The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines differs substantially from the prior versions both in process and in content. In this introduction, we describe some of the differences and the rationale for the changes.

Correspondence to: Gordon H. Guyatt, MD, FCCP, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, L8N 3Z5, Canada; e-mail: guyatt@mcmaster.ca

Other contributions: The authors thank Rachel Gutterman, BA, and Joe Ornelas, DC, for their assistance in managing this complex project.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, and has sat on data safety and monitoring boards. His institution has received research funds from the following companies: Leo Pharma A/S, Pfizer Inc, Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Gutterman has had the following relationships that are entirely unrelated to the AT9 guidelines: ACCP President, GlaxoSmithKline plc grant to study vasodilation in adipose tissue, National Institutes of Health grant to study human coronary dilation, and GE Healthcare consultation on a study for ECG evaluation of chronic heart disease. Drs Guyatt and Schünemann are co-chairs of the GRADE Working Group, and Dr Akl is a member and prominent contributor to the GRADE Working Group. Dr Lewis is a full-time employee of the ACCP.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and systematic review and guideline methodologists.Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without significant conflicts of interest participated in making recommendations. Panelists specified the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources and evidence permitted, they created standardized tables that present the quality of the evidence and key results in a transparent fashion.One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality of evidence and strength of recommendations were based on approaches developed by the Grades of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated with these states based on an additional systematic review of evidence regarding patient values and preferences for antithrombotic therapy. These ratings guided value and preference decisions underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance.AT9 methodology reflects the current science of evidence-based clinical practice guideline development, with reliance on high-quality systematic reviews, a standardized process for quality assessment of individual studies and the body of evidence, an explicit process for translating the evidence into recommendations, disclosure of financial as well as intellectual conflicts of interest followed by management of disclosed conflicts, and extensive peer review.From the Department of Clinical Epidemiology and Biostatistics (Drs Guyatt, Akl, Cook, Schulman, and Schünemann) and Department of Medicine (Drs Guyatt, Schulman, Hirsh, Crowther, Eikelboom, Cook, and Schünemann), McMaster University Faculty of Health Sciences, Hamilton, ON, Canada; Department of Medical Informatics and Clinical Epidemiology (Drs Norris and McDonagh), Oregon Health & Science University, Portland, OR; Division of General Internal Medicine and Center for Clinical Effectiveness (Dr Eckman), University of Cincinnati, Cincinnati, OH; Departments of Medicine and Family Medicine (Dr Akl), State University of New York, Buffalo, NY; Department of Medicine Gjøvik-Innlandet Hospital Trust and Norwegian Knowledge Centre for the Health Services (Dr Vandvik), Oslo, Norway; Evidence-Based Clinical Practice Guidelines and Clinical Standards (Dr Lewis), American College of Chest Physicians, Northbrook, IL; and Cardiovascular Research Center (Dr Gutterman), Medical College of Wisconsin, Milwaukee, WI.

Correspondence to: Gordon H. Guyatt, MD, FCCP, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, L8N 3Z5, Canada; e-mail: guyatt@mcmaster.ca

Author contributions: Authors contributed to the AT9 guideline process in the roles described in the article. As Topic Editor and Chair of the guideline, Dr Guyatt oversaw the development of this article.

Dr Guyatt: produced the first draft and was responsible for the final article.

Dr Norris: undertook a major revision of a late draft of the article.

Dr Schulman: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Hirsh: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Eckman: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Akl: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Crowther: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Vandvik: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Eikelbloom: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr McDonagh: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Lewis: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Gutterman: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Cook: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Dr Schünemann: took responsibility for sections relevant to their role in AT9 and reviewed and approved the final article.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Eckman has received the following university grants: “Using Decision Analytic Modeling to Guide the ACCP Guideline Development Process for Antithrombotic Therapy in Atrial Fibrillation” (Foundation for Informed Medical Decision Making; October 2011-September 2013; $185,000); “Cost-Effectiveness of Screening for Chronic Hepatitis C Infection” (Merck/Schering-Plough; October 2011- September 2012; $58,000); “Greater Cincinnati BEACON Collaborative” (Office of the National Coordinator for Health Information Technology [90BC0016/01]; September 2010-March 2012; ∼15% effort); “Cincinnati Center for Clinical and Translational Science and Training (CTSA) ARRA Supplement for Development of Distance Learning Program in Medical Informatics” (National Institutes of Health [NIH]/National Center for Research Resources [NCRR] [UL1 RR026314-01S1]; August 2009-August 2011; ∼20% effort); “Cincinnati Center for Clinical and Translational Science and Training (CTSA)” (NIH/NCRR [1U54 RR 025216]; January 2009-February 2014; ∼15% effort); “A Patient Specific Decision Support Tool for Bariatric Surgery” (National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK075599]; August 2007-June 2012; no financial support); National Heart, Lung, and Blood Institute (K23 HL085387; June 2008-March 2013; no financial support); and “Cost-Effectiveness of Screening for Chronic Hepatitis B Infection” (Gilead Sciences Inc; March 2008-August 2010; ∼$56,000). He has also served as consultant for Savient Pharmaceuticals (“Cost Effectiveness Analysis of Gout Medication”; 2010; ∼$300) and as editorial consultant for the ACCP (“Physicians’ Information and Education Resource [PIER]: Module on Pre-Operative Assessment for Bleeding Disorders”; 2006-present; ∼$250/y). Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, and has sat on data safety and management boards. His institution has received research funds from the following companies: Leo Pharma A/S, Pfizer Inc, Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Eikelboom has received consulting fees and honoraria from AstraZeneca; Boehringer-Ingelheim GmbH; Bristol-Myers Squibb; Corgenix; Daiichi-Sankyo, Inc; Eisai Co, Inc; Eli Lilly and Company; GlaxoSmithKline plc; Haemonetics Corp; McNeil Consumer Healthcare; and Sanofi-Aventis LLC and grants and in-kind support from Accumetrics, Inc; AspirinWorks; Bayer Healthcare Pharmaceuticals; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Corgenix; Dade Behring Inc; GlaxoSmithKline plc; and Sanofi-Aventis LLC. Dr Gutterman has had the following relationships that are entirely unrelated to the AT9 guidelines: ACCP President, GlaxoSmithKline plc grant to study vasodilation in adipose tissue, National Institutes of Health grant to study human coronary dilation, and GE Healthcare consultation on a study for ECG evaluation of chronic heart disease. Drs Guyatt and Schünemann are co-chairs of the GRADE Working Group, and Drs Akl and Vandvik are members and prominent contributors to the Grade Working Group. Dr Lewis is a full-time employee of the ACCP. Drs Norris, Schulman, Hirsh, McDonagh, and Cook have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Development of clinical practice guidelines involves making trade-offs between desirable and undesirable consequences of alternative management strategies. Although the relative value of health states to patients should provide the basis for these trade-offs, few guidelines have systematically summarized the relevant evidence. We conducted a systematic review relating to values and preferences of patients considering antithrombotic therapy.We included studies examining patient preferences for alternative approaches to antithrombotic prophylaxis and studies that examined, in the context of antithrombotic prophylaxis or treatment, how patients value alternative health states and experiences with treatment. We conducted a systematic search and compiled structured summaries of the results. Steps in the process that involved judgment were conducted in duplicate.We identified 48 eligible studies. Sixteen dealt with atrial fibrillation, five with VTE, four with stroke or myocardial infarction prophylaxis, six with thrombolysis in acute stroke or myocardial infarction, and 17 with burden of antithrombotic treatment.Patient values and preferences regarding thromboprophylaxis treatment appear to be highly variable. Participant responses may depend on their prior experience with the treatments or health outcomes considered as well as on the methods used for preference elicitation. It should be standard for clinical practice guidelines to conduct systematic reviews of patient values and preferences in the specific content area.From the Department of Biostatistics and Clinical Epidemiology (Ms MacLean, Messrs Mulla and Ebrahim, and Drs Akl and Guyatt) and Health Sciences Library (Ms Bhatnagar), McMaster University, Hamilton, ON, Canada; Department of Internal Medicine (Dr Jankowski), Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland; Division of Emergency Medicine (Ms McLeod), Department of Medicine, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada; Department of Medicine (Dr Akl), State University of New York at Buffalo, Buffalo, NY; and Norwegian Knowledge Centre for the Health Services and Department of Medicine Gjøvik (Dr Vandvik), Innlandet Hospital Trust, Gjøvik, Norway.

Correspondence to: Samantha MacLean, MSc, McMaster University, 1200 Main St W, Hamilton, ON, L8N 3Z5, Canada; e-mail: macleast@mcmaster.ca

Author contributions: As Topic Editor, Ms MacLean oversaw the development of this article, including the data analysis and findings contained herein

Ms MacLean: served as Topic Editor

Mr Mulla: served as a panelist

Dr Jankowski: served as a panelist

Dr Akl: served as a panelist

Dr Vandvik: served as a panelist

Mr Ebrahim: served as a panelist

Ms McLeod: served as a panelist

Ms Bhatnagar: served as a panelist

Dr Guyatt: served as a panelist

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Guyatt is co-chair of the GRADE Working Group, and Drs Akl and Vandvik are members and prominent contributors to the Grade Working Group. Mss MacLean, McLeod, and Bhatnagar; Messrs Mulla and Ebrahim; and Dr Jankowski have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

Correspondence to: David A. Garcia, MD, 1 University of New Mexico, MSC07-4025, Albuquerque, NM 87131; e-mail: davgarcia@salud.unm.edu

Author Contributions: As Topic Editor, Dr Garcia oversaw the development of this article, including any analysis and subsequent development of the information contained herein.

Dr Garcia: contributed as a Topic Editor.

Dr Baglin: contributed as a panelist.

Dr Weitz: contributed as a panelist.

Dr Samama: contributed as a panelist.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Drs Weitz and Garcia have served as consultants for Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Bayer, and Johnson & Johnson. Dr Samama has received honoraria for lectures or consulting from Bayer Healthcare, Johnson & Johnson, Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, and Rovi, and has served on a steering committee for Daiichi-Sankyo. Dr Baglin has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management.We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxabanThe antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal.There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.From the University of Insubria (Dr Ageno), Varese, Italy; Flinders University (Dr Gallus), Adelaide, SA, Australia; the University of Washington (Dr Wittkowsky), Seattle, WA; McMaster University (Dr Crowther), St. Joseph’s Hospital, Hamilton, ON, Canada; the Boston University School of Medicine (Dr Hylek), Boston, MA; and the University Hospital S. Orsola-Malpighi (Dr Palareti), Bologna, Italy.

Correspondence to: Walter Ageno, MD, Department of Clinical Medicine, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy; e-mail: walter.ageno@uninsubria.it

Author contributions: As Topic Editor, Dr Ageno oversaw the development of this article, including any analysis and subsequent development of the information contained herein

Dr Ageno: contributed as Topic Editor

Dr Gallus: contributed as a panelist

Dr Wittkowsky: contributed as a panelist

Dr Crowther: contributed as a panelist

Dr Hylek: contributed as a panelist

Dr Palareti: contributed as a panelist

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Ageno has received fees for steering committee or safety advisory boards membership from Bayer Health Care, sanofi-aventis, and Thrombogenics; research grants from GlaxoSmithKline, Alexion Pharmaceutical, Pfizer, and Bayer Health Care; honoraria for speaking activities at national or international meetings and for advisory boards from Bayer Health Care, GlaxoSmithKline, sanofi-aventis, Pfizer, BMS, and Boehringer Ingelheim. Dr Gallus has received fees for steering committee membership from BMS, Pfizer, sanofi-aventis, Bayer, ASTELLAS, Daiichi Sankyo. Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, has sat on data and safety monitoring boards, and his institution has received research funds from the following companies: Leo Pharma, Pfizer, Boehringer Ingelheim, Bayer, Octapharm, CSL Behring, and Artisan. His personal total compensation for these activities over the last 3 years totals less than $10,000. Dr Hylek has served on advisory boards (Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Ortho-McNeil, and Pfizer; total dollar amount less than $10,000). She has served on the Executive Steering Committee-ARISTOTLE trial sponsored by Bristol-Myers Squibb and Pfizer (dollar amount less than $10,000). She has also served on the Executive Steering Committee-ORBIT AF Registry sponsored by Ortho-McNeil (dollar amount less than $10,000). She has participated in a symposium sponsored by Boehringer Ingelheim (dollar amount less than $10,000). Drs Wittkowsky and Palareti have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e44S/suppl/DC1.

The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment.

Correspondence to: John W. Eikelboom, MBBS, McMaster University, Hamilton General Site, 237 Barton St E, Hamilton, ON, L9K 1H8, Canada; e-mail: eikelbj@mcmaster.ca

Author contributions: As Topic Editor, Dr Eikelboom oversaw the development of this article, including any analysis and subsequent development of the information contained herein.

Dr Eikelboom: contributed as Topic Editor.

Dr Hirsh: contributed as a panelist.

Dr Spencer: contributed as a panelist.

Dr Baglin: contributed as a panelist.

Dr Weitz: contributed as a panelist.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Eikelboom has received consulting fees and/or honoraria from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Corgenix, Daiichi-Sankyo, Eisai, Eli-Lilly, GlaxoSmithKline, Haemoscope, Johnson and Johnson, McNeil, Pfizer, Portola and Sanofi. He has received grants and/or in-kind support from Accumetrics, Astra-Zeneca, AspirinWorks, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Corgenix, Dade-Behring, GlaxoSmithKline, Johnson and Johnson, Portola and Sanofi. Dr Weitz has served as a consultant to Boehringer Ingelheim GmbH, Bristol-Myers Squibb; Pfizer Inc; Daiichi-Sankyo, Inc; Bayer Healthcare Pharmaceuticals, and Johnson & Johnson. Drs Hirsh, Spencer, and Baglin have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents.

Correspondence to: Jeffrey I. Weitz, MD, FCCP, Thrombosis and Atherosclerosis Research Institute, 237 Barton St E, Hamilton, ON, L8L 2X2, Canada; e-mail: weitzj@taari.ca

Author contributions: As Topic Editor, Dr Weitz oversaw the development of this article, including any analysis and subsequent development of the information contained herein.

Dr Weitz: contributed as Topic Editor.

Dr Eikelboom: contributed as a panelist.

Dr Samama: contributed as a panelist.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Weitz is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and holds the Heart and Stroke Foundation of Ontario/J. Fraser Mustard Chair in Cardiovascular Research and the Canada Research Chair in Thrombosis at McMaster University. Dr Weitz has served as a consultant at Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Bayer, and Johnson & Johnson. Dr Eikelboom has received consulting fees and/or honoraria from Astra-Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Corgenix, Daiichi-Sankyo, Eisai, Eli-Lilly, GlaxoSmithKline, Haemoscope, Johnson & Johnson, McNeil, Pfizer, Portola, and Sanofi. He has received grants and/or in-kind support from Accumetrics, Astra-Zeneca, AspirinWorks, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corgenix, Dade-Behring, GlaxoSmithKline, Johnson & Johnson, Portola, and Sanofi. Dr Samama has received honoraria for lectures or consulting from Bayer Healthcare, Johnson & Johnson, Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, and Rovi, and has served on a steering committee for Daiichi-Sankyo.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.From the Division of Clinical Pharmacology and Therapeutics (Dr Holbrook), Department of Medicine (Drs Holbrook, Schulman, Crowther, and Guyatt), and Department of Epidemiology and Biostatistics (Drs Holbrook and Guyatt), McMaster University, Hamilton, ON, Canada; Department of Pharmacy (Dr Witt), Kaiser Permanente Colorado, Denver, CO; Department of Medicine (Dr Vandvik), Innlandet Hospital Trust, Gjøvik, Norway; Department of Internal Medicine (Dr Fish), University of California Los Angeles, Los Angeles, CA; Department of Medicine (Dr Kovacs), University of Western Ontario, London, ON, Canada; Department for Coagulation Disorders (Dr Svensson), University of Lund, University Hospital, Malmö, Sweden; and Department of Pharmacy (Dr Veenstra), University of Washington, Seattle, WA.

Correspondence to: Anne Holbrook, MD, PharmD, Division of Clinical Pharmacology and Therapeutics, McMaster University, c/o Centre for Evaluation of Medicines, 105 Main St E, P1 Level, Hamilton, ON, L8N 1G6, Canada; e-mail: holbrook@mcmaster.ca

Author contributions: As Topic Editor, Dr Holbrook oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein

Dr Holbrook: served as Topic Editor.

Dr Schulman: served as Deputy Editor.

Dr Witt: served as a panelist.

Dr Vandvik:^, served as a panelist.

Dr Fish: served as a frontline clinician.

Dr Kovacs: served as a panelist.

Dr Svensson: served as a panelist.

Dr Veenstra: served as a resource consultant.

Dr Crowther: served as a panelist.

Dr Guyatt: served as guideline editor and contributed to the editing of this manuscript.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e152S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Crowther hass served on various advisory boards, has assisted in the preparation of educational materials, and has sat on data safety and monitoring boards. His institution has received research funds from the following companies: Leo Pharma A/S, Pfizer Inc, Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Guyatt is co-chair of the GRADE Working Group and Dr Vandvik is a prominent contributor to the GRADE Working Group. Drs Holbrook, Schulman, Witt, Fish, Kovacs, Svensson, and Veenstra have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e152S/suppl/DC1.

This article provides the rationale for the approach to making recommendations primarily used in four articles of the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines: orthopedic surgery, nonorthopedic surgery, nonsurgical patients, and stroke. Some of the early clinical trials of antithrombotic prophylaxis with a placebo or no treatment group used symptomatic VTE and fatal PE to measure efficacy of the treatment. These trials suggest a benefit of thromboprophylaxis in reducing fatal PE. In contrast, most of the recent clinical trials comparing the efficacy of alternative anticoagulants used a surrogate outcome, asymptomatic DVT detected at mandatory venography. This outcome is fundamentally unsatisfactory because it does not allow a trade-off with serious bleeding; that trade-off requires knowledge of the number of symptomatic events that thromboprophylaxis prevents. In this article, we review the merits and limitations of four approaches to estimating reduction in symptomatic thrombosis: (1) direct measurement of symptomatic thrombosis, (2) use of asymptomatic events for relative risks and symptomatic events from randomized controlled trials for baseline risk, (3) use of baseline risk estimates from studies that did not perform surveillance and relative effect from asymptomatic events in randomized controlled trials, and (4) use of available data to estimate the proportion of asymptomatic events that will become symptomatic. All approaches have their limitations. The optimal choice of approach depends on the nature of the evidence available.

Correspondence to: Gordon H. Guyatt, MD, FCCP, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: guyatt@mcmaster.ca

Author contributions: As Topic Editor, Dr Guyatt oversaw the development of this article, including any analysis and subsequent development of the information contained herein.

Dr Guyatt: served as a Topic Editor and was responsible for drafting the entire article, with the exception of the first part on evidence regarding the impact of antithrombotic prophylaxis on mortality, and for final editing and content.

Dr Eikelboom: served as a panelist and was responsible for drafting the first part of this article dealing with the evidence regarding the impact of antithrombotic prophylaxis on mortality.

Dr Gould: served as a panelist and provided intellectual input, critique, and revisions.

Dr Garcia: served as a panelist and provided intellectual input, critique, and revisions.

Dr Crowther: served as a panelist and provided intellectual input, critique, and revisions.

Dr Murad: served as a panelist and provided intellectual input, critique, and revisions.

Dr Kahn: served as a panelist and provided intellectual input, critique, and revisions.

Dr Falck-Ytter: served as a panelist and provided intellectual input, critique, and revisions.

Dr Francis: served as a panelist and provided intellectual input, critique, and revisions.

Dr Lansberg: served as a panelist and provided intellectual input, critique, and revisions.

Dr Akl: served as a panelist and provided intellectual input, critique, and revisions.

Dr Hirsh: served as a panelist and was responsible for drafting the first part of this article dealing with the evidence regarding the impact of antithrombotic prophylaxis on mortality.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Dr Eikelboom has received consulting fees and honoraria from AstraZeneca; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Corgenix; Daiichi-Sankyo, Inc; Eisai Co, Inc; Eli Lilly and Company; GlaxoSmithKline plc; Haemonetics Corp; McNeil Consumer Healthcare; and Sanofi-Aventis LLC and grants and in-kind support from Accumetrics, Inc; AspirinWorks; Bayer Healthcare Pharmaceuticals; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Corgenix; Dade Behring Inc; GlaxoSmithKline plc; and Sanofi-Aventis LLC. Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, and has sat on data safety and management boards. His institution has received research funds from the following companies: Leo Pharma A/S, Pfizer Inc, Boehringer Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and postthrombotic syndrome prevention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Francis received research grant support from the National Heart Lung and Blood Institute and Eisai Co. Ltd, and served as a steering committee member for a clinical trial sponsored by Eisai Co, Ltd. Dr Francis has also worked on projects supported by Eisai Co, Ltd, and sanofi -aventis. Dr Guyatt is co-chair of the GRADE Working Group and Drs Murad, Falck-Ytter, and Akl are contributing members. Drs Gould, Garcia, Lansberg, and Hirsh have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

This guideline addressed VTE prevention in hospitalized medical patients, outpatients with cancer, the chronically immobilized, long-distance travelers, and those with asymptomatic thrombophilia.This guideline follows methods described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C). For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C). In outpatients with cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B).Decisions regarding prophylaxis in nonsurgical patients should be made after consideration of risk factors for both thrombosis and bleeding, clinical context, and patients’ values and preferences.From the Department of Medicine (Dr Kahn), McGill University, Montreal, QC, Canada; the Department of Medicine (Drs Lim and Cook), Division of Hematology and Thromboembolism (Dr Schulman), and the Department of Clinical Epidemiology and Biostatistics (Drs Akl and Cook), McMaster University, Hamilton, ON, Canada; the Department of Medicine (Dr Dunn), Mount Sinai School of Medicine, New York, NY; the Department of Medicine (Dr Cushman), University of Vermont and Fletcher Allen Health Care, Burlington, VT; the Department of Clinical Medicine (Dr Dentali), University of Insubria, Varese, Italy; the Department of Medicine (Dr Akl), University at Buffalo, Buffalo, NY; the Division of Pulmonary and Critical Care Medicine (Dr Balekian), Keck School of Medicine, University of Southern California, Los Angeles, CA; the Huntington Beach Internal Medicine Group (Dr Klein), Newport Beach, CA; the Department of Pulmonary and Critical Care Medicine (Dr Klein), University of California Irvine School of Medicine, Orange, CA; the Hoag Memorial Hospital Presbyterian (Dr Le), Newport Beach, CA; the Pulmonary Division (Dr Le), Fountain Valley Regional Hospital, Fountain Valley, CA; and the Division of Preventive Medicine and the Knowledge and Evaluation Research Unit (Dr Murad), Mayo Clinic, Rochester, MN.

Correspondence to: M. Hassan Murad, MD, MPH, 200 First St SW, Rochester, MN 55905; e-mail: Murad.Mohammad@mayo.edu

Author contributions: As Topic Editor, Dr Murad oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.Dr Murad: contributed as Topic Editor.

Dr Kahn: contributed as Deputy Editor.

Dr Lim: contributed as a panelist.

Dr Dunn: contributed as a panelist.

Dr Cushman: contributed as a panelist.

Dr Dentali: contributed as a panelist.

Dr Akl: contributed as a panelist.

Dr Cook: contributed as a panelist.

Dr Balekian: contributed as a resource consultant.

Dr Klein: contributed as a frontline clinician.

Dr Le: contributed as a frontline clinician.

Dr Schulman: contributed as a panelist.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e195S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and postthrombotic syndrome prevention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Balekian received industry research support and served as a consultant in areas relating to venous thrombosis. Dr Cook has received donated study drug (dalteparin) from Pfizer for a Canadian government-funded trial of thromboprophylaxis in the ICU. Dr Cushman is the mentor on a mentored research grant from the Hemophilia and Thrombosis Research Society that is studying risk factors for venous thrombosis among medical inpatients, 2009-2011. No specific dollar amount goes toward her salary. Dr Akl is a prominent contributor to the GRADE Working Group. Dr Murad is a member of the GRADE Working Group. Drs Lim, Dunn, Dentali, Klein, Le, and Schulman have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplemental Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e195S/suppl/DC1.

VTE is a common cause of preventable death in surgical patients.We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We developed similar recommendations for other nonorthopedic surgical populations.Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the values and preferences of individual patients.From the Keck School of Medicine (Dr Gould), University of Southern California, Los Angeles, CA; University of New Mexico School of Medicine (Dr Garcia), Albuquerque, NM; Stanford School of Medicine (Dr Wren), Stanford, CA; Surgical Oncology (Dr Karanicolas), Sunnybrook Health Sciences Centre, Toronto, ON, Canada; University of Granada Medical School (Dr Arcelus), Granada, Spain; College of Medicine (Dr Heit), Mayo Clinic, Rochester, MN; and Department of Anaesthesiology and Intensive Care (Dr Samama), Hotel-Dieu University Hospital, Paris, France.

Correspondence to: Michael K. Gould, MD, FCCP, Department of Research and Evaluation, 100 S Los Robles, Pasadena, CA 91101; e-mail: michael.k.gould@kp.org

Author contributions: As Topic Editor, Dr Gould oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Gould: contributed as topic editor and resource consultant.

Dr Garcia: contributed as deputy editor.

Dr Wren: contributed as frontline clinician.

Dr Karanicolas: contributed as panelist.

Dr Arcelus: contributed as panelist.

Dr Heit: contributed as panelist.

Dr Samama: contributed as panelist.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e227S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Arcelus participated as an invited speaker in three lectures in Australia in March 2010 sponsored by Sanofi-Aventis LLC. Dr Samama reports serving as co-investigator for two observational studies of VTE prophylaxis in surgical patients with cancer, sponsored by Sanofi-Aventis. Dr Samama has also received consulting honoraria from companies that manufacture hemostatic agents (LFB, Octapharma, CSL, and Behring) and from companies that manufacture anticoagulants (Boehringer Ingelheim, Bayer, and Daichii Sankyo), though most of the funds have gone to his institution. Dr Samama's travel expenses to two recent conferences were paid by Bayer. Drs Gould, Garcia, Heit, Karanicolas, and Wren have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Other contributions: We gratefully acknowledge the contributions of Peter Mestaz, MS, who served as project manager, and Li Yao, PhD, who performed statistical analyses. In addition, we thank Susan L. Norris, MD, MPH, and Marian S. McDonagh, PharmD, from the Oregon Evidence-Based Practice Center for performing literature searches and abstracting data. Finally, we thank Alex A. Balekian, MD, MSHS, for identifying and synthesizing information about resource utilization.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: Appendix S1 and the supplement Figures and Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e227S/suppl/DC1.

VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT.The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B).Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.From the Department of Medicine (Dr Falck-Ytter), School of Medicine, Case Western Reserve University, Cleveland, OH; Hematology/Oncology Unit (Dr Francis), University of Rochester Medical Center, Rochester, NY; Department of Orthopaedic Surgery (Dr Johanson), Drexel University College of Medicine, Philadelphia, PA; Division of Hospital Medicine (Dr Curley), MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH; Innlandet Hospitals (Dr Dahl), Brumunddal, Norway; Thrombosis Research Institute (Dr Dahl), Chelsea, London, England; Department of Medicine (Dr Schulman), Division of Hematology and Thromboembolism, McMaster University, Hamilton, ON, Canada; Hemostasis and Thrombosis Center (Dr Ortel), Duke University Health System, Durham, NC; Tufts Medical Center (Dr Pauker), Boston, MA; and Shiley Center for Orthopaedic Research and Education at Scripps Clinic (Dr Colwell), La Jolla, CA.

Correspondence to: Yngve Falck-Ytter, MD, Department of Medicine, School of Medicine, Case Western Reserve University, Case and VA Medical Center, 10701 East Blvd, Cleveland, OH 44106; e-mail: Yngve.Falck-Ytter@case.edu

Author contributions: As Topic Editor, Dr Falck-Ytter oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Falck-Ytter: served as Topic Editor.

Dr Francis: served as Deputy Editor.

Dr Johanson: served as a panelist.

Dr Curley: served as frontline clinician.

Dr Dahl: served as a panelist.

Dr Schulman: served as a panelist.

Dr Ortel: served as a panelist.

Dr Pauker: served as a panelist.

Dr Colwell: served as a panelist.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e278S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Francis received research grant support from the National Heart, Lung, and Blood Institute and Eisai Co, Ltd, and served as a steering committee member for a clinical trial sponsored by Eisai Co, Ltd. Dr Dahl has participated in scientific and speaking activities directly and indirectly sponsored by Boehringer Ingelheim GmbH, GlaxoSmithKline plc, Sanofi-Aventis LLC, Bayer Healthcare Pharmaceuticals, and Pfizer Inc. Dr Ortel received research grant support from the National Heart, Lung, and Blood Institute; the Centers for Disease Control and Prevention; Eisai Co, LtD; GlaxoSmithKline plc; Pfizer Inc; and Daiichi Sankyo, and has been a consultant for Sanofi-Aventis LLC and Boehringer Ingelheim GmbH. Dr Ortel has also received grant funds and speaking fees from Instrumentation Laboratories, Inc. Dr Colwell has been a consultant and received research funds from Medical Compression Systems, Ltd, but recused himself in determination of use of compression devices for the Antithrombotic Therapy and Prevention of Thrombosis 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Drs Falck-Ytter, Johanson, Curley, Schulman, and Pauker have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Figures and Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e278S/suppl/DC1.

This guideline addresses the management of patients who are receiving anticoagulant or antiplatelet therapy and require an elective surgery or procedure.The methods herein follow those discussed in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement.In patients requiring vitamin K antagonist (VKA) interruption before surgery, we recommend stopping VKAs 5 days before surgery instead of a shorter time before surgery (Grade 1B). In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during VKA interruption (Grade 2C); in patients at low risk, we suggest no bridging instead of bridging (Grade 2C). In patients who require a dental procedure, we suggest continuing VKAs with an oral prohemostatic agent or stopping VKAs 2 to 3 days before the procedure instead of alternative strategies (Grade 2C). In moderate- to high-risk patients who are receiving acetylsalicylic acid (ASA) and require noncardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C). In patients with a coronary stent who require surgery, we recommend deferring surgery > 6 weeks after bare-metal stent placement and > 6 months after drug-eluting stent placement instead of undertaking surgery within these time periods (Grade 1C); in patients requiring surgery within 6 weeks of bare-metal stent placement or within 6 months of drug-eluting stent placement, we suggest continuing antiplatelet therapy perioperatively instead of stopping therapy 7 to 10 days before surgery (Grade 2C).Perioperative antithrombotic management is based on risk assessment for thromboembolism and bleeding, and recommended approaches aim to simplify patient management and minimize adverse clinical outcomes.From the Department of Medicine (Drs Douketis and Spencer), McMaster University, Hamilton, ON, Canada; Department of Medicine (Dr Spyropoulos), University of Rochester, Rochester, NY; Medical Outpatient Department (Dr Mayr), University Hospital Basel, Basel, Switzerland; Division of Hospital Medicine (Dr Jaffer), Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Division of General Internal Medicine and Center for Clinical Effectiveness (Dr Eckman), University of Cincinnati Medical Center, Cincinnati, OH; Department of Medicine (Dr Dunn), Mount Sinai School of Medicine, New York, NY; and Academy of Swiss Insurance Medicine (Dr Kunz), Department of Medicine, University Hospital Basel, Basel, Switzerland.

Correspondence to: Regina Kunz, MD, MSc (Epi), Academy of Swiss Insurance Medicine, Department of Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland; e-mail: RKunz@uhbs.ch

Author contributions: As Topic Editor, Dr Kunz oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Douketis: contributed as Deputy Editor for this topic.

Dr Spyropoulos: contributed as a panelist.

Dr Spencer: contributed as a panelist.

Dr Mayr: contributed as a frontline clinician.

Dr Jaffer: contributed as a panelist.

Dr Eckman: contributed as a resource consultant.

Dr Dunn: contributed as a panelist.

Dr Kunz: contributed as Topic Editor for this section.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e326S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Douketis was a consultant for Boerhinger-Ingelheim and served as a consultant during four advisory board meetings meetings (by Sanofi-Aventis, Astra-Zeneca, Boehringer-Ingelheim, Pfizer) relating to the development and clinical use of novel, but not approved for clinical use, antiplatelet drugs (ticagrelor) and anticoagulant drugs (apixaban, semuloparin, dabigatran). Dr Eckman has received the following university grants: “Using Decision Analytic Modeling to Guide the ACCP Guideline Development Process for Antithrombotic Therapy in Atrial Fibrillation” (Foundation for Informed Medical Decision Making; October 2011-September 2013; $185,000); “Cost-Effectiveness of Screening for Chronic Hepatitis C Infection” (Merck/Schering-Plough; October 2011-September 2012; $58,000); “Greater Cincinnati BEACON Collaborative” (Office of the National Coordinator for Health Information Technology [90BC0016/01]; September 2010-March 2012; ∼ 15% effort); “Cincinnati Center for Clinical and Translational Science and Training (CTSA) ARRA Supplement for Development of Distance Learning Program in Medical Informatics” (National Institutes of Health [NIH]/National Center for Research Resources [NCRR] [UL1 RR026314-01S1]; August 2009-August 2011; ∼ 20% effort); “Cincinnati Center for Clinical and Translational Science and Training (CTSA)” (NIH/NCRR [1U54 RR 025216]; January 2009-February 2014; ∼ 15% effort); “A Patient Specific Decision Support Tool for Bariatric Surgery” (National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK075599]; August 2007-June 2012; no financial support); National Heart, Lung, and Blood Institute (K23 HL085387; June 2008-March 2013; no financial support); and “Cost-Effectiveness of Screening for Chronic Hepatitis B Infection” (Gilead Sciences Inc; March 2008-August 2010; ∼ $56,000). He has also served as consultant for Savient Pharmaceuticals (“Cost Effectiveness Analysis of Gout Medication”; 2010; ∼ $300) and as editorial consultant for the ACP (“Physicians’ Information and Education Resource [PIER]: Module on Pre-Operative Assessment for Bleeding Disorders”; 2006-present; ∼ $250/year). Dr Spyropoulos has served as a consultant to Pfizer, Sanofi-Aventis, and EISAI. Dr Jaffer served as a consultant to sanofi-aventis, Janssen, Canyon Pharmaceuticals, Boehringer Ingelheim, and Daiichi Sankyo; he has formerly spoken on behalf of sanofi-aventis. Dr Jaffer is also on the steering committee of an NHLBI clinical trial. Dr Kunz is a member of the GRADE Working Group, the methodology of which is used in these guidelines. She has an interest in seeing this methodology applied. Drs Spencer, Mayr, and Dunn have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Other contributions: Deborah Siegal, MD, contributed to the generation of the evidence profiles for the recommendations 2.4 and 4.2-4.4.

Additional information: The Appendix S1 and supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e326S/suppl/DC1.

Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults.The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B).Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.From the Department of Medicine (Drs Bates and Crowther), McMaster University and Thrombosis and Atherosclerosis Research Institute; the Departments of Medicine and Clinical Epidemiology and Biostatistics (Drs Jaeschke, Schunemann, and Guyatt), McMaster University, Hamilton, ON, Canada; the Department of Medicine (Dr Stevens), Intermountain Medical Center, Murray, UT; the School of Health and Related Research (Drs Goodacre and Stevenson), University of Sheffield, Sheffield, England; the Department of Medicine (Dr Wells), University of Ottawa, Ottawa, ON, Canada; the Department of Medicine (Dr Pauker), Tufts New England Medical Center, Boston, MA; and the Department of Medicine (Dr Makdissi), University of Buffalo, Buffalo, NY.

Correspondence to: Shannon M. Bates, MDCM, HSC 3W11, Department of Medicine, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: batesm@mcmaster.ca

Author contributions: As Topic Editor, Dr Jaeschke oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Bates: contributed as Deputy Editor.

Dr Jaeschke: contributed as Topic Editor.

Dr Stevens: contributed as a panelist.

Dr Goodacre: contributed as a panelist.

Dr Wells: contributed as a panelist.

Dr Stevenson: contributed as a panelist.

Dr Kearon: contributed as a panelist.

Dr Schunemann: contributed as a panelist.

Dr Crowther: contributed as a panelist.

Dr Pauker: contributed as a panelist.

Dr Makdissi: contributed as a frontline clinician.

Dr Guyatt: contributed as a panelist.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e351S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Bates has received peer-reviewed research funding for studies evaluating D-dimer in the diagnosis of deep vein thrombosis, as well as research support from Trinity Biotech and Diagnostica Stago (manufacturers of D-dimer assays). Dr Goodacre was Chief Investigator for the project “Non Invasive Diagnostic Tests for DVT,” funded by the UK National Institute for Health Research Health Technology Assessment Programme, reference HTA 02/03/01, from 2003-2006 (see http://www.hta.ac.uk/1340). Dr Stevenson participated in this project. Dr Kearon is a paid Steering Committee member for Boehringer Ingelheim VTE treatment studies, receives grant support from the National Institutes of Health for a study evaluating catheter-directed thrombolysis for treatment of DVT, and receives grant support from the Canadian Institutes of Health Research for a study evaluating D-dimer in the treatment of VTE. He has also received industry support for studies evaluating D-dimer, including grants and in-kind D-dimer kit supplies. Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, has sat on Data Safety Monitoring Boards (DSMBs), and his institution has received research funds from the following companies: Leo Pharma, Pfizer, Boehringer Ingelheim, Bayer, Octapharma, CSL Behring, and Artisan. His personal total compensation for these activities over the last 3 years totals less than $10,000. Further, Dr Crowther has provided expert testimony for Bayer in an area unrelated to antithrombotic therapy. He holds the Leo Pharma Chair in Thromboembolism Research at McMaster University. Dr Wells has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis treatment. He has received honoraria for industry-sponsored (Bayer, Boehringer-Ingelheim, Pfizer, BioMerieux, sanofi-aventis) talks pertaining to venous thrombosis and has attended advisory boards for Bayer, Boerhringer-Ingelheim, Pfizer, and Bristol-Myers-Squibb. Drs Guyatt and Schunemann are co-chairs of the GRADE Working Group, and Dr Jaeschke is a prominent contributor to the GRADE Working Group. Drs Stevens, Pauker, and Makdissi have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e351S/suppl/DC1.

This article addresses the treatment of VTE disease.We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence.For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C).Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke.The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C).Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.From the Department of Medicine (Drs Linkins, Schulman, and Crowther), McMaster University, Hamilton, ON, Canada; the College of Medicine (Dr Dans), University of the Philippines Manila, Manila, Philippines; The Uniformed Services (Dr Moores), University of Health Sciences, Bethesda, MD; School of Medicine (Dr Bona), Quinnipiac University, North Haven, CT; and the University of Washington School of Medicine (Dr Davidson), Seattle, WA.

Correspondence to: Lori-Ann Linkins, MD, Department of Medicine, McMaster University, Juravinski Hospital, Rm-M0118, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: linkinla@mcmaster.ca

Author Contributions: As Topic Editor, Dr Linkins oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Linkins: contributed as Topic Editor.

Dr Dans: contributed as panelist.

COL Moores: contributed as panelist.

Dr Bona: contributed as frontline clinician.

Dr Davidson: contributed as panelist.

Dr Schulman: contributed as panelist.

Dr Crowther: contributed as panelist.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e495S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Linkins has two potential indirect financial conflict of interests based on a peer-reviewed grant received from the Heart and Stroke Foundation of Canada to conduct a research study evaluating a diagnostic assay (PaGIA) for HIT and a single lecture (paid an honorarium by Pfizer) that included a brief discussion about HIT. Dr Linkins also discloses primary intellectual conflict of interest for diagnosis of HIT (holds a peer-reviewed research grant from the Heart and Stroke Foundation) and secondary intellectual conflict of interest (published reviews on HIT). Dr Dans received funding from GlaxoSmithKline for research in an area unrelated to HIT. Dr Davidson received consulting fees from Bayer and Daiichi Sankyo, makers of synthetic oral anticoagulants currently in clinical trials, and expenses for travel to a Steering Committee meeting. Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, has sat on data safety management boards, and his institution has received research funds from the following companies: Leo Pharma A/S, Pfizer Inc, Boehringer Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. COL Moores and Drs Bona and Schulman have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e495S/suppl/DC1.

The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios.We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement.For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS₂ [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS₂ score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS₂ score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy.Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS₂ score of ≥ 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach.From the Department of Medicine (Drs You, Schulman, and Spencer) and Department of Clinical Epidemiology and Biostatistics (Dr You), McMaster University, Hamilton, ON, Canada; Department of Medicine (Dr Singer), Harvard Medical School, and Clinical Epidemiology Unit (Dr Singer), General Medicine Division, Massachusetts General Hospital, Boston, MA; School of Pharmacy (Dr Howard), University of Kansas Medical Center, Kansas City, KS; University of Birmingham Centre for Cardiovascular Sciences (Drs Lane and Lip), City Hospital, Birmingham, England; Department of Clinical Medicine (Dr Eckman), Division of General Internal Medicine and Center for Clinical Effectiveness, University of Cincinnati, Cincinnati, OH; Department of Medicine (Dr Fang), Division of Hospital Medicine, University of California, San Francisco, San Francisco, CA; Boston University Medical Center Research Unit (Dr Hylek), Section of General Internal Medicine, Boston, MA; Comprehensive Clinical Research Unit (Dr Go), Division of Research, Kaiser Permanente Northern California, Oakland, CA; Decision Resources Inc (Dr Hughes), London, England; Section of Non-invasive Cardiac Imaging (Dr Manning), Beth Israel Deaconess Medical Center, Boston, MA; and The Cardiovascular Institute (Dr Halperin), Mount Sinai Medical Center, New York, NY.

Correspondence to: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, England; e-mail: g.y.h.lip@bham.ac.uk

Author contributions: As Topic Editor, Dr You oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr You: contributed as Topic Editor.

Dr Singer: contributed as a panelist.

Dr Howard: contributed as a panelist.

Dr Lane: contributed as a panelist.

Dr Eckman: contributed as a resource consultant.

Dr Fang: contributed as a panelist.

Dr Hylek: contributed as a panelist.

Dr Schulman: contributed as a panelist.

Dr Go: contributed as a panelist.

Dr Hughes: contributed as a panelist.

Dr Spencer: contributed as a panelist.

Dr Manning: contributed as a panelist.

Dr Halperin: contributed as a panelist.

Dr Lip: contributed as Deputy Editor and senior author.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e531S/suppl/DC1. In summary, Dr Whitlock served on the advisory board for AstraZeneca in 2010 and served as a consultant for Boehringer Ingelheim for experimental anticoagulant study in mechanical valves; neither activity is related to the contents of this article. Dr Sun received funds from the University of Washington for research. Drs Freme, Rubens, and Teoh have reported to CHEST the following conflicts of interest: Over the past 3 years, Dr Singer has received grant support from the Eliot B. and Edith C. Shoolman fund of Massachusetts General Hospital (MGH) to study stroke in atrial fibrillation. He has also received research grant support (through MGH) from Daiichi-Sankyo, Inc, to study hemorrhage risk in patients with atrial fibrillation taking warfarin. Dr Singer has been supported by the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute on Aging) grant funding to study stroke risk in patients with atrial fibrillation. He has served as a consultant on stroke prevention in atrial fibrillation to Bayer Healthcare Pharmaceuticals; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi-Sankyo, Inc; Johnson & Johnson; Merck and Co, Inc; Pfizer Inc; and Sanofi-Aventis LLC. Dr. Singer has published numerous articles on stroke prevention in atrial fibrillation and has given numerous lectures and research presentations on this topic. Dr Lane is in receipt of an investigator-initiated educational grant from Bayer Healthcare Pharmaceuticals and has participated in speaker activities for Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb/Pfizer Inc, and the Thrombosis Research Institute. She has also received support (travel and accommodation) to attend conferences from AstraZeneca and Boehringer Ingelheim GmbH. Dr Eckman has received a number of grants, including university grants for “Using Decision Analytic Modeling to Guide the ACCP Guideline Development Process for Antithrombotic Therapy in Atrial Fibrillation” (Foundation for Informed Medical Decision Making; $185,000) and has the following industry grants: “Cost-Effectiveness of Screening for Chronic Hepatitis C Infection” (Merck/Schering-Plough; September 2012; $58,000) and “Cost-Effectiveness of Screening for Chronic Hepatitis B Infection” (Gilead Sciences Inc; $56,000). He served as a consultant for Savient Pharmaceuticals (∼$300). Dr Hylek has participated in a symposium sponsored by Boehringer Ingelheim, served on advisory boards (Bayer Healthcare Pharmaceuticals; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi-Sankyo, Inc; Johnson & Johnson; Merck and Co, Inc; Ortho-McNeil Pharmaceutical, Inc; and Pfizer Inc) for amounts totaling < $10,000 and participated at the steering committee level for several pharmaceutical-sponsored studies (ARISTOTLE trial sponsored by Bristol-Myers Squibb and Pfizer Inc [< $10,000] and ORBIT-AF Registry sponsored by Ortho-McNeil Pharmaceutical, Inc [< $10,000]). Dr Go has received research funding from the National Heart, Lung, and Blood Institute related to antithrombotic therapy in atrial fibrillation and was a site principal investigator for a clinical trial sponsored by Johnson & Johnson and Bayer Healthcare Pharmaceuticals. Dr Halperin has received consulting fees from the following pharmaceutical manufacturers for advisory activities involving the development of anticoagulant drugs, none of which are currently approved for clinical use in any indication in the United States: Astellas Pharma, US; Bayer AG HealthCare; Boehringer Ingelheim; Daiichi Sankyo; Johnson & Johnson; and Sanofi-Aventis. He has received honoraria from Portola Pharmaceuticals, Inc as a member of the Data Safety Monitoring Board of its Phase II EXPLORE-AF trial involving an investigational anticoagulant for prevention of thromboembolism in patients with atrial fibrillation. He has received consulting fees from Biotronik, Inc as co-chair of the Steering Committee for the IMPACT clinical trial evaluating the use ambulatory monitoring technology in approved implanted cardiac arrhythmia devices to guide anticoagulation therapy for stroke prevention. He has received a consulting fee from the Bristol-Myers Squibb/Sanofi Partnership for advisory activities related to the use of the platelet inhibitor drug, clopidogrel, for prevention of thromboembolism in patients with atrial fibrillation. He has been a speaker at CME Symposia that derived partial funding from the following sponsors involved in the development of anticoagulants for potential use in patients with AF: Bayer AG HealthCare, Boehringer Ingelheim, and Sanofi-Aventis. Dr Lip has served as a consultant for Bayer, Astellas, Merck, Daiichi-Sankyo, AstraZeneca, Sanofi-Aventis, BMS/Pfizer, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers bureau for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Sanofi-Aventis. Drs You, Howard, Fang, Schulman, Hughes, Manning, and Spencer have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Other contributions: We thank Louis Kuritzky, MD, for sharing his perspective as a frontline clinician during the development of our recommendations.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e531S/suppl/DC1.

Antithrombotic therapy in valvular disease is important to mitigate thromboembolism, but the hemorrhagic risk imposed must be considered.The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.In rheumatic mitral disease, we recommend vitamin K antagonist (VKA) therapy when the left atrial diameter is > 55 mm (Grade 2C) or when complicated by left atrial thrombus (Grade 1A). In candidates for percutaneous mitral valvotomy with left atrial thrombus, we recommend VKA therapy until thrombus resolution, and we recommend abandoning valvotomy if the thrombus fails to resolve (Grade 1A). In patients with patent foramen ovale (PFO) and stroke or transient ischemic attack, we recommend initial aspirin therapy (Grade 1B) and suggest substitution of VKA if recurrence (Grade 2C). In patients with cryptogenic stroke and DVT and a PFO, we recommend VKA therapy for 3 months (Grade 1B) and consideration of PFO closure (Grade 2C). We recommend against the use of anticoagulant (Grade 1C) and antiplatelet therapy (Grade 1B) for native valve endocarditis. We suggest holding VKA therapy until the patient is stabilized without neurologic complications for infective endocarditis of a prosthetic valve (Grade 2C). In the first 3 months after bioprosthetic valve implantation, we recommend aspirin for aortic valves (Grade 2C), the addition of clopidogrel to aspirin if the aortic valve is transcatheter (Grade 2C), and VKA therapy with a target international normalized ratio (INR) of 2.5 for mitral valves (Grade 2C). After 3 months, we suggest aspirin therapy (Grade 2C). We recommend early bridging of mechanical valve patients to VKA therapy with unfractionated heparin (DVT dosing) or low-molecular-weight heparin (Grade 2C). We recommend long-term VKA therapy for all mechanical valves (Grade 1B): target INR 2.5 for aortic (Grade 1B) and 3.0 for mitral or double valve (Grade 2C). In patients with mechanical valves at low bleeding risk, we suggest the addition of low-dose aspirin (50-100 mg/d) (Grade 1B). In valve repair patients, we suggest aspirin therapy (Grade 2C). In patients with thrombosed prosthetic valve, we recommend fibrinolysis for right-sided valves and left-sided valves with thrombus area < 0.8 cm² (Grade 2C). For patients with left-sided prosthetic valve thrombosis and thrombus area ≥ 0.8 cm², we recommend early surgery (Grade 2C).These antithrombotic guidelines provide recommendations based on the optimal balance of thrombotic and hemorrhagic risk.From McMaster University (Drs Whitlock and Teoh), Hamilton, ON, Canada; the University of Washington School of Medicine (Dr Sun), Seattle, WA; the Sunnybrook Hospital (Dr Fremes), University of Toronto, Toronto, ON, Canada; and the Ottawa Heart Institute (Dr Rubens), Ottawa, ON, Canada.

Correspondence to: Richard P. Whitlock, MD, Population Health Research Institute, McMaster University, David Braley Cardiac, Vascular, and Stroke Research Institute, 237 Barton St East, Room C1-114, Hamilton, ON, L8L 2X2, Canada; e-mail: richard.whitlock@phri.ca

Author Contributions: As Topic Editor, Dr Whitlock oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Whitlock: contributed as the Topic Editor.

Dr Sun: contributed as a panelist.

Dr Fremes: contributed as a panelist.

Dr Rubens: contributed as a panelist.

Dr Teoh: contributed as a panelist.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e576S/suppl/DC1. In summary, Dr Whitlock served on the advisory board for AstraZeneca in 2010 and served as a consultant for Boehringer Ingelheim for experimental anticoagulant study in mechanical valves; neither activity is related to the contents of this article. Dr Sun received funds from the University of Washington for research. Drs Freme, Rubens, and Teoh have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e576S/suppl/DC1.

This article provides recommendations on the use of antithrombotic therapy in patients with stroke or transient ischemic attack (TIA).We generated treatment recommendations (Grade 1) and suggestions (Grade 2) based on high (A), moderate (B), and low (C) quality evidence.In patients with acute ischemic stroke, we recommend IV recombinant tissue plasminogen activator (r-tPA) if treatment can be initiated within 3 h (Grade 1A) or 4.5 h (Grade 2C) of symptom onset; we suggest intraarterial r-tPA in patients ineligible for IV tPA if treatment can be initiated within 6 h (Grade 2C); we suggest against the use of mechanical thrombectomy (Grade 2C) although carefully selected patients may choose this intervention; and we recommend early aspirin therapy at a dose of 160 to 325 mg (Grade 1A). In patients with acute stroke and restricted mobility, we suggest the use of prophylactic-dose heparin or intermittent pneumatic compression devices (Grade 2B) and suggest against the use of elastic compression stockings (Grade 2B). In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended release dipyridamole (25 mg/200 mg bid), or cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B). Of the recommended antiplatelet regimens, we suggest clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or cilostazol (Grade 2C). In patients with a history of stroke or TIA and atrial fibrillation we recommend oral anticoagulation over no antithrombotic therapy, aspirin, and combination therapy with aspirin and clopidogrel (Grade 1B).These recommendations can help clinicians make evidence-based treatment decisions with their patients who have had strokes.From the Stanford Stroke Center (Drs Lansberg and Schwartz), Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA; the HRB-Clinical Research Faculty (Dr O’Donnell), National University of Ireland Galway, Galway, Ireland; the Department of Neurology (Dr Khatri), University of Cincinnati, Cincinnati, OH; the University of Calgary (Dr Lang), Calgary, AB, Canada; the Department of Neurology (Dr Nguyen-Huynh), University of California, San Francisco, CA; the Division of General Internal Medicine (Dr Sonnenberg), UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ; the Department of Medicine (Drs Schulman and Guyatt), McMaster University, ON, Canada; the Norwegian Knowledge Centre for the Health Services (Dr Vandvik), Oslo, Norway; St. Joseph’s Healthcare (Dr Spencer), Hamilton, ON, Canada; the Iberoamerican Cochrane Centre (Dr Alonso-Coello), CIBERESP-IIB Sant Pau, Barcelona, Spain; the State University of New York at Buffalo (Dr Akl), Buffalo, NY; and the Department of Clinical Epidemiology and Biostatistics (Drs Akl and Guyatt), McMaster University, Hamilton, ON, Canada.

Correspondence to: Elie A. Akl, MD, MPH, PhD, State University of New York at Buffalo, ECMC, DK Miller bldg C216, 462 Grider St, Buffalo, NY 14228; e-mail: elieakl@buffalo.edu

Author contributions: As Topic Editor, Dr Akl oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.Dr Lansberg: contributed as Deputy Editor.

Dr O’Donnell: contributed as a panelist.

Dr Khatri: contributed as a panelist.

Dr Lang: contributed as a panelist.

Dr Nguyen-Huynh: contributed as a panelist.

Dr Schwartz: contributed as frontline clinician.

Dr Sonnenberg: contributed as a resource consultant.

Dr Schulman: contributed as a panelist.

Dr Vandvik: contributed as a panelist.

Dr Spencer: contributed as a panelist.

Dr Alonso-Coello: contributed as a panelist.

Dr Guyatt: contributed as a panelist.

Dr Akl: contributed as Topic Editor.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e601S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr O'Donnell has received university grants; received grants, speaking fees, and travel accommodations from Boehringer Ingelheim, and has received speaking fees from sanofi-aventis. Dr Khatri will receive funding from Penumbra, Inc as THERAPY Trial Neurology PI; received research support for third-party survey services and travel support for a 1-day summit in Chicago from Genentech, Inc to study RISS; participated in a one-time advisory board for Otsuka Pharmaceuticals regarding cilostazol; and provided expert witnessing regarding cases related to stroke treatment. Drs Lansberg and Schwartz have served as expert witnesses in cases related to stroke. Dr Nguyen-Huynh received a research grant from Concentric Medical. Dr Lang is a member of the GRADE Working Group. Dr Guyatt is co-chair of the GRADE Working Group, and the following authors have been prominent contributors to the groups work: Drs Vandvik, Alonso-Coello, and Akl. Drs Sonnenberg, Spencer, and Schulman have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Other contributions: We thank the writing groups of the article on antithrombotic and thrombolytic therapy for ischemic stroke in previous iterations of the ACCP evidence-based clinical practice guidelines for providing the framework for the current article; Mark Eckman, MD, for his contribution to the section that deals with antithrombotic therapy for stroke prevention following intracerebral hemorrhage; Aman Rajpal, MD, for his help with reviewing the proofs; and Peter Pellionisz for his contributions in editing the online tables.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e601S/suppl/DC1.

This guideline focuses on long-term administration of antithrombotic drugs designed for primary and secondary prevention of cardiovascular disease, including two new antiplatelet therapies.The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.We present 23 recommendations for pertinent clinical questions. For primary prevention of cardiovascular disease, we suggest low-dose aspirin (75-100 mg/d) in patients aged > 50 years over no aspirin therapy (Grade 2B). For patients with established coronary artery disease, defined as patients 1-year post-acute coronary syndrome, with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, we recommend long-term low-dose aspirin or clopidogrel (75 mg/d) (Grade 1A). For patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI) with stent placement, we recommend for the first year dual antiplatelet therapy with low-dose aspirin in combination with ticagrelor 90 mg bid, clopidogrel 75 mg/d, or prasugrel 10 mg/d over single antiplatelet therapy (Grade 1B). For patients undergoing elective PCI with stent placement, we recommend aspirin (75-325 mg/d) and clopidogrel for a minimum duration of 1 month (bare-metal stents) or 3 to 6 months (drug-eluting stents) (Grade 1A). We suggest continuing low-dose aspirin plus clopidogrel for 12 months for all stents (Grade 2C). Thereafter, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B).Recommendations continue to favor single antiplatelet therapy for patients with established coronary artery disease. For patients with acute coronary syndromes or undergoing elective PCI with stent placement, dual antiplatelet therapy for up to 1 year is warranted.From the Norwegian Knowledge Centre for the Health Services and Department of Medicine (Dr Vandvik), Innlandet Hospital Trust Gjøvik, Gjøvik, Norway; Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research (C5Research) (Dr Lincoff), Cleveland Clinic, Cleveland, OH; Department of Medicine (Dr Gore), University of Massachusetts Medical School, Worcester, MA; Department of Medicine (Dr Gutterman), Medical College of Wisconsin, Milwaukee, WI; Department of Medicine (Dr Sonnenberg), University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ; Iberoamerican Cochrane Centre (Dr Alonso-Coello), CIBERESP-IIB Sant Pau, Barcelona, Spain; Department of Medicine and Department of Clinical Epidemiology and Biostatistics (Dr Akl), State University of New York at Buffalo, Buffalo, NY; Stanford Stroke Center (Dr Lansberg), Stanford University Medical Center, Palo Alto, CA; and Department of Clinical Epidemiology and Biostatistics (Dr Guyatt) and Department of Medicine (Drs Guyatt and Spencer), McMaster University, Hamilton, ON, Canada.

Correspondence to: Frederick A. Spencer, MD, Department of Medicine, McMaster University, St. Joseph’s Health Care, 50 Charlton Ave E, Hamilton, ON, L8N 4A6, Canada; e-mail: fspence@mcmaster.ca

Author contributions: As Topic Editor, Dr Vandvik oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Vandvik: served as Topic Editor.

Dr Lincoff: served as a panelist.

Dr Gore: served as a panelist.

Dr Gutterman: served as a panelist.

Dr Sonnenberg: served as a resource consultant.

Dr Alonso-Coello: served as a panelist.

Dr Akl: served as a panelist.

Dr Lansberg: served as a panelist.

Dr Guyatt: served as a panelist.

Dr Spencer: served as Deputy Editor.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e637S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Lincoff is Director of the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), which has research grants from Anthera Pharmaceuticals, Inc; AstraZeneca; Bristol-Myers Squibb; Eli Lilly and Company; Kai Pharmaceuticals, Inc; Pfizer, Inc; Hoffmann La-Roche Inc; Novartis AG; Sanofi-Aventis LLC; Merck/Schering-Plough; Scios, Inc; Takeda Pharmaceutical Company Limited, and Johnson & Johnson. He has received honoraria for consultations or advisory board activities from AstraZeneca; Avanir Pharmaceuticals; Baxter; Bristol-Myers Squibb; Ikaria, Inc; Hoffmann La-Roche Inc; and Merck/Schering-Plough. Dr Gutterman has had the following relationships that are entirely unrelated to the AT9 guidelines: ACCP President, GlaxoSmithKline plc grant to study vasodilation in adipose tissue, National Institutes of Health grant to study human coronary dilation, and GE Healthcare consultation on a study for ECG evaluation of chronic heart disease. Dr Guyatt is co-chair of the GRADE Working Group. Drs Vandvik, Alonso-Coello, and Akl are members of and prominent contributors to the GRADE Working Group. Drs Gore, Sonnenberg, Lansberg, and Spencer have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Other contributions: We thank Louis Kuritzky, MD, for providing his frontline primary-care clinician perspective on the content of this article, John You, MD, for methodologic contributions (triple therapy in patients with acute LV thrombus), and Colin Baigent, MD, for sharing his methodologic expertise on primary prevention of cardiovascular disease with aspirin

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e637S/suppl/DC1.

This guideline focuses on antithrombotic drug therapies for primary and secondary prevention of cardiovascular disease as well as for the relief of lower-extremity symptoms and critical ischemia in persons with peripheral arterial disease (PAD).The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.The most important of our 20 recommendations are as follows. In patients aged ≥ 50 years with asymptomatic PAD or asymptomatic carotid stenosis, we suggest aspirin (75-100 mg/d) over no therapy (Grade 2B) for the primary prevention of cardiovascular events. For secondary prevention of cardiovascular disease in patients with symptomatic PAD (including patients before and after peripheral arterial bypass surgery or percutaneous transluminal angioplasty), we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A). We recommend against the use of warfarin plus aspirin in patients with symptomatic PAD (Grade 1B). For patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C). For patients with refractory claudication despite exercise therapy and smoking cessation, we suggest addition of cilostazol (100 mg bid) to aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 2C). In patients with critical limb ischemia and rest pain unable to undergo revascularization, we suggest the use of prostanoids (Grade 2C). In patients with acute limb ischemia due to acute thrombosis or embolism, we recommend surgery over peripheral arterial thrombolysis (Grade 1B).Recommendations continue to favor single antiplatelet therapy for primary and secondary prevention of cardiovascular events in most patients with asymptomatic PAD, symptomatic PAD, and asymptomatic carotid stenosis. Additional therapies for relief of limb symptoms should be considered only after exercise therapy, smoking cessation, and evaluation for peripheral artery revascularization.From the Iberoamerican Cochrane Centre (Dr Alonso-Coello), CIBERESP-IIB Sant Pau, Barcelona, Spain; Angiology (Dr Bellmunt), Vascular and Endovascular Surgery Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; The Heart House (Dr McGorrian), Mater Misericordiae University Hospital, Dublin, Ireland; Departments of Medicine and Clinical Epidemiology and Biostatistics (Drs Anand and Guyatt), McMaster University, Hamilton, ON, Canada; Section Vascular Surgery (Dr Guzman), University of Manitoba, St Boniface Hospital, Winnipeg, MB, Canada; Department of Family and Preventive Medicine (Dr Criqui), University of California San Diego School of Medicine, La Jolla, CA; Department of Medicine (Dr Akl), State University of New York at Buffalo, Buffalo, NY; Norwegian Knowledge Centre for the Health Services and Department of Medicine Gjøvik (Dr Vandvik), Innlandet Hospital Trust, Gjøvik, Norway; Stanford Stroke Center (Dr Lansberg), Stanford University Medical Center, Palo Alto, CA; and Department of Medicine (Dr Spencer), McMaster University, Hamilton, ON, Canada.

Correspondence to: Frederick A. Spencer, MD, Department of Medicine, McMaster University, St Joseph’s Health Care, 50 Charlton Ave E, Hamilton, ON, L8N 4A6, Canada; e-mail: fspence@mcmaster.ca

Author contributions: As Topic Editor, Dr Alonso-Coello oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Alonso-Coello: contributed as Topic Editor.

Dr Bellmunt: contributed as a frontline clinician.

Dr McGorrian: contributed as a panelist.

Dr Anand: contributed as a panelist.

Dr Guzman: contributed as a panelist.

Dr Criqui: contributed as a panelist.

Dr Akl: contributed as a panelist.

Dr Vandvik: contributed as a panelist.

Dr Lansberg: contributed as a panelist.

Dr Guyatt: contributed as a panelist.

Dr Spencer: contributed as Deputy Editor.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e669S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Bullmunt received funds from Roche for a study unrelated to this guideline and received funds from Ferrer Laboratory for writing a public document related to cilostazol. Dr McGorrian has received conference travel support from Pfizer Ireland Ltd. Dr Guyatt is co-chair of the GRADE Working Group. Drs Alonso-Coello, Akl, and Vandvik are members of and prominent contributors to the GRADE Working Group. Drs Anand, Guzman, Criqui, Lansberg, and Spencer have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Other contributions: We acknowledge Saurabh Kalra for his important contribution to this article, especially in the section on acute limb ischemia. We acknowledge Kristian Thorlund, PhD, for assistance on presentation of continuous outcomes. We thank John Eikelboom, MD, for his contribution of estimates of total mortality for patients on or off aspirin (primary prevention) and Sam Schulman, MD, for assistance with interpretation of bleeding definitions. We thank John Wong, MD, for assistance in identifying cost-effectiveness implications.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e669S/suppl/DC1.

The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy.The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B).Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population.From the Department of Medicine (Dr Bates), McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; Faculty of Health and Life Sciences (Dr Greer), University of Liverpool, Liverpool, England; Department of Vascular Medicine (Dr Middeldorp), Academic Medical Center, Amsterdam, The Netherlands; Department of Pharmacy (Dr Veenstra), University of Washington, Seattle, WA; Department of Obstetrics and Gynecology (Dr Prabulos), University of Connecticut School of Medicine, Farmington, CT; and Medical Department (Dr Vandvik), Innlandet Hospital Trust and Norwegian Knowledge Centre for the Health Services, Gjøvik, Norway.

Correspondence to: Shannon M. Bates, MDCM, Department of Medicine, HSC 3W11, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: batesm@mcmaster.ca

Author contributions: As Topic Editor, Dr Vandvik oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Bates: contributed as Deputy Editor.

Dr Greer: contributed as a panelist.

Dr Middeldorp: contributed as a panelist.

Dr Veenstra: contributed as a resource consultant.

Dr. Prabulos: contributed as a front line clinician.

Dr Vandvik: contributed as Topic Editor.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e691S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Bates has received honoraria for lectures from Leo Pharma, Inc. (anticoagulant manufacturer), Sanofi-Aventis Canada (anticoagulant manufacturer), Boehringer Ingelheim GmbH (anticoagulant manufacturer), and Thrombosis Education, Ltd. Dr Greer has received honoraria for lectures and advisory board contributions from Leo Pharma and Sanofi-Aventis. Dr Middeldorp has received unrestricted research funding from GlaxoSmithKline plc and MedaPharma for the ALIFE study and has received speakers fees from GlaxoSmithKline plc; Boehringer Ingelheim GmbH; Bayer Healthcare Pharmaceuticals; Leo Pharma, Inc. Dr Vandvik is a member of and prominent contributor to the GRADE Working Group. Drs Veenstra and Prabulos have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additionally, the guidelines presented in this article have been endorsed by the American College of Obstetricians and Gynecologists.

Additional Information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e691S/suppl/DC1.

Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children.The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C).The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.From the Haematology Department (Dr Monagle), The Royal Children’s Hospital, Department of Paediatrics, The University of Melbourne, Murdoch Children’s Research Institute, Melbourne, VIC, Australia; Department of Pediatrics (Dr Chan), McMaster University, Hamilton, ON, Canada; Department of Pediatrics (Dr Goldenberg), Section of Hematology/Oncology/Bone Marrow Transplantation and Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado, Aurora, CO; Department of Neurology (Dr Ichord), Children’s Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics (Dr Journeycake), University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Thrombosis and Hemostasis Unit (Dr Nowak-Göttl), Institute of Clinical Chemistry, University Hospital Kiel, Kiel, Germany; and Department of Biostatistics and Epidemiology (Dr Vesely), University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Correspondence to: Sara K. Vesely, PhD, Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, 801 NE 13th St, CHB 309, Oklahoma City, OK 73104; e-mail: sara-vesely@ouhsc.edu

Author contributions: As Topic Editor, Dr Vesely oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Monagle: contributed as Deputy Editor.

Dr Chan: contributed as a panelist.

Dr Goldenberg: contributed as a panelist.

Dr Ichord: contributed as a panelist.

Dr Journeycake: contributed as a panelist.

Dr Nowak-Göttl: contributed as a panelist.

Dr Vesely: contributed as Topic Editor.

Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e737S/suppl/DC1. In summary, the authors have reported to CHEST the following conflicts of interest: Dr Goldenberg has received an NIH career development award and an investigator-initiated study grant from Eisai Co., Ltd. He is also Chair of the steering committee for a Phase II study of Dalteparin for Eisai Co. and Chair of a data monitoring committee for Bristol-Myers Squibb. Dr Ichord is a member of the Clinica Event Committee for Berlin Heart’s IDE trial of the EXCOR-Pediatric (pediatric ventricular assist device). This involved reimbursement for travel expenses for study meetings and for time spent on committee meetings for a total financial reimbursement or < $1,000/y from 2007 to 2012. Drs Monagle, Chan, and Nowak-Göttl have contracted with Bayer (rivaroxaban). Dr Journeycake has received honoraria from hemophilia companies (CSL, Baxter, Novo-Nordisk). Dr Vesely has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org.

Other contributions: We thank Eliza Mertyn for contributions related to the article citations. She managed the EndNote database and referencing in the present article and posted pdf copies of > 800 articles to http://box.net for the present authors’ use and for authors of subsequent versions. We also thank Susan Millard, MD, and Julie Zimbelman, MD, for their contributions.

Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis.

Additional information: Table S1 can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e737S/suppl/DC1.