Marjan Wouthuyzen-Bakker, Kresimir Crnogaca, Marc W. Nijhof.
Response/Recommendation: Yes, the type of venous thromboembolism (VTE) prophylaxis influences the risk of subsequent periprosthetic joint infection (PJI). The strongest association is observed for vitamin K antagonists (VKA) when compared to acetylsalicylic acid (Aspirin [ASA]).
Strength of Recommendation: Moderate.
Rationale: Impaired hemostasis and bleeding in an arthroplasty wound, resulting in hematoma formation and persistent wound drainage, might favor bacterial growth and the subsequent development of PJI. Therefore, it is reasonable to assume that the risk to develop a PJI is influenced by the type of VTE prophylaxis used. We have conducted a literature search in PubMed and Embase according to the search strategy defined in the appendix. From the total of 107 articles, a final number of 23 articles met the predefined inclusion and exclusion criteria. The details of these studies are summarized in Table 1.
Most of the included studies compared the infection risk between low-molecular-weight heparin (LMWH) and direct oral anticoagulants (DOAC)1-10. The largest analysis has been performed by Jameson et al., a retrospective multicenter observational analysis in which the authors compared the incidence of several wound complications after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in 12 hospitals in the United Kingdom before and after a change of VTE prophylaxis protocol from LMWH to rivaroxaban3. One of the primary endpoints of the study was deep infection in which early reoperation was necessary. A total of 13,123 patients were included in the study, in which the infection rate was 0.53% in the LMWH group and 0.62% in the rivaroxaban group (no significant difference [NS]). A major limitation of this study was the fact that it was not possible to discriminate between surgical wound irrigation for infection or hematoma. In addition, two randomized trials comparing LMWH and DOAC were performed, in which one was too small a sample size to detect any infection complication5. The other, performed by Lassen et al., in patients undergoing THA or TKA (RECORD programme), a post-operative wound infection rate of 0.27% in the LMWH group was observed compared to 0.16% in the rivaroxaban group (NS)6. No differences were observed between THA and TKA. Again, no clear definition was provided for post-operative wound infection. Figure 1A depicts a forest plot of all studies comparing LMWH with DOAC with respect to their risk of developing an infection. Only the studies in which the absolute numbers were depicted by the authors are included. The analyzed studies showed low heterogeneity, and no differences between both types of VTE prophylaxis were observed.
The second most common comparison has been made between ASA and VKA9-14. All of these studies were retrospective analyses. The study performed by Huang et al., was the only one that defined PJI according to the Musculoskeletal Infection Society (MSIS) criteria12. In this study, the authors divided patients into those with a high-risk (n = 4,898) versus low-risk for VTE (n = 22,751), and consistently demonstrated a significantly lower PJI incidence in the ASA groups vs. the VKA groups (Table 1), with a PJI incidence of 0.18 versus 1.26% of the total cohort, respectively. The studies of Cafri et al., and Singh et al., showed a clear trend towards a lower infection rate in the ASA group, but this difference was NS10,13. Tan et al., also reported a lower risk for PJI when using ASA, but absolute numbers in this study were not provided14. In the study from Agaba et al., analyzing different VTE agents9, warfarin, (VKA) was the only one significantly associated with the highest PJI risk, in particular in the early post-operative period, with an odds ratio (OR) of 1.44. An international normalized ratio (INR) greater than 1.5 was found to be more prevalent in patients who had post-operative wound complications and subsequent PJI19. Figure 1B depicts the forest plot of the three studies comparing ASA with VKA, including solely those studies in which the absolute numbers were depicted by the authors. With a high heterogeneity between studies, there was a significant difference observed in infection rate between the ASA and the VKA group in the pooled analysis. The dose of ASA (80 mg vs. 325 mg) does not seem to have any influence on the infection rate, either for THA or TKA when analyzed separately15-18.
Unfortunately, only a few studies have directly compared infection rates between LMWH vs. ASA. In a retrospective analysis, Agaba et al., evaluated different types of VTE prophylaxis in 72,670 patients undergoing THA9. Rivaroxaban (DOAC), ASA, enoxaparin (LMWH), and fondaparinux had a significant protective effect on the development of PJI within 90 days after the index surgery, with OR of 0.27, 0.34, 0.40, and 0.47, respectively. For another DOAC, apixaban, a protective effect was not observed. With overlapping confidence intervals, the PJI risk for LMWH versus ASA was not significantly different. The largest analysis in which LMWH was directly compared to ASA is the study of Tan et al.14. In this study, 60,467 primary and revision total joint arthroplasties were retrospectively evaluated. The use of ASA was associated with a significantly lower risk for PJI development compared to LMWH and VKA (both p < 0.001). For LMWH vs. VKA, the PJI rate was lower for the high-risk VTE group only (p < 0.001). Unfortunately, no absolute numbers on PJI rates per type of VTE prophylaxis were provided in this study.
In conclusion, based on the literature review, VKA seem to be associated with the highest, and ASA (at least when compared to VKA) with the lowest risk for PJI. For LMWH and DOAC, no significant difference in PJI risk could be identified. Important limitations of the reviewed articles were the lack of a clear and adequate definition for (deep) infection and/or PJI. In addition, few studies performed multivariate analyses in which it remains unclear whether the type of VTE prophylaxis is an independent predictor for PJI.
Figure 1A. Forest plot. Depicting studies comparing LMWH with DOAC.

LMWH=Low-molecular-weight heparin; DOAC=Direct oral anticoagulants; C.I.=Confidence interval; PJI=Periprosthetic joint infection.
Figure 1B. Forest plot. Depicting studies comparingASA with VKA.

ASA=Aspirin; VKA=Vitamin K antagonist; C.I.=Confidence interval; PJI=Periprosthetic joint infection.
Table 1. Overview results selected studies.
Author | Year | Joint | VTE prophylaxis | Dose | Duration | Outcome | Infection rate/odds | p-value | Study design | |
Agaba et al.9 | 2017 | Hip | ASA (n = 551) enoxaparin (n = 6,791) warfarin (n = 12,008) rivaroxaban (n = 5,403) fondaparinux (n = 876) apixaban (n = 337) ASA (n = 551) enoxaparin (n = 6,791) warfarin (n = 12,008) rivaroxaban (n = 5.403) fondaparinux (n = 876) apixaban (n = 337) | NP NP | ≤ 30 days ≤ 30 days | PJI < 30 days1 PJI < 90 days1 | OR 0.86 (0.54, 1.38) OR 0.53 (0.44, 0.65) OR 1.44 (1.26, 1.64) OR 0.36 (0.29, 0.46) OR 0.40 (0.24, 0.67) OR 1.58 (0.83, 3.01) OR 0.47 (0.25, 0.88) OR 0.34 (0.27, 0.44) OR 1.17 (1.01, 1.34) OR 0.27 (0.20, 0.35) OR 0.40 (0.24, 0.67) OR 0.77 (0.31, 1.87) | NP NP | Retrospective cohort Retrospective cohort | |
Brimmo et al.20 | 2015 | Hip, Knee | Rivaroxaban (n = 159) other (n = 480)2 | 10 – 20 mg OD | ≥ 2 weeks | Deep SSI (≥ 2 cultures) | 2.5% 0.2% | < 0.015 | Retrospective cohort | |
Cafri et al.10 | 2017 | Knee | ASA (n = 5,124) enoxaparin (n=13,318) fondaparinux (n=3,225) warfarin (n=8,832) | 325 mg OD 40 – 60 mg OD 2.5 mg OD INR goal 1.8 – 2.0 | NP | SSI: deep infection or revision surgery for infection related reasons < 90 days index procedure | 0.39% / 1.00 0.39% / 0.90 (0.48 – 1.67) 0.41% / 0.84 (0.36 – 1.92) 0.46% / 0.80 (0.42 – 1.53) (OR: vs. ASA) | – 0.732 /0.148 0.674/ 0.172 0.500/ 0.089 (superiority /non-inferiority) | Retrospective cohort | |
Chahal et al.1 | 2013 | Hip, knee | Enoxaparin (n = 227) rivaroxaban (n = 160) | 40 mg OD 10 mg OD | 6 weeks or stopped at discharge and continued on ASA 10 days for knees, 30 days for hips | Infection defined as returning to theatre < 12 months | 0.88% 1.88% | NP | Comparison with retrospective cohort after change in protocol | |
Charters et al.2 | 2015 | Hip, knee | Enoxaparin (n = 1,113) rivaroxaban (n = 649) | 30 mg BID for knees 40 mg OD for hips 10 mg OD for knees 10 mg OD for hips | 14 days 21 days 12 days 35 days | Deep infection requiring DAIR | 0.9% 0.9% | 0.99 | Comparison with retrospective cohort after change in protocol | |
Di Benedetto et al.21 | 2017 | Hip | Rivaroxaban (n = 145) other (n = 60)3 | NP | 35 days | PJI < 4 weeks | 0% 0% | 1.00 | Retrospective cohort | |
Feldstein et al.15 | 2017 | Hip, knee | ASA 325 mg BID (n = 282) ASA 81 mg BID (n = 361) | 325 mg BID 81 mg BID | 1 month | PJI < 1 month | 0% 0% | 1.00 | Prospective cohort | |
Glassberg et al.22 | 2019 | Hip | Community insured warfarin (n = 12,876) rivaroxaban (n = 10,892) Medicare warfarin (n = 7,416) rivaroxaban (n = 4,739) | NP NP NP NP | No info | PJI < 90 days | 0.88% 0.62% OR 1.57 (1.16, 2.13) 0.85% 0.49% OR 1.79, (1.14 – 2.81) | 0.02 0.02 | Retrospective cohort | |
Huang et al.12 | 2016 | All joints | ASA low risk (n = 4,102) warfarin low-risk (n = 18,649) ASA high-risk (n = 796) warfarin high-risk (n = 6,723) warfarin high-risk (n = 6,723) | 81 or 325 mg BID INR goal 1.8 -2.0 81 or 325 mg BID INR goal 1.8 – 2.0 INR goal 1.8 – 2.0 | 4 weeks postop 4 weeks postop 4 weeks postop 4 weeks postop 4 weeks postop | PJI < 90 days (MSIS criteria) | 0.2% 1.1% 0.1% 1.7% An OR 13.7 (1.9, 98.5) | < 0.001 0.001 | Retrospective | |
Huang et al.11 | 2015 | All joints | ASA (n = 1,456) warfarin (n = 1,700) warfarin (n = 1,700) | 325 BID INR goal 1.8 – 2.0 INR goal 1.8 – 2.0 | 6 weeks postop | PJI < 90 days | 0.4% 1.5% An OR 2.77 (1.19, 6.45) | < 0.001 | Comparison with retrospective cohort after change in protocol | |
Jameson et al.3 | 2012 | Hip, knee | LMWH (n = 10,361) rivaroxaban (n = 2,762) | NP | 14 days knees 21 days hips | SSI and PJI requiring return to surgery < 30 days | 0.53% 0.62% | 0.59 | Comparison with retrospective cohort after change in protocol | |
Jensen et al.4 | 2011 | Hip, knee | LMWH (n = 489) rivaroxaban (n = 559) | 4500 U 10 mg OD | 28 days 14 days knees 28 days hips | Deep infection requiring DAIR < 30 days | 1.0% 2.5% | 0.10 | Comparison with retrospective cohort after change in protocol | |
Kim et al.5 | 2015 | Hip | Rivaroxaban (n = 350) enoxaparin (n = 351) placebo (n = 185) | 10 mg OD 40 mg OD | 7 – 12 days postop | PJI | 0% 0% 0% | 1.00 | Randomized trial | |
Kulshrestha et al.23 | 2013 | Knee | Routine LMWH (n = 450) Risk stratification (ASA ± LMWH) (n = 450) | 40 mg OD 325 BID ± 40 mg OD | 2 weeks postop 4 weeks postop ± 2 weeks postop | PJI | 0.9% 0.2% | Randomized trial | ||
Lassen et al.6 | 2012 | Hip, Knee | Rivaroxaban (n = 6,183) enoxaparin (n = 6,200) | 10 mg OD 40 mg OD or 30 mg BID | 10 – 40 days | Wound-infection < 30 days | 0.16% 0.27% | Randomized trial | ||
Matharu et al.24 | 2020 | Hip Knee | ASA ± LMWH (n = 28,049) direct thrombin inhibitor ± LMWH (n = 28,049) ASA ± LMWH (n = 19,021) factor Xa inhibitor ± LMWH (n = 19,021) ASA ± LMWH (n = 34,161) direct thrombin inhibitor ± LMWH (n = 34,161) ASA ± LMWH (n = 25,114) factor Xa inhibitor ± LMWH (n = 25,114) | NP | NP | SSI < 90 days | OR 1.04 (0.84, 1.28) OR 0.91 (0.70, 1.17) OR 1.09 (0.93, 1.27) OR 0.91 (0.75, 1.11) | Retrospective (national joint registry) | ||
Parvizi et al.16 | 2017 | Hip Knee | ASA 81 mg BID (n = 1,459) ASA 325 mg BID (n = 3,192) | 81 mg BID 325 mg BID | 4 weeks | PJI < 90 days | 0.2% 0.5% | 0.28 | Prospective crossover study | |
Singh et al.13 | 2020 | Hip, Knee | ASA 325 mg BID (n = 2,183) warfarin (n = 3,333) | 325 mg BID | 6 weeks | PJI < 6 months | 1.4% 1.8% | 0.23 | Retrospective | |
Tan et al.14 | 2019 | All joints4 | LMWH (n = 17,554) warfarin (n = 29,303) ASA (13,610) | NP INR goal 1.8 – 2.0 81 mg or 325 mg BID | 4 – 6 weeks | PJI < 90 days | No absolute numbers or % reported | Retrospective | ||
Tang et al.17 | 2020 | Knee 5 | ASA (n = 435) ASA (n = 1,003) | 81 mg BID 325 mg BID | 1 month | PJI < 90 days6 | 0.2% 0.6% | 0.36 | Retrospective | |
Tang et al.18 | 2020 | Hip5 | ASA (n = 388) ASA (n = 973) | 81 mg BID 325 mg BID | 1 month | PJI <90 days6 | 0.77% 1.2% | 0.46 | Retrospective | |
Yen et al.7 | 2014 | Knee | Rivaroxaban (n = 61) enoxaparin (n = 52) | 10 mg once 20 mg BID | 2 weeks | Need for I&D < 90 days | 0% 0% | 1.00 | Retrospective | |
Zou et al.8 | 2014 | Knee | Rivaroxaban (n = 102) LMWH (n = 112) ASA 100 mg (n = 110) | 10 mg/day 0.4 ml/day 100 mg/day | 14 days | Wound complications < 4 weeks | 4.9% 2.7% 1.8% | 0.027, 0.014 | Prospective randomized controlled trial |
- Based on ICD – 9 – CM codes 996.60, 996.66, 996.67, 998.6
- Other: 322 enoxaparin, 161 ASA, 33 warfarin
- Other: 25 fondaparinux, 19 warfarin/acenocumarol, 5 calciparin, 3 dabigatran, 8 nadroparin /enoxaparin.
- High-risk patients for VTE
- Revisions
- Acute PJI ICD – 9 (996.6) and ICD – 10 (T84.5)
ASA=Aspirin; n=Number; NP=not presented; PJI=Periprosthetic joint infection; OR=Odds ratio; OD=once daily; mg=milligrams; SSI=Surgical site infection; INR=International normalized ratio; BID=twice daily; DAIR=Debridement antibiotics implant retention; LMWH=Low-molecular-weight heparin; MSIS=Musculoskeletal infection society; U=Units; I&D=Incision and drainage.
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