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.
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