121 – Does the type of VTE prophylaxis influence the risk of subsequent surgical site infection (SSI) in patients undergoing orthopaedic procedures?

121 – Does the type of VTE prophylaxis influence the risk of subsequent surgical site infection (SSI) in patients undergoing orthopaedic procedures?

Francisco Bengoa, Luiz S. Marcelino Gomes, Óliver Marin-Peña, Willian V. de Paula Ferreira, Juan José Pellegrini, Augustin Vial.

Response/Recommendation: The use of warfarin is associated with significantly higher surgical site infection (SSI) and periprosthetic infection (PJI) rates when used for venous thromboembolism (VTE) prophylaxis, especially in patients undergoing total joint arthroplasty (TJA). Limited evidence points to lower or similar rates of SSI using aspirin (ASA) as prophylaxis compared to more potent anticoagulants.

Strength of Recommendation: Limited.

Rationale: The most suitable pharmacological agent for VTE prophylaxis in patients undergoing orthopaedic procedures is yet to be identified, given the need to balance clinical effectiveness and inherent bleeding risk1–3. Several studies have shown that increased rates of wound drainage and SSI are associated with chemical thromboprophylaxis use, most notably when more potent agents are favored4–9.

Warfarin: Is one of the earliest thromboprophylaxis agents described, but its use in the perioperative orthopaedic setting remains controversial to this day10–13. A vast body of level one studies, prospective cohorts, and relevant retrospective studies have shown statistically higher rates of SSI associated with warfarin use when compared to ASA1,7,10,14–17, low-molecular-weight heparin (LMWH)10,14,18, and rivaroxaban10,12. Agaba et al., using a nationwide healthcare database in the US, analyzed 25,966 total hip arthroplasty (THA) patients without a previous history of VTE10. They compared the use of ASA, enoxaparin, warfarin, apixaban, fondaparinux and rivaroxaban. Warfarin use was associated with the highest number of 30- and 90-days complications, including SSI10. Huang et al., described prophylactic warfarin use as an independent risk factor for PJI following TJA, after a retrospective investigation and logistic regression analysis37.

Low-molecular-weight heparin (LMWH): There is conflicting evidence regarding the rate of infectious complications following the use of LMWH. Using the Global Orthopaedic Registry, Wang et al., evaluated the 90-day postoperative complication rates in 3,755 patients undergoing primary THA and total knee arthroplasty (TKA) using LMWH or warfarin in the US18. Patients that received LMWH had a significantly higher risk of SSI and reoperation. Turpie et al., performed a meta-analysis of four randomized controlled trials (RCT) comparing fondaparinux against enoxaparin in 7,344 patients undergoing THA, TKA, and hip fracture surgery for 11 days after surgery19. An increased bleeding risk was associated with fondaparinux use, but no differences in infection rates were identified19.

Factor Xa inhibitors and direct thrombin inhibitors: The published evidence pertaining to the effects of both factor Xa inhibitors and direct thrombin inhibitors on wound complications has been inconsistent. After rivaroxaban was approved, several observational studies found increased rates of wound complications when it was compared with LMWH20–22. Jensen et al., evaluated the infection and reoperation rates in 559 consecutive patients undergoing TKA or THA using rivaroxaban, compared to 489 consecutive patients using tinzaparin20.A significant increase in wound complications and reoperation rates were found to be associated with rivaroxaban, especially in patients undergoing TKA. However, they did not find significant differences in infection rates. Jameson et al., found similar results, in a multicentric study evaluating 2,762 patients using rivaroxaban compared to a retrospective cohort of 10,361 patients using LMWH after TJA21. To further evaluate these concerns, a meta-analysis was performed, evaluating the 12,383 patients of the four Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trials, looking at their bleeding and infection rates23. They found an overall similar complication rate between patients using enoxaparin and rivaroxaban. However, in TKA patients specifically, higher infection rates were associated with enoxaparin use, and higher bleeding rates were associated with rivaroxaban use. Other studies have found similar results3,17,24–29. When directly compared with warfarin, rivaroxaban seems to have lower SSI rates10,12. Glassber et al., retrospectively studied patients undergoing elective THA from a US administrative database between 2010 and 201512. They included 20,292 patients that received warfarin and 15,631 patients that received rivaroxaban and found significantly higher rates of PJI associated with warfarin use. Several observational studies have expressed concern about problems with wound discharge when using dabigatran30–33. However, pooled analysis of the two oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE) trials, which included 4,374 patients, found no differences in wound complications or infections between dabigatran and enoxaparin34.

Aspirin (ASA): The last two decades have seen renewed interest in the use of ASAas a VTE chemoprophylactic agent, especially due to reports of lower surgical wound complications rates. Tan et al., published a multi-institutional, retrospective study on 60,467 primary and revision THA and TKA, performed between 2000 and 201516. They compared the use of ASA, LMWH, and warfarin over 90 days postoperatively. They found a significantly lower rate of PJI in patients that received ASA compared to those that received either warfarin or LMWH. This finding was consistent across all the VTE risk groups. However, Bozic et al., did not find such differences. They retrospectively analyzed 93,840 patients undergoing primary TKA between 2003 and 20052 and compared the use of ASA, warfarin, and injectable medications such as enoxaparin and fondaparinux. They found no differences in infection rates or mortality. Similar results were found in a meta-analysis done by Matharu et al., who studied 13 RCT including 6,060 THA and TKA patients35. In a pooled analysis, they found no differences in infection rates between ASA and other VTE prophylaxis agents but did not clarify further with a subgroup analysis.

Compared to ASA, prophylactic warfarin use has demonstrated an increased risk of SSI and PJI1,7,10,14–17,36. Huang et al., studied 3,156 patients undergoing THA or TKA37. As mentioned above, following logistic regression analysis, the use of warfarin was identified as an independent risk factor for PJI37. Huang et al., conducted a retrospective study including 30,270 THA and TKA patients who received ASA 81 mg or 325 mg twice a day, or warfarin with an INR goal of 1.8 – 2.0, for four weeks15. They compared patients considered high-risk to those considered low-risk for the development of VTE. High-risk patients that received warfarin had a higher risk of both PJI and mortality than patients receiving ASA. However, other studies have not found differences in SSI rates1,38,39.

When comparing ASA with LMWH, the data is less clear40–43. Kulshrestha, and Kumar, randomized patients undergoing TKA to receive either routine anticoagulation, consisting of enoxaparin 40 mg for two weeks postoperatively followed by ASA for two further weeks thereafter or a risk-stratified thromboprophylaxis strategy40. The risk-stratified study group was identified as either being “high-risk”, thus receiving enoxaparin and ASA as above, or “standard-risk”, receiving ASA 325 mg only for four weeks. No difference was identified in infection rates between the two groups, but patients were nearly eight times more likely to experience a wound complication whilst receiving LMWH as opposed to ASA. Haac et al., recently conducted an open-label RCT of adult patients admitted to an academic trauma center with operative extremity fractures, or a pelvis or acetabular fracture, comparing ASA with LMWH42. Deep infections were identified in 4.3% of patients receiving ASA, and in 5.5% in those receiving LMWH. Given the significant heterogeneity in dosage, duration, and timing of VTE chemoprophylaxis initiation in different studies, Farey et al., performed a meta-analysis on the use of early postoperative thromboprophylaxis with ASA versus enoxaparin in TJA patients43. They included four trials, consisting of 1,507 patients, and found no difference in adverse event rates. However, they cautioned about the high risk of bias and low quality of available evidence.

Numerous studies have focused on comparing the use of ASA with direct oral anticoagulants. A recent meta-analysis included eight studies with 97,677 THA and TKA patients, three of which were RCT, comparing the use of rivaroxaban and ASA44. No difference was identified with regards to the rate of wound complications. Using data from the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man, Matharu et al., studied 218,650 patients undergoing TJA between 2003 and 201745. They reviewed patients using ASA and compared to patients receiving either direct thrombin inhibitors or factor Xa inhibitors. They found no differences in either SSI or re-operations between either of the VTE chemoprophylactic classes.

Several issues limit the available evidence regarding VTE prophylaxis and SSI in orthopaedic procedures. Orthopaedic surgeries encompass interventions spanning the entire spectrum of operative invasiveness and duration, across a wide variety of anatomical locations, within both the elective and emergency settings. Routine VTE chemoprophylaxis use has not been universally adopted throughout all orthopaedic subspecialties, as controversy continues to exist in many domains. Most studies evaluating the association between infection risk and thromboprophylaxis modalities are of a retrospective design, and their heterogeneity reflects the persistent variety in thromboprophylaxis practices46. Furthermore, perioperative management has progressed dramatically in the last decade with a trend towards enhanced recovery programs, early mobilization, outpatient rehabilitation and ambulatory same-day procedures. As such, many of the simultaneous temporal changes in surgical technique and perioperative care over the last decade may confound the results. Also, thromboprophylaxis protocols vary in their doses and duration, making comparisons difficult. Infection risk is often reported as a secondary outcome in studies evaluating VTE rates and thus any attempted sub-analyses are often underpowered. Moreover, SSI definitions demonstrate variety across the studies in the literature, further compromising the comparisons of pooled results. Finally, most publications have investigated VTE prophylaxis within a specific subset of the orthopaedic population: those undergoing TJA surgery42. Considering that most of the relevant current published evidence demonstrates heterogeneity and a high risk of bias, additional level one studies are needed to truly evaluate the associations between VTE prophylaxis and SSI across all orthopaedic surgery subspecialties45.

References:

1.      Raphael IJ, Tischler EH, Huang R, Rothman RH, Hozack WJ, Parvizi J. Aspirin: an alternative for pulmonary embolism prophylaxis after arthroplasty? Clinical orthopaedics and related research. 2014 Feb;472(2):482–8.

2.      Bozic KJ, Vail TP, Pekow PS, Maselli JH, Lindenauer PK, Auerbach AD. Does Aspirin Have a Role in Venous Thromboembolism Prophylaxis in Total Knee Arthroplasty Patients? The Journal of Arthroplasty. 2010 Oct;25(7):1053–60.

3.      Chahal GS, Saithna A, Brewster M, Gilbody J, Lever S, Khan WS, et al. A comparison of complications requiring return to theatre in hip and knee arthroplasty patients taking enoxaparin versus rivaroxaban for thromboprophylaxis. Ortop Traumatol Rehabil. 2013 Apr;15(2):125–9.

4.      Sachs RA, Smith JH, Kuney M, Paxton L. Does anticoagulation do more harm than good?: A comparison of patients treated without prophylaxis and patients treated with low-dose warfarin after total knee  arthroplasty. J Arthroplasty. 2003 Jun;18(4):389–95.

5.      Sanchez-Ballester J, Smith M, Hassan K, Kershaw S, Elsworth CS, Jacobs L. Wound infection in the management of hip fractures: a comparison between low-molecular weight heparin and mechanical prophylaxis. Acta Orthop Belg. 2005 Feb;71(1):55–9.

6.      Kim S-M, Moon Y-W, Lim S-J, Kim D-W, Park Y-S. Effect of oral factor Xa inhibitor and low-molecular-weight heparin on surgical complications following total hip arthroplasty. Thromb Haemost. 2016 Mar;115(3):600–7.

7.      Runner RP, Gottschalk MB, Staley CA, Roberson JR, Pour AE. Utilization Patterns, Efficacy, and Complications of Venous Thromboembolism Prophylaxis Strategies in Primary Hip and Knee Arthroplasty as Reported by American Board of Orthopedic Surgery Part II Candidates. J Arthroplasty. 2019;34(4):729–34.

8.      Kaiser CL, Freehan MK, Driscoll DA, Schwab JH, Bernstein KDA, Lozano-Calderon SA. Predictors of venous thromboembolism in patients with primary sarcoma of bone. Surg Oncol. 2017;26(4):506–10.

9.      Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet (London, England). 2000 Apr;355(9212):1295–302.

10.    Agaba P, Kildow BJ, Dhotar H, Seyler TM, Bolognesi M. Comparison of postoperative complications after total hip arthroplasty among patients receiving aspirin, enoxaparin, warfarin, and factor Xa inhibitors. JOURNAL OF ORTHOPAEDICS. 2017 Dec;14(4):537–43.

11.    Almustafa MA, Ewen AM, Deakin AH, Picard F, Clarke JV, Mahmood FF. Risk Factors for Surgical Site Infection Following Lower Limb Arthroplasty: A Retrospective Cohort Analysis of 3932 Lower Limb Arthroplasty Procedures in a High  Volume Arthroplasty Unit. J Arthroplasty. 2018 Jun;33(6):1861–7.

12.    Glassberg MB, Lachiewicz PF. Changing Patterns of Anticoagulation After Total Hip Arthroplasty in the United States: Frequency of Deep Vein Thrombosis, Pulmonary Embolism, and Complications  With Rivaroxaban and Warfarin. J Arthroplasty. 2019 Aug;34(8):1793–801.

13.    Cafri G, Paxton EW, Chen Y, Cheetham CT, Gould MK, Sluggett J, et al. Comparative Effectiveness and Safety of Drug Prophylaxis for Prevention of Venous Thromboembolism After Total Knee Arthroplasty. J Arthroplasty. 2017 Nov;32(11):3524-3528.e1.

14.    Hughes LD, Lum J, Anand A, Mahfoud Z, Malik RA, Charalambous CP. Comparison of Surgical Site Infection Risk Between Warfarin, LMWH, and Aspirin for Venous Thromboprophylaxis in TKA or THA: A Systematic Review and Meta-Analysis. JBJS Rev. 2020;8(12):e20.

15.    Huang RC, Parvizi J, Hozack WJ, Chen AF, Austin MS. Aspirin Is as Effective as and Safer Than Warfarin for Patients at Higher Risk of Venous Thromboembolism Undergoing Total Joint Arthroplasty. The Journal of Arthroplasty. 2016 Sep;31(9):83–6.

16.    Tan TL, Foltz C, Huang R, Chen AF, Higuera C, Siqueira M, et al. Potent Anticoagulation Does Not Reduce Venous Thromboembolism in High-Risk Patients. J Bone Joint Surg Am. 2019 Apr 3;101(7):589–99.

17.    Ning G-Z, Kan S-L, Chen L-X, Shangguan L, Feng S-Q, Zhou Y. Rivaroxaban for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis with trial sequential analysis of randomized controlled trials. Sci Rep. 2016 Mar 29;6:23726.

18.    Wang Z, Anderson FAJ, Ward M, Bhattacharyya T. Surgical site infections and other postoperative complications following prophylactic anticoagulation in total joint arthroplasty. PLoS One. 2014;9(4):e91755.

19.    Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: A meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833–40.

20.    Jensen CD, Steval A, Partington PF, Reed MR, Muller SD. Return to theatre following total hip and knee replacement, before and after the introduction of rivaroxaban: a retrospective cohort study. J Bone Joint Surg Br. 2011 Jan;93(1):91–5.

21.    Jameson SS, Rymaszewska M, Hui ACW, James P, Serrano-Pedraza I, Muller SD. Wound complications following rivaroxaban administration: a multicenter comparison with low-molecular-weight heparins for thromboprophylaxis in lower limb  arthroplasty. J Bone Joint Surg Am. 2012 Sep 5;94(17):1554–8.

22.    Brimmo O, Glenn M, Klika AK, Murray TG, Molloy RM, Higuera CA. Rivaroxaban Use for Thrombosis Prophylaxis Is Associated With Early Periprosthetic Joint Infection. J Arthroplasty. 2016 Jun;31(6):1295–8.

23.    Lassen MR, Gent M, Kakkar AK, Eriksson BI, Homering M, Berkowitz SD, et al. The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme. J Bone Joint Surg Br. 2012 Nov;94(11):1573–8.

24.    Russell RD, Huo MH. Apixaban and rivaroxaban decrease deep venous thrombosis but not other complications after total hip and total knee arthroplasty. J Arthroplasty. 2013 Oct;28(9):1477–81.

25.    Sindali K, Rose B, Soueid H, Jeer P, Saran D, Shrivastava R. Elective hip and knee arthroplasty and the effect of rivaroxaban and enoxaparin thromboprophylaxis on wound healing. Eur J Orthop Surg Traumatol. 2013;23(4):481–6.

26.    Rogers BA, Phillips S, Foote J, Drabu KJ. Is there adequate provision of venous thromboembolism prophylaxis following hip arthroplasty? An audit and international survey. Ann R Coll Surg Engl. 2010 Nov;92(8):668–72.

27.    Charters MA, Frisch NB, Wessell NM, Dobson C, Les CM, Silverton CD. Rivaroxaban Versus Enoxaparin for Venous Thromboembolism Prophylaxis after Hip and Knee Arthroplasty. J Arthroplasty. 2015 Jul;30(7):1277–80.

28.    Chen D, Jia S, Xue Y. Efficacy and safety of rivaroxaban in preventing deep venous thromboembolism after major orthopedic operations. Int J Clin Exp Med. 2016;9(2):4077–82.

29.    Lassen MR, Haas S, Kreutz R, Mantovani LG, Holberg G, Turpie AGG. Rivaroxaban for thromboprophylaxis after fracture-related orthopedic surgery in routine clinical practice. Clin Appl Thromb Hemost. 2016;22(2):138–46.

30.    Gill SK, Theodorides A, Smith N, Maguire E, Whitehouse SL, Rigby MC, et al. Wound problems following hip arthroplasty before and after the introduction of a direct thrombin inhibitor for thromboprophylaxis. Hip Int. 2011 Dec;21(6):678–83.

31.    Aquilina AL, Brunton LR, Whitehouse MR, Sullivan N, Blom AW. Direct thrombin inhibitor (DTI) vs. aspirin in primary total hip and knee replacement using wound ooze as the primary outcome measure. A prospective cohort  study. Hip Int. 2012 Feb;22(1):22–7.

32.    Bloch BV, Patel V, Best AJ. Thromboprophylaxis with dabigatran leads to an increased incidence of wound leakage and an increased length of stay after total joint replacement. The Bone & Joint Journal. 2014 Jan;96-B(1):122–6.

33.    Mayer A, Schuster P, Fink B. A comparison of apixaban and dabigatran etexilate for thromboprophylaxis following hip and knee replacement surgery. Arch Orthop Trauma Surg. 2017 Jun;137(6):797–803.

34.    Eriksson BI, Dahl OE, Rosencher N, Clemens A, Hantel S, Feuring M, et al. Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials. Thromb J. 2015;13:36.

35.    Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical Effectiveness and Safety of Aspirin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement: A Systematic Review and Meta-analysis of  Randomized Clinical Trials. JAMA Intern Med. 2020 Mar 1;180(3):376–84.

36.    Ng C, Zavala S, Davis ES, Adams W, Pinzur MS. Evaluation of a Simplified Risk Stratification Twice-Daily Aspirin Protocol for Venous Thromboembolism Prophylaxis After Total Joint Replacement. JOURNAL OF PHARMACY PRACTICE. 2020 Aug;33(4):443–8.

37.    Huang R, Buckley PS, Scott B, Parvizi J, Purtill JJ. Administration of Aspirin as a Prophylaxis Agent Against Venous Thromboembolism Results in Lower Incidence of Periprosthetic Joint Infection. The Journal of Arthroplasty. 2015 Sep;30(9):39–41.

38.    Singh V, Shahi A, Saleh U, Tarabichi S, Oliashirazi A. Persistent Wound Drainage among Total Joint Arthroplasty Patients Receiving Aspirin vs Coumadin. J Arthroplasty. 2020 Dec;35(12):3743–6.

39.    Deirmengian GK, Heller S, Smith EB, Maltenfort M, Chen AF, Parvizi J. Aspirin Can Be Used as Prophylaxis for Prevention of Venous Thromboembolism After Revision Hip and Knee Arthroplasty. The Journal of Arthroplasty. 2016 Oct;31(10):2237–40.

40.    Kulshrestha V, Kumar S. DVT Prophylaxis After TKA: Routine Anticoagulation Vs Risk Screening Approach — A Randomized Study. The Journal of Arthroplasty. 2013 Dec;28(10):1868–73.

41.    Arsoy D, Giori NJ, Woolson ST. Mobile Compression Reduces Bleeding-related Readmissions and Wound Complications After THA and TKA. Clin Orthop Relat Res. 2018 Feb;476(2):381–7.

42.    Haac BE, O’Hara NN, Manson TT, Slobogean GP, Castillo RC, O’Toole RV, et al. Aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial. PLoS One. 2020 Aug 3;15(8):e0235628.

43.    Farey JE, An VVG, Sidhu V, Karunaratne S, Harris IA. Aspirin versus enoxaparin for the initial prevention of venous thromboembolism following elective arthroplasty of the hip or knee: A systematic review and  meta-analysis. Orthop Traumatol Surg Res. 2021 Feb;107(1):102606.

44.    Le G, Yang C, Zhang M, Xi L, Luo H, Tang J, et al. Efficacy and safety of aspirin and rivaroxaban for venous thromboembolism prophylaxis after total hip or knee arthroplasty: A protocol for meta-analysis. Medicine (Baltimore). 2020 Dec 4;99(49):e23055.

45.    Matharu GS, Garriga C, Whitehouse MR, Rangan A, Judge A. Is Aspirin as Effective as the Newer Direct Oral Anticoagulants for Venous Thromboembolism Prophylaxis After Total Hip and Knee Arthroplasty? An Analysis From  the National Joint Registry for England, Wales, Northern Ireland, and the Isle of  Man. J Arthroplasty. 2020 Sep;35(9):2631-2639.e6.

46.    Hovik O, Amlie EJ, Jenssen KK. No Increased Risk of Venous Thromboembolism in High-Risk Patients Continuing Their Dose of 75 mg Aspirin Compared to Healthier Patients Given Low-Molecular-Weight Heparin. J Arthroplasty. 2021 Jun 10;S0883-5403(21)00541-6.

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