74 – What endpoint should be used to determine the efficacy of a VTE prophylactic agent?

74 – What endpoint should be used to determine the efficacy of a VTE prophylactic agent?

Jessica Morton, Irfan A. Khan, Diana Fernández-Rodríguez, Colin Baker, Javad Parvizi.

Response/ Recommendation: The occurrence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) should be used as an endpoint to evaluate the efficacy of a venous thromboembolism (VTE) prophylactic agent.

Strength of Recommendation: Moderate.

Rationale: Patients undergoing orthopaedic procedures have an increased risk of DVT and PE, collectively referred to as VTE, due to hypercoagulability, endothelial damage of blood vessels, and venous stasis1. The development of multimodal prophylactic regimens that utilize chemical and mechanical prophylaxis have significantly reduced the incidence of perioperative VTE2-4. Despite this, it remains crucial to continually evaluate the efficacy of VTE prophylactic agents since VTE can cause significant morbidity and mortality5.

The Food and Drug Administration (FDA) stated in its clinical outcome assessment (COA) compendium that asymptomatic proximal DVT, symptomatic proximal or distal DVT, non-fatal PE, or VTE-related death, among others, should be used as efficacy and safety outcomes for VTE prophylaxis studies6. The aim of this document is to provide a clinically useful endpoint for researchers when developing clinical trials, from amongst the COA listed6.

Many Phase III trials have been conducted in the last 20 years evaluating VTE prophylaxis in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA)7-20. The purpose of those trials were to establish efficacy of VTE prophylaxis and monitor for adverse events11. Commonly used primary outcomes included symptomatic VTE, asymptomatic VTE (as assessed by venography typically at the 5 – 14-day mark for standard therapy or days 28 – 35 for extended prophylaxis), and all-cause mortality7-20.

Given that the rates of VTE are relatively low with current treatment guidelines and prophylaxis, less than 1% of primary THA and TKA and less than 1.5% of revision THA and TKA experiencing VTE occurrence21, it is reasonable that researchers prefer an objective measurement of an uncommon event. This has led to venographic evidence of asymptomatic DVT being used as an endpoint for determining efficacy of VTE prophylaxis. The objectivity of venographic studies is helpful to researchers since many DVT are clinically silent4,22.

To date, despite the frequent use of venography and venous duplex for diagnosis of DVT in clinical trials, routine venous duplex and venography screening following THA and TKA is not recommended by the clinical practice guidelines developed by the American Academy of Orthopaedic Surgery (AAOS) and the American College of Chest Physicians (AACP)23-27.

There are numerous studies that prove routine screening by ultrasound for the presence of DVT is not warranted. In a study by Schmidt et al., patients undergoing THA or TKA received a 10-day regimen of low-molecular-weight heparin (LMWH) and randomized to receive prolonged LMWH or screening for DVT by ultrasound (with a positive screen being treated appropriately). Both groups developed similar rates of proximal DVT by day 35 postoperatively (below 9%), questioning the utility of screening ultrasound25. Furthermore, a recent retrospective single-center study found that in patients who underwent total joint arthroplasty and had a duplex ultrasound, only 0.7% of them had a DVT and none of them exhibited clinical symptoms27. Shahi et al., found that the rate of in-patient DVT being diagnosed has decreased significantly during the past decade, likely due to less screening of asymptomatic patients, while the rate of PE development has remained stable3.

Propagation of DVT leading to a PE is a feared complication28. The latter is the rationale behind screening patients for asymptomatic DVT in an effort to prevent development of a PE. However, the association between a distal DVT and PE remains unproven. In addition, many distal DVT developed in the postoperative period resolve even without a treatment29. It is believed that DVT and PE can arise independently of each other and in hypercoagulable states, such as the postoperative period30,27. In addition, a recent systematic review of contemporary trials of anticoagulation, the importance of asymptomatic DVT detected by mandatory screening was questioned31.

In this regard, using symptomatic DVT and PE as primary endpoints for studies evaluating the efficacy of a VTE prophylactic agent would provide clinicians with clinically important information that would help determine the best course of management of these patients.


  1. Solayar GN, Shannon FJ. Thromboprophylaxis and orthopaedic surgery: options and current guidelines. Malays J Med Sci. 2014;21(3):71-77.
  2. Geerts WH, Pineo GF, Heit JA, Bergquist D, Lassen MR, Colwell CW, et al. Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S-400S. https://doi.org/10.1378/CHEST.126.3_SUPPL.338S.
  3. Shahi A, Chen AF, Tan TL, Maltenfort MG, Kucukdurmaz F, Parvizi J. The Incidence and Economic Burden of In-Hospital Venous Thromboembolism in the United States. J Arthroplasty 2017;32:1063–6. https://doi.org/10.1016/J.ARTH.2016.10.020.
  4. Mangwani J, Sheikh N, Cichero M, Williamson D. What is the evidence for chemical thromboprophylaxis in foot and ankle surgery? Systematic review of the English literature. Foot (Edinb). 2015;25(3):173-178. doi:10.1016/j.foot.2014.07.007.
  5. Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A, Hunt BJ, Hylek EM, Kakkar A, Konstantinides SV, McCumber M, Ozaki Y, Wendelboe A, Weitz JI; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. 2014 Nov;34(11):2363-71. doi: 10.1161/ATVBAHA.114.304488. PMID: 25304324.
  6. Food and Drug Administration. Clinical Outcome Assessment Compendium (COA) Compendium. June 2021 Available from: https://www.fda.gov/media/130138/download. [Accessed October 13, 2021].
  7. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ (2009) Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 361(6):594–604. doi:10.1056/ NEJMoa0810773
  8. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P (2010) Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 375(9717):807–815. doi:10.1016/s0140-6736(09)62125-5
  9. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM (2010) Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 363(26):2487–2498. doi:10. 1056/NEJMoa1006885
  10.  Lassen MR, Bauer KA, Eriksson BI, Turpie AG (2002) Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a Suggestions for a radical reappraisal 237 123 randomised double-blind comparison. Lancet 359(9319): 1715–1720. doi:10.1016/s0140-6736(02)08652-x
  11. Bauer KA, Eriksson BI, Lassen MR, Turpie AG (2001) Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 345(18):1305–1310. doi:10.1056/NEJMoa011099
  12. Turpie AG, Bauer KA, Eriksson BI, Lassen MR (2002) Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 359(9319):1721–1726. doi:10.1016/s0140-6736(02)08648-8
  13. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W (2008) Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 358(26): 2765–2775. doi:10.1056/NEJMoa0800374
  14. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S (2008) Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 372(9632): 31–39. doi:10.1016/s0140-6736(08)60880-6
  15. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG (2008) Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 358(26):2776–2786. doi:10.1056/NEJMoa076016
  16. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD (2009) Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 373(9676):1673–1680. doi:10.1016/s0140-6736(09)60734-0
  17. Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML, Hantel S, Schnee JM, Caprini JA (2009) Oral thrombin inhibitor dabigatran etexilate versus North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 24(1):1–9. doi:10.1016/j.arth.2008.01.132
  18. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Buller HR (2007) Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 5(11):2178–2185. doi:10.1111/ j.1538-7836.2007.02748.x
  19. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Buller HR (2007) Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 370(9591):949–956. doi:10.1016/s0140-6736(07)61445-7
  20. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Friedman RJ (2011) Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost 105(4):721–729. doi:10. 1160/th10-10-0679
  21. Step 3: Clinical Research | FDA n.d. https://www.fda.gov/patients/drug-development-process/step-3-clinical-research (accessed September 5, 2021).
  22. Leung KH, Chiu KY, Yan CH, Ng FY, Chan PK. Review article: Venous thromboembolism after total joint replacement. J Orthop Surg (Hong Kong). 2013;21(3):351-360. doi:10.1177/230949901302100318
  23. Mont MA, Jacobs JJ, Boggio LN, et al. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2011;19(12):768-776. doi:10.5435/00124635-201112000-00007
  24. Falck-Ytter Y, Francis CW, Johanson NA, 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(2 Suppl):e278S-e325S. doi:10.1378/chest.11-2404
  25. Schmidt B, Michler R, Klein M, Faulmann G, Weber C, Schellong S. Ultrasound screening for distal vein thrombosis is not beneficial after major orthopedic surgery. A randomized controlled trial. Thromb Haemost. 2003 Nov;90(5):949-54. doi: 10.1160/TH03-03-0154. PMID: 14597992.
  26. Robinson KS, Anderson DR, Gross M, Petrie D, Leighton R, Stanish W, Alexander D, Mitchell M, Flemming B, Gent M. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty: the post-arthroplasty screening study. A randomized, controlled trial. Ann Intern Med. 1997 Sep 15;127(6):439-45. doi: 10.7326/0003-4819-127-6-199709150-00004. PMID: 9313000.
  27. Vira S, Ramme AJ, Alaia MJ, Steiger D, Vigdorchik JM, Jaffe F. Duplex Ultrasonography Has Limited Utility in Detection of Postoperative DVT After Primary Total Joint Arthroplasty. HSS J. 2016;12(2):132-136. doi:10.1007/s11420-015-9476-2
  28. Gudipati S, Fragkakis EM, Ciriello V, et al. A cohort study on the incidence and outcome of pulmonary embolism in trauma and orthopedic patients. BMC Med. 2014;12:39. Published 2014 Mar 4. doi:10.1186/1741-7015-12-39.
  29. Solis G, Saxby T. Incidence of DVT following surgery of the foot and ankle. Foot Ankle Int. 2002;23(5):411-414. doi:10.1177/107110070202300507
  30. ​​Della Valle CJ, Steiger DJ, DiCesare PE. Duplex ultrasonography in patients suspected of postoperative pulmonary embolism following total joint arthroplasty. Am J Orthop (Belle Mead NJ). 2003;32(8):386-388.
  31. Chan NC, Siegal D, Lauw MN, et al. A systematic review of contemporary trials of anticoagulants in orthopaedic thromboprophylaxis: suggestions for a radical reappraisal. J Thromb Thrombolysis. 2015;40(2):231-239. doi:10.1007/s11239-014-1153-7

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: