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.From the Department of Clinical Epidemiology and Biostatistics (Dr Guyatt) and Department of Medicine (Drs Guyatt and Eikelboom), McMaster University, Hamilton, ON, Canada; Keck School of Medicine (Dr Gould), University of Southern California, Los Angeles, CA; University of New Mexico (Dr Garcia), Albuquerque, NM; St. Joseph’s Hospital (Dr Crowther), Hamilton, ON, Canada; Mayo Clinic (Dr Murad), Rochester, MN; Centre for Clinical Epidemiology and Community Studies (Dr Kahn), Jewish General Hospital, Montreal, QC, Canada; Case and VA Medical Center (Dr Falck-Ytter), Case Western Reserve University, Cleveland, OH; University of Rochester (Dr Francis), Rochester, NY; Stanford Stroke Center (Dr Lansberg), Palo Alto, CA; State University of New York at Buffalo (Dr Akl), Buffalo, NY; and David Braley Cardiac, Vascular, and Stroke Research Institute (Dr Hirsh), Hamilton, ON, Canada.
Correspondence to: Gordon H. Guyatt, MD, FCCP, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: firstname.lastname@example.org
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.Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.Disclaimer:American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).