Assessing the Utility of Venous Thrombosis Prophylaxis in Orthopedic Surgery Patients
Authors: Marc Carrier, Mary Cushman
Journal: Annals of Internal Medicine (2012)

Editorials15 May 2012Assessing the Utility of Venous Thrombosis Prophylaxis in Orthopedic Surgery PatientsFREEMarc Carrier, MD, MSc and Mary Cushman, MD, MScMarc Carrier, MD, MScFrom University of Ottawa, Ottawa, Ontario K1H 8L6, Canada, and University of Vermont College of Medicine, Burlington, VT 05405.Search for more papers by this author and Mary Cushman, MD, MScFrom University of Ottawa, Ottawa, Ontario K1H 8L6, Canada, and University of Vermont College of Medicine, Burlington, VT 05405.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-156-10-201205150-00422 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Studies using symptomatic venous thromboembolism (VTE) as the end point are responsible for most treatment advances in the management of patients at risk for VTE in the past 50 years (1). In the past few decades, clinical trials of drugs to prevent VTE after major orthopedic surgery focused on asymptomatic deep venous thrombosis (DVT) detected by imaging tests as the primary efficacy end point. This is an efficient way to complete a trial rapidly and to document a treatment's ability to prevent thrombus formation in vivo. The hope is that the asymptomatic end points are a surrogate for the important outcomes of symptomatic DVT and pulmonary embolism (PE). However, some suggest that only symptomatic VTE confirmed by objective testing, called “patient-important outcomes,” are clinically important (1–3).Recommendations in the recently released 9th edition of the American College of Chest Physicians (ACCP) Guidelines on Antithrombotic Therapy and Prevention of Thrombosis are based on the risk–benefit ratio of patient-important outcomes (4). For example, the benefits of thromboprophylaxis in major orthopedic surgery to reduce fatal PE, symptomatic nonfatal PE, and symptomatic DVT are balanced with the hazard of increased symptomatic bleeding (5). Although the definitions of end points—especially for bleeding—vary among trials, these patient-important outcomes can usually be extracted from the original trials.Two systematic reviews assessing the effect of type and duration of thromboprophylaxis on patient-important outcomes appear in this issue. Methodologically, both studies adhered to the high standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (6).The systematic review by Sobieraj and colleagues (7) compared outcomes of prolonged versus standard-duration thromboprophylaxis after major orthopedic surgery. The authors showed, using high- and moderate-strength evidence, that prolonged thromboprophylaxis reduces the risk for PE and symptomatic objectively confirmed VTE while increasing the risk for minor bleeding in patients having total hip replacement surgery. Evidence of the utility of prolonged prophylaxis after total knee replacement or hip fracture surgery was insufficient. Major bleeding could also not be evaluated. It is important to note that most trials included in the analysis evaluated vitamin K antagonists or low-molecular-weight heparin (LMWH), and the most recent trial was published in 2003. Secular trends of reduced adverse outcomes with advances in surgical technique and reduced length of stay over time may affect the generalizability of these older trials. In summary, it is unclear if the risk–benefit ratio reported for total hip replacement extends to total knee replacement or hip fracture surgery, or to newer medications (oral direct factor Xa or thrombin inhibitors). These findings confirm the ACCP guideline recommendation that suggested extending thromboprophylaxis for up to 35 days after major orthopedic surgery and add a considerable contribution by specifically reporting the evidence according to the type of major orthopedic surgery.The systematic review by Neumann and colleagues (8) assessed the efficacy of thromboprophylaxis on patient-important outcomes using oral direct factor Xa inhibitors compared with LMWH among patients undergoing total hip and total knee replacement. Using high-quality evidence, the authors found no important difference between factor Xa inhibitors and LMWH for all-cause mortality and nonfatal PE. Factor Xa inhibitors decreased risk for symptomatic DVT, but moderate-strength evidence demonstrated that they may increase risk for major bleeding compared with LMWH, particularly the higher-dose factor Xa inhibitors. Limitations of this analysis include the assumption that all factor Xa inhibitors are the same and that only 1 trial followed patients for 90 days, a duration that would seem minimally acceptable given the duration of risk for VTE after surgery. The authors state that factor Xa inhibitors are more expensive than LMWH, but a few recent cost analyses suggest the opposite (9–11).It is inspiring that the 9th edition of the ACCP guideline consistently considered patient-important outcomes in all of its chapters. Although systematic reviews that provide input to guidelines help clinicians understand a large body of literature, they are limited by flaws in the data reported in that literature. Two examples can be discussed: the lack of consideration of the postthrombotic syndrome as an outcome, and the short duration of follow-up in most trials. The postthrombotic syndrome is a burden to patients (11) and may complicate symptomatic or asymptomatic DVT. This end point has been assessed in few clinical trials of surgery patients; a systematic review of 7 studies found a 59% increased risk for the postthrombotic syndrome after asymptomatic postoperative DVT (12). Supporting the potential importance of clinically unrecognized DVT, such risk factors for thrombosis as obesity, protein C deficiency, and elevated factor VIII or d-dimer levels are also risk factors for venous insufficiency in patients without previous clinically recognized thrombosis (13, 14). Adequate study of the postthrombotic syndrome in orthopedic surgery would require much longer follow-up than the few weeks assessed in most trials. Another important flaw in this literature is the short follow-up of most trials. Detection of DVT on screening probably reduces subsequent detection of some symptomatic VTE, leading to underestimation of efficacy on patient-important outcomes. The risk for VTE associated with surgery extends for months afterward, so onset of VTE beyond discontinuation of thromboprophylaxis in trials that do not use screening imaging for DVT should be studied.What do these new studies mean for orthopedic surgery patients? Clinicians and patients undergoing total hip or knee replacement should discuss the benefits of oral factors Xa inhibitors (convenience, reduction of symptomatic DVT) and potential risks (lack of postmarketing surveillance data, increased bleeding). It is tempting to treat higher-risk patients more aggressively, but all patients are at high risk (5), and unfortunately no trials of a risk-adjusted approach are available. In patients favoring oral factor Xa inhibitors, a lower dose should be considered to abrogate bleeding. Prolonged thromboprophylaxis (up to 35 days) could be considered in patients having total hip replacement; however, it is unclear if the benefit extends to total knee replacement or to the newer anticoagulants.What studies are needed in the future? The most important outcome of any prophylaxis strategy is its effect on mortality from thrombosis and bleeding. Current evidence suggests no effect. It is unknown if PE and major bleeding episodes are equally likely to cause mortality in orthopedic surgery patients. A clinical trial examining the mortality tradeoff of thromboprophylaxis in orthopedic surgery patients is probably not feasible because of the large sample size that would be required to detect what would probably be small differences in mortality with treatment. Knowledge of case-fatality rates of DVT and PE from the literature may allow weighted analyses of existing data to estimate the risk–benefit ratio of anticoagulant therapy (15). Unfortunately, case-fatality rates of PE and major bleeding in patients undergoing major orthopedic surgery are unknown, and could be a topic for future comparative effectiveness research. Given the similar rates of patient-important outcomes among various preventive strategies, as evidenced by the systematic reviews in this issue, further evaluation of existing data to determine the most cost-efficient approach is also needed.We hope that future clinical trials will address the full range of outcomes of thromboprophylaxis in orthopedic surgery patients, including death, symptomatic VTE in the months after surgery among patients who were not screened for asymptomatic DVT, clinically important bleeding, the postthrombotic syndrome, and quality of life.Marc Carrier, MD, MScUniversity of OttawaOttawa, Ontario K1H 8L6, CanadaMary Cushman, MD, MScUniversity of Vermont College of MedicineBurlington, VT 05405References1. Anderson DR, Gross M, Robinson KS, Petrie D, Leighton R, Stanish W, et al. Ultrasonographic screening for deep vein thrombosis following arthroplasty fails to reduce posthospital thromboembolic complications: the Postarthroplasty Screening Study (PASS). Chest. 1998;114:119S-122S. [PMID: 9726705] CrossrefMedlineGoogle Scholar2. Robinson KS, Anderson DR, Gross M, Petrie D, Leighton R, Stanish W, et al. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty: the post-arthroplasty screening study. A randomized, controlled trial. Ann Intern Med. 1997;127:439-45. [PMID: 9313000] LinkGoogle Scholar3. Anderson DR. Symptomatic endpoints for venous thromboembolism treatment. Haemostasis. 1998;28 Suppl 3 120-6. [PMID: 10069773] MedlineGoogle Scholar4. Guyatt GH, Eikelboom JW, Gould MK, Garcia DA, Crowther M, Murad MH, et al. Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:185S-94S. [PMID: 22315260] CrossrefMedlineGoogle Scholar5. Falck-Ytter Y, Francis CW, Johanson , Curley C, Dahl OE, Schulman S, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:278S-325S. [PMID: 22315265] CrossrefMedlineGoogle Scholar6. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9, W64. [PMID: 19622511] LinkGoogle Scholar7. Sobieraj DM, Lee S, Coleman CI, Tongbram V, Chen W, Colby J, et al. Prolonged versus standard-duration venous thromboprophylaxis in major orthopedic surgery. A systematic review. Ann Intern Med. 2012;156:720-7. LinkGoogle Scholar8. Neumann I, Rada G, Claro JC, Carrasco-Labra A, Thorlund K, Akl EA, et al. Oral direct factor Xa inhibitors versus low-molecular-weight heparin to prevent thromboembolism in patients undergoing total hip or knee replacement. A systematic review and meta-analysis. Ann Intern Med. 2012;156:710-9. LinkGoogle Scholar9. Duran A, Sengupta N, Diamantopoulos A, Forster F, Kwong L, Lees M. Cost effectiveness of rivaroxaban versus enoxaparin for prevention of post-surgical venous thromboembolism from a U.S. payer's perspective. Pharmacoeconomics. 2012;30:87-101. [PMID: 22187932] CrossrefMedlineGoogle Scholar10. Ryttberg L, Diamantopoulos A, Forster F, Lees M, Fraschke A, Björholt I. Cost-effectiveness of rivaroxaban versus heparins for prevention of venous thromboembolism after total hip or knee surgery in Sweden. Expert Rev Pharmacoecon Outcomes Res. 2011;11:601-15. [PMID: 21958104] CrossrefMedlineGoogle Scholar11. Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med. 2002;162:1144-8. [PMID: 12020185] CrossrefMedlineGoogle Scholar12. Wille-Jørgensen P, Jorgensen LN, Crawford M. Asymptomatic postoperative deep vein thrombosis and the development of postthrombotic syndrome. A systematic review and meta-analysis. Thromb Haemost. 2005;93:236-41. [PMID: 15711738] CrossrefMedlineGoogle Scholar13. Emmerich J, Vossen CY, Callas PW, Demers C, Naud S, Long GL, et al. Chronic venous abnormalities in symptomatic and asymptomatic protein C deficiency. J Thromb Haemost. 2005;3:1428-31. [PMID: 15978099] CrossrefMedlineGoogle Scholar14. Cushman M, Callas PW, Denenberg JO, Bovill EG, Criqui MH. Risk factors for peripheral venous disease resemble those for venous thrombosis: the San Diego Population Study. J Thromb Haemost. 2010;8:1730-5. [PMID: 20492466] CrossrefMedlineGoogle Scholar15. Carrier M, LeGal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010;152:578-89. [PMID: 20439576] LinkGoogle Scholar Comments0 CommentsSign In to Submit A Comment Marysia, Meylan, EpidemiologistSelf-employed16 May 2012 Starting anticoagulation after ortho surgery If the surgery is performed in a teaching hospital - even one of the best - Surgical residents should always have their anticoagulation orders DOUBLE-CHECKED by the surgeon or another experienced MD before administration. I know of case in which the patient was put to risk by the fact that: a) the resident had not checked the patient's coagulation panel and b) the resident didn't know that some antidepressants tend to affect coagulation in the wrong direction...Conflict of Interest:None declared Author, Article, and Disclosure InformationAuthors: Marc Carrier, MD, MSc; Mary Cushman, MD, MScAffiliations: From University of Ottawa, Ottawa, Ontario K1H 8L6, Canada, and University of Vermont College of Medicine, Burlington, VT 05405.Disclosures: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0530.Corresponding Author: Mary Cushman, MD, MSc, Department of Medicine, University of Vermont, 208 South Park Drive, Colchester, VT 05446; e-mail, Mary.Cushman@uvm.edu.Current Author Addresses: Dr. Carrier: Ottawa Hospital–General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.Dr. Cushman: Department of Medicine, University of Vermont, 208 South Park Drive, Colchester, VT 05446. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoProlonged Versus Standard-Duration Venous Thromboprophylaxis in Major Orthopedic Surgery Diana M. Sobieraj , Soyon Lee , Craig I. Coleman , Vanita Tongbram , Wendy Chen , Jennifer Colby , Jeffrey Kluger , Sagar Makanji , Ajibade O. Ashaye , and C. Michael White Oral Direct Factor Xa Inhibitors Versus Low-Molecular-Weight Heparin to Prevent Venous Thromboembolism in Patients Undergoing Total Hip or Knee Replacement Ignacio Neumann , Gabriel Rada , Juan Carlos Claro , Alonso Carrasco-Labra , Kristian Thorlund , Elie A. Akl , Shannon M. Bates , and Gordon H. Guyatt Metrics Cited byPatients’ perception about risks and benefits of antithrombotic treatment for the prevention of venous thromboembolism (VTE) after orthopedic surgery: a qualitative study 15 May 2012Volume 156, Issue 10Page: 748-749KeywordsForecastingHemorrhageLow molecular weight heparinMortalityOrthopedic surgerySurgerySystematic reviewsThrombosisTotal hip replacementTotal knee replacement ePublished: 15 May 2012 Issue Published: 15 May 2012 Copyright & PermissionsCopyright © 2012 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...