Abstr actBackground

Optimum venous thromboembolism (VTE) prophylaxis for patients undergoing total hip or knee arthroplasty remains undefined. The purpose of this study is to compare complication rates among total joint arthroplasty patients using either low-dose aspirin (75 mg once daily) or low-molecular-weight heparin (LMWH; Fragmin/dalteparin 5000 U) for VTE prophylaxis.

Methods

This is a prospective observational study. All total hip or knee arthroplasties from 2014 to 2020 were included. One thousand eighty-four patients already taking aspirin 75 mg as primary or secondary prophylaxis for cardiovascular disease continued their daily aspirin dose throughout their hospital stay and after discharge without any other kind of thromboprophylaxis. Five thousand ten patients not already taking aspirin were given LMWH for 12-14 days starting the day of surgery. Both groups consisted of patients undergoing either primary or revision total hip or knee arthroplasty. The aspirin group was older (73 ± 7.8 vs 66 ± 10.2 years, P < .01, 95% CI −7.6, −6.3) with more comorbidities but otherwise did not differ from the LMWH group. Outcome measures were recorded at 3-month follow-up and included the following complications: clinically deep venous thrombosis (DVT), pulmonary embolism (PE), deep infection, blood transfusion, and death.

Results

The aspirin group had 0.28% DVT and 0.28% PE, and the LMWH group had 0.24% DVT and 0.16% PE (P = .42 and .74, respectively). No difference in deep infection, allogenic blood transfusion, or mortality was found.

Conclusion

No statistically significant difference in complication rates was found between aspirin 75 mg and LMWH used for VTE prophylaxis. Aspirin 75 mg daily is safe for VTE prophylaxis after total hip or knee arthroplasty.

KeywordsAlthough venous thromboembolism (VTE) is a rare complication, it is of significant clinical concern in patients after total joint arthroplasty (TJA). Without prophylaxis, historical data have shown that VTE may occur in 20%-50% of cases [[1]Falck-Ytter Y. Francis C.W. Johanson N.A. 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.,[2]An V.V. Phan K. Levy Y.D. Bruce W.J. Aspirin as thromboprophylaxis in hip and knee arthroplasty: a systematic review and meta-analysis.]. With prophylaxis, rates of VTE during the 90 days after total hip arthroplasty (THA) and total knee arthroplasty (TKA) are reported to be up to 2% for pulmonary embolism (PE) and up to 5% for deep vein thrombosis (DVT) [[3]Bala A. Huddleston 3rd, J.I. Goodman S.B. Maloney W.J. Amanatullah D.F. Venous thromboembolism prophylaxis after TKA: aspirin, warfarin, enoxaparin, or factor Xa inhibitors?.].Most American hip and knee surgeons agree that some form of prophylactic agent to prevent VTE should be used [[4]Markel D.C. York S. Liston Jr., M.J. Venous thromboembolism: management by American Association of Hip and Knee Surgeons.,[5]Shah S.S. Satin A.M. Mullen J.R. Merwin S. Goldin M. Sgaglione N.A. Impact of recent guideline changes on aspirin prescribing after knee arthroplasty.]. In the guidelines endorsed by the American Academy of Orthopedic Surgeons and the American College of Chest Physicians, aspirin is accepted as a suitable prophylactic agent. It is also the most commonly used agent by members of the American Association of Hip and Knee Surgeons [[6]Current practice trends in primary hip and knee arthroplasties among members of the American Association of Hip and Knee Surgeons: a long-term update.]. Aspirin is found to be more cost-effective than low-molecular-weight heparin (LMWH) and is also cheaper than the new oral anticoagulants [[7]Schousboe J.T. Brown G.A. Cost-effectiveness of low-molecular-weight heparin compared with aspirin for prophylaxis against venous thromboembolism after total joint arthroplasty.,[8]Jiang Y. Du H. Liu J. Zhou Y. Aspirin combined with mechanical measures to prevent venous thromboembolism after total knee arthroplasty: a randomized controlled trial.]. However, there is no consensus regarding the appropriate dose of aspirin to use [[9]Feldstein M.J. Low S.L. Chen A.F. Woodward L.A. Hozack W.J. A comparison of two dosing regimens of ASA following total hip and knee arthroplasties.]. The dosing regimen varies from 81 mg once daily to 325 mg twice daily (BID) [9Feldstein M.J. Low S.L. Chen A.F. Woodward L.A. Hozack W.J. A comparison of two dosing regimens of ASA following total hip and knee arthroplasties., 10Anderson D.R. Dunbar M. Murnaghan J. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty., 11Gelfer Y. Tavor H. Oron A. Peer A. Halperin N. Robinson D. Deep vein thrombosis prevention in joint arthroplasties: continuous enhanced circulation therapy vs low molecular weight heparin.].

Many patients take aspirin as primary or secondary prophylaxis for cardiovascular disease. According to the national guidelines in Norway, the dose is 75 mg. Interruption of this regimen for patients undergoing TJA could result in adverse events such as stroke or myocardial infarction. For that reason, national guidelines in Norway, which are based on American Academy of Orthopedic Surgeons guidelines, recommend that TJA patients already on low-dose aspirin continue their aspirin regimen without any other form of VTE prophylaxis throughout their hospital stay and after discharge. However, the effectiveness of this approach for VTE prophylaxis has not been adequately evaluated in comparison to other agents, such as LMWH. Therefore, the purpose of this study is to compare low-dose aspirin (75 mg) with LMWH for preventing VTE in patients after THA or TKA. We also compared the groups with respect to other complications linked to prophylaxis for VTE, including deep infection, major bleeding requiring transfusion, and death.

Materials and Methods Study Design

The study was designed as a prospective observational study with at least 3 months of follow-up. A cohort of 6094 consecutive patients in a single orthopedic unit were included. All data were collected and stored in a local database. The cohort consisted of all patients undergoing primary or revision hip or knee arthroplasty between 2014 and 2020. All patients received either aspirin 75 mg or LMWH as dalteparin 5000 U for VTE prophylaxis after TJA, depending on their existing anticoagulant regimen.

 Patients

All patients in a single orthopedic unit were eligible for the study and included. Patients in the aspirin 75 mg group (n = 1084) had an average age of 73 years and 64% were women. In the LMWH group (n = 5010), the average age was 66 years and 67% were women. Patients on existing anticoagulation therapy with aspirin 75 mg daily for any reason continued this medication without interruption for the duration of their hospital stay and after their discharge. Patients on any other existing anticoagulant therapy (warfarin or newer direct oral anticoagulant [DOAC] agents) had a 2- to 3-day washout before their operation and were given LMWH 6 hours after surgery and for the next 11-13 days before they resumed their usual anticoagulant. Patients taking no anticoagulants prior to surgery were also given LMWH for 6 hours after surgery and for 11-13 days after surgery.

Patients in the aspirin group were on average 7 years older than patients in the LMWH group and had more comorbidities. Using the Association of American Society of Anesthesiologists (ASA) physical status classification system, 55.2% of the aspirin group were classified as ASA 2 (mild systemic disease) and 43.3% as ASA 3 (severe systemic disease). In the LMWH group, 74.5% were classified as ASA 2 and 10.7% as ASA 3. In the aspirin group, 9.0% were undergoing a revision surgery compared to 8.4% in the LMWH group.

Tranexamic acid (10 mg/kg intravenous) was given to every patient at the induction of anesthesia and repeated after 3 hours or 1500 mg was given locally into the wound. Eighty-eight percent underwent spinal anesthesia, and the rest had general anesthesia. All TKAs (primary and revision) used the medial parapatellar approach and all THAs (primary and revision) used the posterior approach.

All patients were mobilized on the day of surgery and, with the exception of patients undergoing revision THA, all were allowed immediate full weight bearing. If there was clinical suspicion of VTE in the days after surgery, DVT was confirmed by ultrasound and PE by pulmonary computed tomography angiography. Allogenic blood transfusions were recorded as well as complications such as DVT, PE, and deep infection at the 3-month follow-up visit in our outpatient clinic. The follow-up rate was 99.7% (Table 1).

Table 1Characteristics of Patients Continuing Aspirin (75 mg Daily) Compared to Those Receiving LMWH (14 d) for VTE Prophylaxis After TKA/THA.

ASA, American Society of Anesthesiologists classification of physical status; CI, confidence interval; LMWH, low-molecular-weight heparin; SD, standard deviation; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism.

 Statistical Methods

Descriptive statistics for continuous data were provided as means with standard deviation, and mean differences were provided with 95% confidence intervals. Descriptive statistics for categorical data were provided as frequencies and proportions. Group comparisons were performed on both the baseline characteristics and complication rates at 3-month follow-up. Categorical data were analyzed using cross-tabulation and tested with Pearson’s chi-squared test or Fisher’s exact test as appropriate. Continuous measurements were compared using independent t-test or Mann-Whitney U-test depending on the distribution of data. P < .05 was considered statistically significant for all analyses. Data were analyzed using SPSS version 24.0 software (IBM Corporation, Armonk, NY).

Results Patient CharacteristicsPatient characteristics for both the aspirin group and the LMWH group are summarized in Table 1. Comparison of the 2 groups indicated that on average patients in the aspirin group were older and had more comorbidities than patients in the LMWH group (both P Venous Thromboembolism OutcomesThe DVT rate was 0.28% in the aspirin group and 0.24% in the LMWH group (P = .74). The PE rate was 0.28% in the aspirin group and 0.16% in the LMWH group (P = .42) (Table 2).

Table 2Complications in Patients Continuing Aspirin (75 mg Daily) Compared to Those Receiving LMWH (5000 U for 12-14 d) for VTE Prophylaxis After TKA/THA.

LMWH, low-molecular-weight heparin; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism.

Table 3Adjusted Effects of Continued Aspirin Use, Age, ASA Score, and Revision Surgery on VTE Risk.

P < .05 was considered statistically significant.

ASA, American Society of Anesthesiologists classification of physical status; CI, confidence interval; OR, odds ratio; VTE, venous thromboembolism.

None of the patients on DOACs before surgery and LMWH after surgery had PE or DVT. In the Fragmin group, 3.1% (155 patients) used DOACs before the operation and none in the aspirin group. The overall VTE rate (DVT and PE combined) was 0.55% in this study’s aspirin group. In the aspirin group, 3 patients had DVT 23 and 41 (2 patients) days after surgery, respectively. These 3 patients were all classified as ASA 3, aged 65, 78, and 91 years. In addition, 3 patients in the aspirin group had PE, at 3, 6, and 9 days after the operation, respectively. Of these 3 patients with PE, 2 were classified as ASA 2 and 1 as ASA 3. They were all women, aged 72, 84, and 87 years, respectively. Pulmonary cancer was detected on computed tomography angiography on the eldest woman, and she died of metastatic disease 19 months later.

In the LMWH group, 12 patients had DVT between 7 and 64 days after surgery. They ranged from 51 to 81 years of age. In addition, 8 patients in the LMWH group had PE between 2 and 90 days after surgery. Of these 8 patients, 5 were classified as ASA 2, 2 as ASA 1, and 1 as ASA 3.

A total of 521 patients had revision THA or TKA (98 in the aspirin group, 423 in the LMWH group). Of these 521 patients, none in the aspirin group and 1 (0.2%) in the LMWH group had DVT. None of the patients undergoing revision surgery had PE. The overall VTE rate was 0.40% in the LMWH group compared to 0.55% in the aspirin group. This difference was not significant (P = .44). Subsequently, we conducted multivariate logistic regression analysis to adjust for age, ASA score, and revision surgery. The estimated odds ratio for sustaining a VTE when using aspirin compared to LMWH was 1.05 (95% confidence interval 0.36-2.74, P = .92) (Table 3). Other Adverse OutcomesRates of deep infection, blood transfusion, and death are summarized in Table 2 and did not differ significantly between the aspirin and LMWH groups. During the 3-month follow-up period, 1 patient in the aspirin group died, a 94-year-old patient who died 32 days after surgery from causes other than VTE. A total of 5 patients in the LMWH group died between 20 and 67 days after surgery, 2 from stroke, 1 from pulmonary failure (not PE), and 2 from unknown causes.Discussion

This prospective cohort study demonstrates that there was no statistically significant difference in the risk of VTE comparing aspirin with LMWH for VTE prophylaxis in patients undergoing hip or knee TJA. There were also no differences in the risk of adverse events, such as deep infection, major bleeding, and death.

In 2012, the American College of Chest Physicians endorsed aspirin for VTE prophylaxis after THA and TKA [[1]Falck-Ytter Y. Francis C.W. Johanson N.A. 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.]. In 2018, the National Institute for Health and Care Excellence in the UK approved aspirin alone for VTE prophylaxis after TKA [[12]National Guideline Centre (UK) Venous thromboembolism in over 16s: Reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.]. Some studies have shown aspirin to be effective in preventing VTE and not statistically different from other commonly used anticoagulants [[2]An V.V. Phan K. Levy Y.D. Bruce W.J. Aspirin as thromboprophylaxis in hip and knee arthroplasty: a systematic review and meta-analysis.,[13]Matharu G.S. Kunutsor S.K. Judge A. Blom A.W. Whitehouse M.R. 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.]. In contrast, a registry study from England, Wales, Northern Ireland, and Isle of Man found aspirin to be significantly less effective than the newer DOACs [[14]Matharu G.S. Garriga C. Whitehouse M.R. 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.]. In that study, aspirin had a VTE rate of 0.63% after THA, which was higher than for either direct thrombin inhibitors (0.44%) or Xa inhibitors (0.37%). The numbers were similar for TKA. DOACs did not show an increase in risk for further surgery, wound problems, bleeding complications, or mortality compared to aspirin. However, factor Xa inhibitors were associated with an increased risk of acute renal failure. They also noted that the statistically significant difference observed between the different prophylactic agents may not have reached clinical significance.In a 2020 systematic review and meta-analysis of randomized clinical trials published in JAMA, the conclusion was: “In terms of clinical effectiveness and safety profile, aspirin did not differ statistically significantly from other anticoagulants used for VTE prophylaxis after THR and TKR” [[13]Matharu G.S. Kunutsor S.K. Judge A. Blom A.W. Whitehouse M.R. 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.]. Aspirin has been found to be more cost-effective than LMWH [[7]Schousboe J.T. Brown G.A. Cost-effectiveness of low-molecular-weight heparin compared with aspirin for prophylaxis against venous thromboembolism after total joint arthroplasty.]. Whether the same is true for aspirin vs DOACs remains to be shown.Despite the promising evidence of aspirin’s efficacy for VTE prophylaxis, the best dose of aspirin to use has yet to be established. Former systematically compared doses range between 81 mg once daily to 325 mg BID [[13]Matharu G.S. Kunutsor S.K. Judge A. Blom A.W. Whitehouse M.R. 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.]. In our prospective nonrandomized study, we used aspirin 75 mg once daily, which is a low dose compared to what has been previously studied. For cardiovascular prophylaxis, this is the most commonly used dose in Norway, as a low dose of aspirin is beneficial for reducing unwanted side effects such as gastrointestinal bleeding and nausea [[9]Feldstein M.J. Low S.L. Chen A.F. Woodward L.A. Hozack W.J. A comparison of two dosing regimens of ASA following total hip and knee arthroplasties.]. Because aspirin 75 mg is such a low dose and is also the patients’ regular medication, the probability of these patients having side effects after TJA is low.Several prior studies have compared aspirin to LMWH for VTE prophylaxis [[2]An V.V. Phan K. Levy Y.D. Bruce W.J. Aspirin as thromboprophylaxis in hip and knee arthroplasty: a systematic review and meta-analysis.,[11]Gelfer Y. Tavor H. Oron A. Peer A. Halperin N. Robinson D. Deep vein thrombosis prevention in joint arthroplasties: continuous enhanced circulation therapy vs low molecular weight heparin.,[15]Westrich G.H. Bottner F. Windsor R.E. Laskin R.S. Haas S.B. Sculco T.P. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty.,[16]Jameson S.S. Baker P.N. Charman S.C. The effect of aspirin and low-molecular-weight heparin on venous thromboembolism after knee replacement: a non-randomised comparison using National Joint Registry Data.]. However, our study evaluates a lower dose of aspirin than in prior studies and has a larger sample, which is critical for examining rare adverse events. Unlike prior studies, the present aspirin group was already at higher risk due to pre-existing cardiovascular disease, making them a particularly vulnerable group for whom the standard recommendations regarding VTE prophylaxis after TJA may be less appropriate. A systematic review and meta-analysis from 2016 by An et al [[2]An V.V. Phan K. Levy Y.D. Bruce W.J. Aspirin as thromboprophylaxis in hip and knee arthroplasty: a systematic review and meta-analysis.] found an overall DVT rate of 1.2% and PE rate of 0.6% when aspirin was used as thromboprophylaxis. Even with the lower aspirin dose of 75 mg daily used in our study, our corresponding numbers are notably lower at 0.28% for DVT and 0.28% for PE. The overall VTE rate (DVT and PE combined) of 0.55% in this study’s aspirin group is also comparable to rates for other agents used for VTE prophylaxis [[2]An V.V. Phan K. Levy Y.D. Bruce W.J. Aspirin as thromboprophylaxis in hip and knee arthroplasty: a systematic review and meta-analysis.,[13]Matharu G.S. Kunutsor S.K. Judge A. Blom A.W. Whitehouse M.R. 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.]. Given that the patients in our cohort’s aspirin group likely had pre-existing cardiovascular disease and received a lower dose than in most other studies and were also older and had more comorbidities than the other TJA patients in our study, the low VTE rate observed in this study’s aspirin group is particularly notable.In the recent systematic review and meta-analysis of randomized clinical trials for VTE prophylaxis, aspirin was compared to other anticoagulants [[13]Matharu G.S. Kunutsor S.K. Judge A. Blom A.W. Whitehouse M.R. 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.]. No difference in the risk of adverse events such as bleeding, wound complications, myocardial infarction, or death was found, and aspirin was associated with reduced risk of bruising and lower limb edema. The low and equal risk of allogenic blood transfusion in the 2 groups in our study is probably due to our strict policy on the use of tranexamic acid for all patients. The deep infection rate was higher in our study’s aspirin group (1.4% vs 0.9%), possibly due to their comorbidities and older age [[17]Cordero-Ampuero J. de Dios M. What are the risk factors for infection in hemiarthroplasties and total hip arthroplasties?.,[18]Huang R. Buckley P.S. Scott B. Parvizi J. Purtill J.J. Administration of aspirin as a prophylaxis agent against venous thromboembolism results in lower incidence of periprosthetic joint infection.], although this difference was not statistically significant. The mortality rate was 0.1% in both groups, despite the aspirin group being older and having more comorbidities than the LMWH group. This is comparable to other studies, which report mortality rates from 0.1% to 0.4% [[2]An V.V. Phan K. Levy Y.D. Bruce W.J. Aspirin as thromboprophylaxis in hip and knee arthroplasty: a systematic review and meta-analysis.,[19]Faour M. Piuzzi N.S. Brigati D.P. Low-dose aspirin is safe and effective for venous thromboembolism prophylaxis following total knee arthroplasty.,[20]Ogonda L. Hill J. Doran E. Dennison J. Stevenson M. Beverland D. Aspirin for thromboprophylaxis after primary lower limb arthroplasty: early thromboembolic events and 90 day mortality in 11,459 patients.].

This study has several strengths and limitations. Given that the existing literature and knowledge about preventing VTE after primary or revision THA and TKA are often based on small randomized controlled trials, small cohorts, or large registry data, our study’s large sample size and 99.7% follow-up rate are considerable strengths. In addition, the data are from a single orthopedic unit, which reduces sources of variation related to the surgical protocol and patient population but may also limit the generalizability of the findings. However, no patients were excluded from the study due to severe comorbidity or prior VTE, thereby increasing its generalizability. As is common in cohort studies, one limitation of this study is that the patients who continued their low-dose aspirin prophylaxis differed from those who were given LMWH. The aspirin group was older and had worse ASA scores on average than the LMWH group, which may have increased their risk of adverse outcomes. However, prior or family history of VTE and pulmonary disease are stronger predictors of VTE than age or ASA classification score. In the LMWH group, one of the patients who had PE had a Leiden mutation and another had a prior DVT. A patient in the LMWH group who had postoperative DVT also had a prior history of DVT. In the aspirin group, 2 patients with DVT after surgery had a prior history of DVT and another had a previous stroke. One patient in the aspirin group who had postoperative PE was later diagnosed with pulmonary cancer. Finally, although this study was larger than many prior studies, DVT and PE are rare events, and thus, the sample size may still not have been sufficient for detecting a clinically significant difference in VTE rates.

Conclusion

Aspirin was not significantly different from LMWH in preventing VTE after primary or revision THA or TKA. Despite the aspirin group patients being older and having more comorbidities, we found no difference in other adverse events, including deep infection, blood transfusion, or death during the first 3 months after surgery. By not having to discontinue aspirin for patients already taking this medication as prophylaxis for cardiovascular disease, the risk of adverse events, such as stroke or myocardial infarction, is minimized in this vulnerable patient group.

Acknowledgment

The authors thank Caryl Gay, MS, PhD, Lovisenberg Diaconal Hospital, Oslo, Norway for proofreading the manuscript.

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