Benjamin Emmerson, Karan Goswami, Mike Reed.
Response/Recommendation: There is no evidence that venous thromboembolism (VTE) prophylaxis reduces the risk of fatal pulmonary embolism (PE) in elective orthopaedics, including lower limb joint replacement. In patients with a hip fracture, there is limited evidence that aspirin (ASA) may reduce fatal PE, but the strength of evidence does not support a recommendation.
Strength of Recommendation: Limited.
Rationale: Preventing fatal PE remains a priority for both physicians and patients1. The American Academy of Orthopedic Surgeons (AAOS), the American College of Chest Physicians (ACCP), and the National Institute for Health and Care Excellence (NICE) have produced evidence-based clinical guidelines that aim to reduce VTE in orthopaedic patients2–4. All three documents use “reducing the rate of fatal PE” as a critical outcome. Despite this, controversy remains as to whether VTE prophylaxis is effective in reducing the risk of fatal PE.
A systematic literature review was performed; the methodology and search results are shown in the appendix. Studies were included in this recommendation if they compared any method of VTE chemoprophylaxis with a control; a control could include mechanical VTE prophylaxis. Nineteen studies met the inclusion criteria with most focusing on total hip arthroplasty (THA) and total knee arthroplasty (TKA)5–23.
The Pulmonary Embolism Prevention (PEP) trial was a large international multicenter, double-blinded, randomized control trial assessing ASA vs. placebo for VTE prophylaxis in hip fracture patients and elective THA and TKA surgery5. In 13,356 hip fracture patients, ASA use was found to reduce the number of fatal PE by 58% (27-76; p=0.002). There were 3 fatal PE in the 4,088 arthroplasty patients enrolled in the study, 1 in the ASA group and 2 in the placebo group (hazard ratio 0.5 [0.04-5.49]). The key limitation of this study is that 44% of the hip fracture patients and 37% of the arthroplasty patients also received either unfractionated heparin (UH) or low-molecular-weight heparin (LMWH) in both groups. Thus, diminishing the validity of the results of assessing the benefit of ASA compared with the placebo.
Three meta-analyses studied the rate of fatal PE in relation to VTE prophylaxis following total joint arthroplasty (TJA)6–8. Poultsides et al., identified 70 studies which encompassed 99,441 THA or TKA patients6. There was no statistically significant difference in rates of fatal PE between any prophylactic regimens when compared with, “no routine chemoprophylaxis.” Murray et al., included 93,000 THA patients and found no statistical difference in the rate of fatal PE between patients who received no VTE prophylaxis and those who received a chemoprophylaxis agent7. This meta-analysis uses data from 1970s – 1990s and may therefore not be representative of current practice. Both studies are limited by the heterogeneity of the data and rely on the original authors’ cause of death description to identify fatal PE, rather than autopsy proven events. Tasker et. al., assessed LMWH vs. placebo following THA, but with only 2 fatal PE seen in a total of 1,847 patients, they were unable to statistically assess any relationship8.
Three retrospective reviews of prospective arthroplasty registries met the inclusion criteria9–11. In a regional UK arthroplasty registry, that included 1,893 patients who had undergone THA9, there was no statistically significant difference in the rate of fatal PE between patients who had received chemical thromboprophylaxis (0.24%, [0.05 to 0.71]) and patients who had not (0.15%, [0.00 to 0.84]) (p=0.56). Khatod et al., reviewed two separate US joint registries between 2001 and 200810,11. The control group used for the purpose of this recommendation was “mechanical prophylaxis only”. From the Kaiser Permanente Joint Replacement Registry, in 17,595 patients who had undergone THA10, there was only 1 confirmed fatal PE, with 44 possible fatal PE using a worst-case scenario analysis. There was no significant difference between the control and any mode of chemical thromboprophylaxis for confirmed fatal PE (p=0.757) or worst-case scenario analysis (p=0.712). Using the Total Joint Replacement Registry (TJRR) in 30,020 patients who had undergone a TKA11, 3 confirmed fatal PE occurred; in worst-case scenario analysis, this gave a fatal PE rate of 0.13% (0.09%-0.17%). There was no significant difference between the control and any thromboprophylaxis group for confirmed fatal PE or worst-case scenario fatal PE (p=0.954). Limitations of all three registry studies include: potential for coding errors, possible under reporting of complications, risk of bias, and difficulty ascertaining the precise cause of death.
A further 5 randomized control trials (RCT) and 2 cohort studies looking at TJA met the inclusion criteria12–18. Across these 7 studies comparing different thromboprophylactic agents (LMWH, unfractionated heparin, warfarin, antiplatelet agents) with a control group, 6 fatal PE were reported from a combined total of 6,187 patients. Due to the low number of fatal PE observed in these studies, none of the authors could determine the relationship between VTE prophylaxis and fatal PE.
The incidence of fatal PE is also low in other orthopedic sub-specialties and therefore the strength of evidence regarding the role of VTE prophylaxis in reducing the risk of fatal PE is limited. A Cochrane review of LMWH, rivaroxaban, and ASA compared with a control, “no intervention,” in patients undergoing knee arthroscopy found no incidences of fatal PE in any of the 3,818 participants in any group19. Hickey et. al., performed a systematic review and meta-analysis of patients treated with a below knee cast for foot and ankle trauma20. In 6 studies, comparing LMWH to a control group which received no thromboprophylaxis, encompassing 914 patients receiving thromboprophylaxis and 901 patients in the control group, there were no incidences of fatal PE. A Cochrane review of LMWH vs. no thromboprophylaxis in patients being treated with a lower limb immobilization device (either plaster or brace) found no deaths due to PE in 3,111 participants included from 7 studies21. A RCT by Selby et al., compared dalteparin to a placebo in lower leg fractures and found no fatal PE in either group22. In a meta-analysis of VTE prophylaxis in elective spinal procedures, there was 1 episode of fatal PE in 4,383 patients23.
In summary, there is no evidence that VTE prophylaxis is effective in reducing the risk of fatal PE in elective orthopaedics. Based on the current incidence of fatal PE in TJA, it is reported that a RCT with an 80% power would require over 67,000 patients to demonstrate a statistically significant change if fatal PE were to be the primary end point9,24. Even the current evidence from large joint registries falls short of this number; thus, the available evidence to answer this important clinical question is limited. In patients with a hip fracture, there is limited evidence that ASA may reduce fatal PE, but the strength of evidence does not support a recommendation.
1. Haac BE, O’Hara NN, Mullins CD, et al. Patient preferences for venous thromboembolism prophylaxis after injury: a discrete choice experiment. BMJ Open. 2017;7(8):e016676. doi:10.1136/bmjopen-2017-016676
2. Jacobs JJ, Mont MA, Bozic KJ, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am. 2012;94(8):746-747. doi:10.2106/JBJS.9408.ebo746
3. 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
4. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. Pulm Embolism. Published online 2019:44.
5. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet Lond Engl. 2000;355(9212):1295-1302.
6. Poultsides LA, Gonzalez Della Valle A, Memtsoudis SG, et al. Meta-analysis of cause of death following total joint replacement using different thromboprophylaxis regimens. J Bone Joint Surg Br. 2012;94(1):113-121. doi:10.1302/0301-620X.94B1.27301
7. Murray DW, Britton AR, Bulstrode CJ. Thromboprophylaxis and death after total hip replacement. J Bone Joint Surg Br. 1996;78(6):863-870. doi:10.1302/0301-620x78b6.6714
8. Tasker A, Harbord R, Bannister GC. Meta-analysis of low molecular weight heparin versus placebo in patients undergoing total hip replacement and post-operative morbidity and mortality since their introduction. Hip Int J Clin Exp Res Hip Pathol Ther. 2010;20(1):64-74. doi:10.1177/112070001002000110
9. Fender D, Harper WM, Thompson JR, Gregg PJ. Mortality and fatal pulmonary embolism after primary total hip replacement. Results from a regional hip register. J Bone Joint Surg Br. 1997;79(6):896-899. doi:10.1302/0301-620x.79b6.7677
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12. Kaempffe FA, Lifeso RM, Meinking C. Intermittent pneumatic compression versus coumadin. Prevention of deep vein thrombosis in lower-extremity total joint arthroplasty. Clin Orthop. 1991;(269):89-97.
13. Sagar S, Nairn D, Stamatakis JD, et al. Efficacy of low-dose heparin in prevention of extensive deep-vein thrombosis in patients undergoing total-hip replacement. Lancet Lond Engl. 1976;1(7970):1151-1154. doi:10.1016/s0140-6736(76)91541-5
14. Warwick D, Harrison J, Glew D, Mitchelmore A, Peters TJ, Donovan J. Comparison of the use of a foot pump with the use of low-molecular-weight heparin for the prevention of deep-vein thrombosis after total hip replacement. A prospective, randomized trial. J Bone Joint Surg Am. 1998;80(8):1158-1166. doi:10.2106/00004623-199808000-00009
15. Warwick D, Harrison J, Whitehouse S, Mitchelmore A, Thornton M. A randomised comparison of a foot pump and low-molecular-weight heparin in the prevention of deep-vein thrombosis after total knee replacement. J Bone Joint Surg Br. 2002;84(3):344-350. doi:10.1302/0301-620x.84b3.12372
16. Chin PL, Amin MS, Yang KY, Yeo SJ, Lo NN. Thromboembolic prophylaxis for total knee arthroplasty in Asian patients: a randomised controlled trial. J Orthop Surg Hong Kong. 2009;17(1):1-5. doi:10.1177/230949900901700101
17. Malhotra K, Marciniak JL, Bonczek SJ, Hunt N. Venous thromboembolism after lower limb arthroplasty: is chemical prophylaxis still needed? Eur J Orthop Surg Traumatol Orthop Traumatol. 2016;26(8):895-899. doi:10.1007/s00590-016-1820-9
18. Migita K, Bito S, Nakamura M, et al. Venous thromboembolism after total joint arthroplasty: results from a Japanese multicenter cohort study. Arthritis Res Ther. 2014;16(4):R154. doi:10.1186/ar4616
19. Perrotta C, Chahla J, Badariotti G, Ramos J. Interventions for preventing venous thromboembolism in adults undergoing knee arthroscopy. Cochrane Database Syst Rev. 2020;5:CD005259. doi:10.1002/14651858.CD005259.pub4
20. Hickey BA, Watson U, Cleves A, et al. Does thromboprophylaxis reduce symptomatic venous thromboembolism in patients with below knee cast treatment for foot and ankle trauma? A systematic review and meta-analysis. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2018;24(1):19-27. doi:10.1016/j.fas.2016.06.005
21. Zee AA, van Lieshout K, van der Heide M, Janssen L, Janzing HM. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-limb immobilization. Cochrane Database Syst Rev. 2017;8:CD006681. doi:10.1002/14651858.CD006681.pub4
22. Selby R, Geerts WH, Kreder HJ, et al. A double-blind, randomized controlled trial of the prevention of clinically important venous thromboembolism after isolated lower leg fractures. J Orthop Trauma. 2015;29(5):224-230. doi:10.1097/BOT.0000000000000250
23. Sansone JM, del Rio AM, Anderson PA. The prevalence of and specific risk factors for venous thromboembolic disease following elective spine surgery. J Bone Joint Surg Am. 2010;92(2):304-313. doi:10.2106/JBJS.H.01815
24. Cusick LA, Beverland DE. The incidence of fatal pulmonary embolism after primary hip and knee replacement in a consecutive series of 4253 patients. J Bone Joint Surg Br. 2009;91(5):645-648. doi:10.1302/0301-620X.91B5.21939