    • c. If life-threatening bleeding persists, or the patient has renal insufficiency, we suggest redosing protamine (0.5 mg of protamine per 100 anti-Xa units or per 1 mg of enoxaparin) (Conditional recommendation, very low quality evidence).
  • We suggest considering rFVIIa (90 μg/kg IV) if protamine is contraindicated (Conditional recommendation, very low quality evidence).
  • We recommend against the reversal of LMWH in patients with intracranial hemorrhage receiving prophylactic dosing of LMWH (Good Practice statement).
  • We suggest against reversing danaparoid with protamine (Conditional recommendation, low quality evidence).
  • We suggest reversing danaparoid with rFVIIa (90 μg/kg IV once) in the context of intracranial hemorrhage (Conditional recommendation, very low quality evidence).
  • We suggest against using FFP, PCC, or aPCC to reverse LMWH (Conditional recommendation, low quality evidence).
Back to Top | Article Outline

Pentasaccharides Reversal

  • We recommend discontinuing pentasaccharides when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We suggest reversing pentasaccharides in patients with intracranial hemorrhage receiving full therapeutic doses (Good Practice statement).
    • a. We suggest administration of aPCC (20 IU/kg) for reversal of pentasaccharides (Conditional recommendation, low quality evidence).
    • b. If aPCC is contraindicated or not available, we suggest administration of rFVIIa (90 μg/kg) (Conditional recommendation, low quality evidence).
    • c. We recommend against protamine for reversal of pentasaccharides (Strong recommendation, low quality evidence).
  • In intracranial hemorrhage patients receiving pentasaccharides for venous thromboembolism prophylaxis, we suggest against reversal unless there is evidence of bioaccumulation or impaired clearance (Good Practice statement).
Back to Top | Article Outline

Thrombolytic Reversal

  • We recommend discontinuing thrombolytic agents when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We suggest using cryoprecipitate (10 units initial dose) in patients with thrombolytic agent-related symptomatic intracranial hemorrhage who have received a thrombolytic agent in the previous 24 hours (Conditional recommendation, low quality evidence).
  • In cases where cryoprecipitate is contraindicated or not available in a timely manner, we suggest using an antifibrinolytic agent (tranexamic acid 10–15 mg/kg IV over 20 min or ε-aminocaproic acid 4–5 g IV) as an alternative to cryoprecipitate (Conditional recommendation, very low quality evidence).
  • We suggest checking fibrinogen levels after administration of reversal agents. If the fibrinogen is less than 150 mg/dL, we suggest administration of additional cryoprecipitate (Conditional recommendation, very low quality evidence).
  • It is unclear if platelet transfusion is useful and we cannot offer a recommendation at this time.
Back to Top | Article Outline

Antiplatelet Agent Reversal

  • We recommend discontinuing antiplatelet agents when intracranial hemorrhage is present or suspected (Good Practice statement).
  • We suggest against platelet transfusion for patients with antiplatelet-associated intracranial hemorrhage who will “not” undergo a neurosurgical procedure, regardless of the type of platelet inhibitor, platelet function testing, hemorrhage volume, or neurologic examination (Conditional recommendation, low quality evidence).
  • We suggest platelet transfusion for patients with aspirin- or adenosine diphosphate (ADP) inhibitor-associated intracranial hemorrhage that will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence).
    • a. We recommend platelet function testing prior to platelet transfusion if possible (Strong recommendation, moderate quality evidence).
    • b. When platelet testing is not readily available, empiric platelet transfusion may be reasonable (Conditional recommendation, low quality evidence).
    • c. We recommend against platelet transfusion for patients with laboratory-documented platelet function within normal limits or documented antiplatelet resistance (Strong recommendation, moderate quality evidence).
  • We suggest against platelet transfusion in nonsteroidal anti-inflammatory drug or glycoprotein IIb/IIIa inhibitor-related intracranial hemorrhage, even in the context of neurosurgical intervention (Conditional recommendation, very low quality evidence).
  • In candidates for platelet transfusion, we suggest an initial dose of one single donor apheresis unit of platelets. Platelet testing is suggested prior to repeat platelet transfusion, if available and repeat transfusion should be used only for those with persistently abnormal platelet function tests (Conditional recommendation, moderate quality evidence).
  • We suggest consideration of a single dose of desmopressin in intracranial hemorrhage (0.4 μg/kg IV) associated with aspirin/cyclooxygenase-1 inhibitors or ADP receptor inhibitors. In patients deemed appropriate (e.g., those undergoing a neurosurgical procedure), desmopressin can be used in addition to platelet transfusion (Conditional recommendation, low quality evidence).
Back to Top | Article Outline

ACKNOWLEDGMENTS

We thank Zoe Oliver, MD, and Frederick A. Zeiler, MD, for their contributions to this document.

Back to Top | Article Outline

REFERENCES

1. Frontera JA, Lewin JJ 3rd, Rabinstein AA, 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. Neurocrit Care 2016; 24:6–46
2. Levy JH, Ageno W, Chan NC, et al; Subcommittee on Control of Anticoagulation: When and how to use antidotes for the reversal of direct oral anticoagulants: Guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14:623–627
3. Jaeschke R, Guyatt GH, Dellinger P, et al; GRADE Working Group: Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ 2008; 337:a744
4. Alexander PE, Gionfriddo MR, Li SA, et al: A number of factors explain why WHO guideline developers make strong recommendations inconsistent with GRADE guidance. J Clin Epidemiol 2016; 70:111–122
5. Rosand J, Eckman MH, Knudsen KA, et al: The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880–884
6. Guyatt GH, Oxman AD, Schünemann HJ, et al: GRADE guidelines: A new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011; 64:380–382
7. Guyatt GH, Schünemann HJ, Djulbegovic B, et al: Guideline panels should not GRADE good practice statements. J Clin Epidemiol 2015; 68:597–600
8. Brozek JL, Akl EA, Alonso-Coello P, et al; GRADE Working Group: Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy 2009; 64:669–677
9. Flaherty ML, Kissela B, Woo D, et al: The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology 2007; 68:116–121
10. Veltkamp R, Rizos T, Horstmann S: Intracerebral bleeding in patients on antithrombotic agents. Semin Thromb Hemost 2013; 39:963–971
11. Franke CL, de Jonge J, van Swieten JC, et al: Intracerebral hematomas during anticoagulant treatment. Stroke 1990; 21:726–730
12. Flibotte JJ, Hagan N, O’Donnell J, et al: Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059–1064
Keywords:

anticoagulant; coagulopathy; guideline; intracranial hemorrhage; reversal

Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.