ReviewsAugust 20, 2013
A Systematic Review
    Author, Article, and Disclosure Information

    Pharmacologic thromboprophylaxis reduces the risk for venous thromboembolism after total hip replacement (THR) or total knee replacement (TKR). New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, are emerging options for thromboprophylaxis after these procedures.


    To compare the benefits and risks of NOACs versus standard thromboprophylaxis for adults having THR or TKR.

    Data Sources:

    MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2009 through March 2013.

    Study Selection:

    English-language systematic reviews.

    Data Extraction:

    Two independent reviewers abstracted data and rated study quality and strength of evidence.

    Data Synthesis:

    Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin, aspirin, or unfractionated heparin.


    Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice.


    New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding.

    Primary Funding Source:

    U.S. Department of Veterans Affairs.


    • 1. Falck-Ytter YFrancis CWJohanson NACurley CDahl OESchulman Set alAmerican College of Chest PhysiciansPrevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest2012;141:278S-325S. [PMID: 22315265] CrossrefMedlineGoogle Scholar
    • 2. Lieberman JR and Hsu WKPrevention of venous thromboembolic disease after total hip and knee arthroplasty. J Bone Joint Surg Am2005;87:2097-112. [PMID: 16140827] CrossrefMedlineGoogle Scholar
    • 3. Sobieraj DM, Coleman CI, Tongbram V, Lee S, Colby J, Chen WT, et al. Venous Thromboembolism in Orthopedic Surgery. Comparative Effectiveness Review no. 49. AHRQ Publication no. 12-EHC020-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2012. Accessed at on 7 November 2012. Google Scholar
    • 4. Mont MAJacobs JJBoggio LNBozic KJDella Valle CJGoodman SBet alAAOSPreventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg2011;19:768-76. [PMID: 22134209] CrossrefMedlineGoogle Scholar
    • 5. Hill J and Treasure TReducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. BMJ2007;334:1053-4. [PMID: 17510154] CrossrefMedlineGoogle Scholar
    • 6. Friedman RJGallus AGil-Garay EFitzGerald G, and Cushner FPractice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty—insights from the Multinational Global Orthopaedic Registry (GLORY). Am J Orthop (Belle Mead NJ)2010;39:14-21. [PMID: 21290027] MedlineGoogle Scholar
    • 7. Molnar RBJenkin DEMillar MJCampbell D, and Harris IAThe Australian arthroplasty thromboprophylaxis survey. J Arthroplasty2012;27:173-9. [PMID: 21752576] CrossrefMedlineGoogle Scholar
    • 8. Ettema HBMulder MCNurmohamed MTBüller HR, and Verheyen CCDutch orthopedic thromboprophylaxis: a 5-year follow-up survey. Acta Orthop2009;80:109-12. [PMID: 19234891] CrossrefMedlineGoogle Scholar
    • 9. Hirsh J and Levine MNLow molecular weight heparin: laboratory properties and clinical evaluation. A review. Eur J Surg Suppl1994;:9-22. [PMID: 7519092] MedlineGoogle Scholar
    • 10. Wilke T and Müller SNonadherence in outpatient thromboprophylaxis after major orthopedic surgery: a systematic review. Expert Rev Pharmacoecon Outcomes Res2010;10:691-700. [PMID: 21155702] CrossrefMedlineGoogle Scholar
    • 11. Weitz JILow-molecular-weight heparins. N Engl J Med1997;337:688-98. [PMID: 9278467] CrossrefMedlineGoogle Scholar
    • 12. Turpie AGPentasaccharide Org31540/SR90107A clinical trials update: lessons for practice. Am Heart J2001;142:S9-15. [PMID: 11479485] CrossrefMedlineGoogle Scholar
    • 13. Nutescu ECharacteristics of novel anticoagulants and potential economic implications. Am J Manag Care2011;17:S27-32. [PMID: 21517653] MedlineGoogle Scholar
    • 14. Fareed JThethi I, and Hoppensteadt DOld versus new oral anticoagulants: focus on pharmacology. Annu Rev Pharmacol Toxicol2012;52:79-99. [PMID: 21819239] CrossrefMedlineGoogle Scholar
    • 15. Montori VMWilczynski NLMorgan D, and Haynes RBHedges TeamOptimal search strategies for retrieving systematic reviews from Medline: analytical survey. BMJ2005;330:68. [PMID: 15619601] CrossrefMedlineGoogle Scholar
    • 16. Shojania KG and Bero LATaking advantage of the explosion of systematic reviews: an efficient MEDLINE search strategy. Eff Clin Pract2001;4:157-62. [PMID: 11525102] MedlineGoogle Scholar
    • 17. Gómez-Outes ATerleira-Fernández AISuárez-Gea ML, and Vargas-Castrillón EDabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ2012;344:3675. [PMID: 22700784] CrossrefMedlineGoogle Scholar
    • 18. Jacobs JJMont MABozic KJDella Valle CJGoodman SBLewis CGet alAmerican Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am2012;94:746-7. [PMID: 22517391] CrossrefMedlineGoogle Scholar
    • 19. Loke YK and Kwok CSDabigatran and rivaroxaban for prevention of venous thromboembolism—systematic review and adjusted indirect comparison. J Clin Pharm Ther2011;36:111-24. [PMID: 21198726] CrossrefMedlineGoogle Scholar
    • 20. Neumann IRada GClaro JCCarrasco-Labra AThorlund KAkl EAet alOral direct factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis. Ann Intern Med2012;156:710-9 LinkGoogle Scholar
    • 21. Ringerike THamidi VHagen GReikvam A, and Klemp MThromboprophylactic treatment with rivaroxaban or dabigatran compared with enoxaparin or dalteparin in patients undergoing elective hip- or knee replacement surgery. Norwegian Knowledge Centre for the Health Services report no. 13. Health Technology Assessment. Oslo Norwegian Knowledge Centre for the Health Services 2011. Google Scholar
    • 22. Shea BJGrimshaw JMWells GABoers MAndersson NHamel Cet alDevelopment of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol2007;7:10. [PMID: 17302989] CrossrefMedlineGoogle Scholar
    • 23. Moher DCook DJEastwood SOlkin IRennie D, and Stroup DFImproving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet1999;354:1896-900. [PMID: 10584742] CrossrefMedlineGoogle Scholar
    • 24. Marinopoulos SSDorman TRatanawongsa NWilson LMAshar BHMagaziner JLet alEffectiveness of continuing medical education. Evid Rep Technol Assess (Full Rep)2007;:1-69. [PMID: 17764217] MedlineGoogle Scholar
    • 25. Song FLoke YKWalsh TGlenny AMEastwood AJ, and Altman DGMethodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ2009;338:b1147. [PMID: 19346285] CrossrefMedlineGoogle Scholar
    • 26. Mills EJIoannidis JPThorlund KSchünemann HJPuhan MA, and Guyatt GHHow to use an article reporting a multiple treatment comparison meta-analysis. JAMA2012;308:1246-53. [PMID: 23011714] CrossrefMedlineGoogle Scholar
    • 27. Guyatt GHOxman ADSantesso NHelfand MVist GKunz Ret alGRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol2013;66:158-72. [PMID: 22609141] CrossrefMedlineGoogle Scholar
    • 28. Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality. Accessed at on 1 August 2012. Google Scholar
    • 29. Schünemann HJSchünemann AHOxman ADBrozek JGlasziou PJaeschke Ret alGRADE Working GroupGrading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ2008;336:1106-10. [PMID: 18483053] CrossrefMedlineGoogle Scholar
    • 30. Alves CBatel-Marques F, and Macedo AFApixaban and rivaroxaban safety after hip and knee arthroplasty: a meta-analysis. J Cardiovasc Pharmacol Ther2012;17:266-76. [PMID: 22134134] CrossrefMedlineGoogle Scholar
    • 31. Adam SSMcDuffie JRLachiewicz PFOrtel TL, and Williams JWComparative Effectiveness of Newer Oral Anticoagulants and Standard Anticoagulant Regimens for Thromboprophylaxis in Patients Undergoing Total Hip or Knee Replacement. Washington, DC Veterans Affairs Evidence-based Synthesis Program 2012. Google Scholar
    • 32. Eriksson BIDahl OEBüller HRHettiarachchi RRosencher NBravo MLet alBISTRO II Study GroupA new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost2005;3:103-11. [PMID: 15634273] CrossrefMedlineGoogle Scholar
    • 33. Bucher HCGuyatt GHGriffith LE, and Walter SDThe results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol1997;50:683-91. [PMID: 9250266] CrossrefMedlineGoogle Scholar
    • 34. Li XMSun SG, and Zhang WDApixaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials. Chin Med J (Engl)2012;125:2339-45. [PMID: 22882859] MedlineGoogle Scholar
    • 35. Kwok CSPradhan SYeong JK, and Loke YKRelative effects of two different enoxaparin regimens as comparators against newer oral anticoagulants: meta-analysis and adjusted indirect comparison. Chest2013;:. [PMID: 23519234] CrossrefMedlineGoogle Scholar