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Low-Dose Aspirin Is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty
Accepted Manuscript Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty Mhamad Faour, MD, Nicolas S. Piuzzi, MD, David P. Brigati, MD, Alison K. Klika, MS, Michael A. Mont, MD, Wael K. Barsoum, MD, Carlos Higuera Rueda, MD PII:
S0883-5403(18)30236-5
DOI:
10.1016/j.arth.2018.03.001
Reference:
YARTH 56484
To appear in:
The Journal of Arthroplasty
Received Date: 4 December 2017 Revised Date:
2 March 2018
Accepted Date: 3 March 2018
Please cite this article as: Faour M, Piuzzi NS, Brigati DP, Klika AK, Mont MA, Barsoum WK, Rueda CH, Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty, The Journal of Arthroplasty (2018), doi: 10.1016/j.arth.2018.03.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis
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Following Total Knee Arthroplasty
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Mhamad Faour, MD,1
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Nicolas S. Piuzzi, MD,1,2
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David P. Brigati, MD,1
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Alison K. Klika, MS,1
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Michael A. Mont, MD,1
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Wael K. Barsoum, MD,1
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Authors:
Carlos Higuera Rueda, MD1
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Department of Orthopaedic Surgery Cleveland Clinic Foundation Cleveland, Ohio
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Instituto Universitario del Hospital Italiano de Buenos Aires Buenos Aires, Argentina Correspondence to:
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Mhamad Faour, MD. Cleveland Clinic Foundation 9500 Euclid Ave. A-41 Cleveland, Ohio 44195 216-444-4954 [email protected]
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Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis
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Following Total Knee Arthroplasty ABSTRACT:
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Aspirin is an effective prophylactic agent for venous thromboembolism (VTE) after total knee
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arthroplasty (TKA). However, the optimal prophylactic dose of aspirin has not been established.
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The aim of the study was to compare two aspirin regimens with regard to the incidence of: 1)
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symptomatic deep venous thrombosis (DVT), 2) pulmonary embolism (PE), 3) bleeding, and 4)
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mortality within 90 days following TKA. We retrospectively identified 5,666 patients who
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received aspirin twice daily (BID) for 4 to 6 weeks following TKA. A total of 1,327 patients
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received 81-mg BID and 4,339 patients received 325-mg BID aspirin. Postoperative
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complications collected were: VTEs (DVT and PE), bleeding (gastrointestinal or wound
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bleeding) and mortality.
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The incidence of VTE was 0.5% in 325-mg group and 0.7% in 81-mg group (p=0.02).
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Symptomatic DVT was 1.4% in the 325-mg aspirin compared to 0.3% for 81-mg aspirin
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(p=0.0009). After accounting for confounders, regression model showed no correlation between
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aspirin dose and VTE incidence (Odds Ratio [OR] = 1.03; 95% Confidence Interval [95% CI]:
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0.45-2.36; p=0.94) or DVT (OR=0.50; 95% CI: 0.16-1.55; p=0.20). The incidence of PE was
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0.2% in high- compared to 0.4% in low- aspirin (p=0.13). Bleeding was 0.2% in 325-mg aspirin
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and 0.2% in 81-mg aspirin (p=0.62) and 90-day mortality was similar (0.1%) between the groups
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(p=0.56). Low-dose aspirin was not inferior to high-dose aspirin for the prevention of VTE after
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TKA. Low-dose aspirin can be considered a safe and effective agent in the prevention of VTE
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after TKA.
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Level of evidence: III
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Key Words:
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Aspirin; venous thromboembolism; prophylaxis; knee arthroplasty; deep venous thrombosis;
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pulmonary embolism; bleeding.
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INTRODUCTION:
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Venous thromboembolism (VTE) is considered the third most frequent cause for hospital
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readmission following total knee arthroplasty (TKA) [1]. The risk of VTE has dropped
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dramatically in modern days (<1%), mostly due to the continuous improvement in perioperative
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protocols [2–5][6–8]. With such a low incidence and the standardization of multimodal
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prophylaxis practices, it became difficult to distinguish differences in efficacy of different
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chemoprophylactic modalities. There is a wide and expanding array of VTE chemoprophylactic
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agents for patients undergoing TKA. Many well-known challenges associated with these agents,
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such as the risk of bleeding and wound-related infections, and difficulties with administration,
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titration, and monitoring, are still under scrutiny in the search for an ideal chemoprophylaxis [9–
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12].
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Compared to other anticoagulants, aspirin is considered an appealing alternative because
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of its low cost and ease of administration with no need for routine blood monitoring. The
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rationale for the use of aspirin is based on its proven effectiveness and safety to reduce the
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incidence of VTE following total knee and hip arthroplasty and a large body of research that
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spans over four decades [13–16]. The American Association of Orthopedic Surgeons (AAOS)
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and the American College of Chest Physicians (ACCP) have jointly recommended the use of
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aspirin alone for the prophylaxis of VTE after TKA (recommended dose: 325mg twice daily
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[BID] for 6 weeks after surgery) [17,18]. Since then, accumulating literature has demonstrated
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that aspirin is not inferior to other agents for the prevention of VTEs [10,19]. Additionally, low-dose aspirin (81mg) is reportedly not inferior to high-dose aspirin for
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the primary and secondary prevention of cardiovascular and cerebrovascular events. The
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literature also demonstrated that low-dose aspirin was more effective than higher doses in
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preventing cerebrovascular events and mortality following vascular surgery[20]. Since the
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toxicity of aspirin is reportedly dose-dependent, especially the risk of gastrointestinal (GI)
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bleeding [21], the least effective dose of aspirin in the prevention of VTE is still unknown and
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the evidence to support the use of low-dose aspirin for VTE after TKA is lacking. To date only
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one study has shown potential benefits to the use of low-dose aspirin when compared to high-
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dose aspirin for VTE prevention following lower extremity joint arthroplasty [22].
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Thus, the aims of this study were to: 1) compare the efficacy of high- and low-dose
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aspirin in the prevention of VTE (deep venous thrombosis [DVT] and pulmonary embolism
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[PE]) following TKA, and 2) compare the adverse events of high- and low-dose aspirin regimens
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in terms of GI and wound-related bleeding and mortality within 90 days following TKA.
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METHODS:
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After institutional review board approval, a query was performed to obtain electronic
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medical records to identify patients who underwent elective primary TKA between 2012 and
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2016. In this retrospective cohort study we identified a total of 9,081 patients who underwent
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TKA in this time period. Then through manual chart review we identified patients who received
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only aspirin following TKA. A total of 3,415 patients were excluded because they received other 3
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modalities of chemoprophylaxis (e.g., Coumadin, enoxaparin) with or without aspirin on the day
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of the procedure, leaving a study cohort of 5,666 patients. All included patients received either 81-mg aspirin BID or 325-mg aspirin BID on the
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evening of or the next day after the procedure for 4 to 6 weeks depending on the surgeons’
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preference. In addition, all patients received pneumatic compression stockings after the
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procedure as standard of care. Physical therapy was initiated either on the day of surgery or on
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postoperative day 1 and continued daily throughout the hospital stay.
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From the electronic medical records, patient demographic characteristics, comorbidities,
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and perioperative details were collected by three of the authors (MF, NP, KB). Complications
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occurring within 90 days postoperatively, including symptomatic VTE (DVT and PE), upper and
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lower gastrointestinal (GI) bleeding requiring medical attention and wound bleeding that
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required surgical intervention or change in management protocols, and mortality and cause of
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death were collected through reviewing electronic medical records. Patients were not routinely
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screened for venous thromboembolism. Symptomatic deep venous thrombosis was diagnosed
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using physical examination and confirmed with lower-extremity ultrasound, and pulmonary
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embolism was detected using either computed tomography (CT) or ventilation perfusion (VQ)
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studies in cases of symptomatic VTE following AAOS and ACCP recommendations [18,23].
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Statistical analysis
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All analyses were performed using the R statistical programming language (R version
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3.3.3, Vienna, Austria). All testing was two-sided and considered significant at the 5% level. A
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non-inferiority margin is an amount for which would be borderline clinically relevant. We
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utilized a 0.25 percentage point difference as the non-inferiority margin for the power calculation
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based on Parvizi et al [22]. At 0.80 standard for power, the current study is adequately powered
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to test for non-inferiority given the non-inferiority margin of 0.25%. For the “unadjusted” (univariate) comparisons, categorical variables were compared
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between groups using either Pearson’s chi-squared test or Fisher’s exact test, as appropriate.
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Continuous variables were compared between groups using Welch’s two sample t-test. A
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multivariate mixed effects logistic regression model was considered for each response variable
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where each response was modeled as a function of aspirin dosage and the covariates. The
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covariates included in the regression model were: Age, sex, body mass index (BMI), age-
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adjusted Charlson comorbidity index (CCI), and surgeon. All covariates were treated as fixed
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effects except surgeon, which was treated as a random effect.
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Patient characteristics were similar between the 325-mg aspirin group and the 81-
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mg aspirin group (Table 1). The mean age was 68 years in both aspirin groups (p=0.93).
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The mean BMI was 32.6 kg/m2 in the 325-mg aspirin group compared to 32.5 kg/m2 in the
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81-mg aspirin group (p=0.60). Sex distribution was not different between the groups
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(p=0.82). Age-adjusted Charlson comorbidity index (CCI) was 4.3 in the 325-mg aspirin
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group compared to 4.5 in the 81-mg aspirin group (p=0.03).
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RESULTS
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The incidence of symptomatic VTE in the both groups was 1.3% (74 of 5,666 patients).
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There was a significant difference (p=0.02) in the incidence of VTE between groups: 0.7% in the
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81-mg aspirin group compared to 1.5% in the 325-mg aspirin group (Table 2). The overall 5
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incidence of symptomatic DVT following surgery was 1.1% (65 of 5,666 patients). The
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incidence of symptomatic DVT in the 325-mg aspirin group was 1.4% compared to 0.3% in the
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81-mg aspirin group (p<0.001). As for PE, the overall incidence in the study population was
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0.2% (12 of 5,666 patients). The incidence of PE in the 325-mg aspirin group was 0.2%
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compared to 0.4% in the 81-mg aspirin group (p=0.13) (Table 2).
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The incidence of bleeding in the study population was 0.2% (10 of 5,666 patients). The
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incidence of bleeding after surgery was 0.2% in the 325-mg aspirin group compared to 0.2% in
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the 81-mg aspirin group (p=0.62). In the 325-mg group, 2 patients had wound-related bleeding, 4
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had lower GI bleeding, and 1 had upper GI bleeding. In the 81-mg group, 1 patient had wound
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hematoma, and 2 patients had upper GI bleeding. Of the 5,666 study patients, 7 (0.1%) died
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within the first 90 days following surgery, with 6 deaths (n=1 cardiac arrest, n=1 myocardial
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infarction, n=1 respiratory failure, n=1 cerebral hemorrhage, and n=2 unknown) in the 325-mg
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aspirin group and 1 death due to cardiac arrest in the 81-mg aspirin group (p=0.56).
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Univariate analyses showed significant correlation between aspirin dose and the risk of
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VTE (OR=0.45; 95% CI: 0.22-0.90; p=0.02) and DVT (OR=0.21; 95% CI: 0.07-0.58; p<0.01).
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Furthermore, no correlation was found between aspirin dose and the incidence of PE (p=0.13),
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bleeding (p=0.62), or mortality (p=0.56) within 90 days following TKA (Table 3). After
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accounting for age, sex, BMI, CCI and surgeon, mixed linear regression model showed no
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correlation between aspirin dose and the incidence of VTE (OR = 1.03; 95% CI: 0.45-2.36;
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p=0.94) or the incidence of DVT following TKA (OR=0.50; 95% CI: 0.16-1.55; p=0.20) (Table
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3).
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DISCUSSION:
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For the prevention of cardiovascular and cerebrovascular events, aspirin has been used
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successfully, with lower doses being as effective as higher doses of aspirin [20,24,25]. In joint
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arthroplasty, high-dose aspirin has been shown to be effective and safer than other
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anticoagulation modalities in the prevention of VTE after total knee and hip arthroplasty [10,26–
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29]. However, very few studies have compared the efficacy and safety of different aspirin
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regimens for the prevention of VTEs following TKA [22,30] and the optimal dose for the
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prevention following TKA is still yet to be determined. Thus, the aim of this study was to
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evaluate the efficacy and safety of low-dose aspirin compared to high-dose aspirin in the
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prevention of VTE after TKA.
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This retrospective study has a number of limitations and strengths. This cohort
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comparative study may be limited by the retrospective design, and the discrepancies in patient
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characteristics and aspirin prescription disparities among surgeons. Furthermore, it was not
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possible to evaluate patient adherence to taking aspirin after they were discharged from the
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hospital. However, to the best of our knowledge this is the largest cohort reported in TKA, and
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all patient medical records were carefully reviewed by the authors to identify the outcomes of
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interest and identify patients who received aspirin only after surgery. In addition, mixed linear
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regression model was used to account for the differences in patient characteristics as well as
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surgeon prescribing patterns. Furthermore, post hoc analysis of the study population showed that
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our study was powered to detect non-inferiority difference between low-dose and high-dose
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aspirin. However, it was not powered to detect superiority effect of low-dose vs high-dose
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aspirin.
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important outcomes such as the incidence of periprosthetic joint infection which have been
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correlated to chemoprophylactic agents after TKA [10,22].
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Our study was also limited in the outcomes assessed and did not evaluate other
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This study showed similar findings to what have been previously reported in the literature
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that aspirin is an effective treatment for the prevention of VTE after TKA[10,26,29,31]. High-
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dose aspirin demonstrated similar efficacy and safer profile in the prevention of VTE following
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TKA compared to other anticoagulants. Gesell et al evaluated if aspirin can be safely used for
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adjuvant chemoprophylaxis in patients who have a low thromboembolic risk. They compared the
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efficacy and safety of high-dose aspirin (325mg BID) in 1,016 patients to warfarin in 1,001
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patients undergoing TKA and found no significant difference in rates of VTE (aspirin: 25
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patients [2.5%] vs warfarin: 22 patients [2.6%]; p=0.7), PE (aspirin: 11 patients [1.1%] vs
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warfarin: 9 patients [0.9%]; p=0.68), and 90-day mortality (aspirin: 1 patient [0.1%] vs
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warfarin:1 patient [0.1%]; p=0.5) between the two groups. They also found higher rate of wound
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related complications in the warfarin group (p=0.03) [2].
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The literature evaluating the use of low-dose aspirin in the prevention of VTE following
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TKA is very scarce. One previously published study by Parvizi et al examined, in a prospective
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crossover design, the efficacy and adverse event profiles of low-dose (81-mg BID) vs high-dose
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aspirin (325-mg BID) regimens for patients undergoing total hip and knee arthroplasty[22]. They
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found that low-dose aspirin was not inferior to high-dose aspirin in the prevention of VTE. The
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results of our study corroborate with the findings of Parvizi et al study. We showed that low-
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dose aspirin was non-inferior to high-dose aspirin in the prevention of VTE following TKA[22].
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The incidence of VTE in this study is considered very low compared to the incidence reported in
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the literature [2,32–34]. The low incidence of VTE can be attributed, in addition to aspirin use, to
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other multimodal protocols employed perioperatively to minimize the risk of VTE including
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spinal anesthesia [3], pneumatic compression during inpatient stay [5,16] as well as early
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mobilization after the procedure [4].
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The study also showed no significant difference in the incidence of bleeding (GI and
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wound) between the two doses. Despite the risk of GI bleed being dose-dependent as previously
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reported, the incidence of GI bleeding was very low in this study population and we did not
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detect any significant difference when comparing high versus low aspirin doses. The incidence
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of bleeding reported in this study (0.13%) included both wound-related and GI bleeding. Parvizi
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et al reported 0.3% incidence rate of GI bleeding alone in their study comparing two aspirin
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regimens for the prevention of VTE [22]. Feldstein et al prospectively compared the incidence of
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GI side effects of different regimens of aspirin following total knee and hip arthroplasty in 643
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patients. They found that 81-mg aspirin BID was associated with significantly less GI distress
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and nausea compared with 325-mg BID aspirin dose. They also reported an overall GI bleeding
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was 0.9%, with 2/282 (0.7%) in the aspirin 325-mg group, vs 4/361 (1.1%) in the aspirin 81-mg
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group (p = 0.7). [30]. Jones et al, in a prospective study comparing low-dose aspirin (150mg
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daily) to Enoxaparin for the prevention of VTE in 327 patients undergoing total knee and hip
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arthroplasty, demonstrated that low-dose aspirin was associated with lower risk of wound
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discharge after TKA and similar efficacy in the prevention of VTE when compared to
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Enoxaparin [35]. In addition, the study reported 0.12% overall 90-day mortality rate after TKA
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which was lower than what has been reported in the literature [36].
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The optimal dose and frequency of administration of aspirin for the prevention of VTE
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following total joint arthroplasty has yet to be discerned. One potential challenge to the use of
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aspirin as a prophylactic agent for VTE is aspirin resistance also known as the aspirin response
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variability. There is increasing evidence that some patients may exhibit low response to the anti-
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platelet effects of aspirin (also referred to as aspirin resistance) during the early post-operative
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period in cardiac surgery, which is associated with an increased risk of cardiovascular
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events [37–39]. The mechanism of post-operative aspirin low response remains uncertain but
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might be related to an increased rate of platelet production post-operatively, as a consequence of
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an initial consumptive thrombocytopenia, leading to an excess of platelets unexposed to aspirin
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postoperatively. Li et al reported aspirin response variability in patients after total hip and knee
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arthroplasty, with one-half of the patients (6 of 12 patients) exhibiting post-operative aspirin low
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response [40]. Studies testing diverse aspirin treatments showed that twice-daily low doses were
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more effective than once-daily higher aspirin doses on surrogate end points of platelet inhibition
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[41]. Consequently, additional studies will need to evaluate the ideal dosage and administration
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frequency of aspirin in the prevention of VTE after total joint arthroplasty.
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Furthermore, aspirin is known to cause gastrointestinal side effects, primarily
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dyspepsia or peptic ulcer[42]. Enteric-coated aspirin has been developed to decrease the
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risk of gastrointestinal side effects [43]. However, clinical trials have shown that enteric
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coating can significantly reduce the antiplatelet effect of aspirin [44–46]. Therefore,
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enteric-coated aspirin might not be bioequivalent to plain aspirin, entailing the risk of
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insufficient thrombosis prophylaxis [47]. In addition, a recent review of the literature
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demonstrated that there seems to be no effect of enteric-coating on the incidence of
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clinically relevant dyspepsia or gastrointestinal bleeding compared to plain aspirin [48].
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Since higher doses of aspirin (325mg twice daily) are associated with higher
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gastrointestinal complications; enteric-coating does not provide clinically significant
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reduction in gastrointestinal bleeding; and low-dose aspirin was not inferior to high-dose
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aspirin in the prevention of VTE after TKA as was demonstrated in this study, low-dose
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(81mg) plain aspirin twice daily can play an important role in conjunction with other
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perioperative measures in the prevention of VTE after total joint arthroplasty. Future 10
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studies need to assess the difference between a single-dose aspirin and aspirin twice daily
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for the prevention of VTE after total joint arthroplasty. In conclusion, low-dose aspirin can be considered a safe and effective agent in the
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prevention of VTE since it was not inferior to high-dose aspirin for the prevention of VTE after
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TKA. With the overall low incidence of VTE, the role of chemoprophylaxis may be considered
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minimal in the perioperative prevention in low risk patients. Future studies should identify the
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optimal aspirin regimen for the prevention of VTE following TKA and evaluate the efficacy of
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other non-chemoprophylactic agents with and without the additional use of chemoprophylaxis.
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Furthermore precise patient VTE risk stratification is needed in order to establish the optimal
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multimodal perioperative VTE prevention approach.
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Haastrup P, Jarbøl DE. [Enteric-coated aspirin does not reduce the risk of gastrointestinal side effects]. Ugeskr Laeger 2014;176.
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Table 1: Population characteristics 325 mg aspirin (n=4,339)
81 mg aspirin (n=1,327)
p-value
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Factor
0.82
Sex Female
2,588 (59.7%)
Male
1,751 (40.3%)
Age (Mean ± SD) BMI (kg/m2) (Mean ± SD)
32.6 ± 6.7
Age-adjusted CCI (Mean ± SD)
4.3 ± 2.2
68 ± 10
0.93
32.5 ± 6.7
0.60
4.5 ± 2.2
0.07
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BMI-Body Mass Index; CCI-Charlson comorbidity Index.
540 (40.7%)
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68 ± 10
787 (59.3%)
Table 2: Incidence of complications within 90 days of total knee arthroplasty
Venous Thromboembolism Deep Venous Thrombosis
Bleeding
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Mortality
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Pulmonary Embolism
325 mg BID aspirin (n=4,339) 65 (1.5%)
81 mg BID aspirin (n=1,327) 9 (0.7%)
0.02
61 (1.4%)
4 (0.3%)
<0.001
7 (0.2%)
5 (0.4%)
0.13
7 (0.2%)
3 (0.2%)
0.62
6 (0.1%)
1 (0.1%)
0.56
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Complication
p-value
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Table 3: Multivariate and univariate analyses of aspirin dosage and outcomes after total knee arthroplasty. Outcomeα Events Adjusted OR P-value Unadjusted OR P-value ¶ ¶ (95% CI)* (95% CI) 74 1.03 (0.45 – 2.36) 0.94 0.45 (0.22 – 0.90) 0.02 VTE 65 0.50 (0.16 – 1.55) 0.20 0.21 (0.07 – 0.58) DVT <0.001 β 12 N/A N/A 2.34 (0.74 – 7.39) 0.13 PE β 10 N/A N/A 0.54 (0.06 – 4.52) 0.56 Mortality β N/A N/A 1.40 (0.36 – 5.43) 0.62 7 Bleeding
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VTE-Venous Thromboembolism; DVT-Deep Venous Thrombosis; PE-Pulmonary Embolism. ¶ The ORs given are between 81-mg aspirin group and the 325-mg aspirin group as a reference. *Adjusted Odds ratio in the regression model reported after accounting for age, gender, CCI, BMI, and surgeon as confounders. Surgeon was used as a random effect in the regression model. α Outcomes are measured within 90 days following TKA β Multivariate regressions were not generated due to the high risk of small sample bias due to the low number of events observed for those outcome measures.
S0883-5403(18)30236-5
DOI:
10.1016/j.arth.2018.03.001
Reference:
YARTH 56484
To appear in:
The Journal of Arthroplasty
Received Date: 4 December 2017 Revised Date:
2 March 2018
Accepted Date: 3 March 2018
Please cite this article as: Faour M, Piuzzi NS, Brigati DP, Klika AK, Mont MA, Barsoum WK, Rueda CH, Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty, The Journal of Arthroplasty (2018), doi: 10.1016/j.arth.2018.03.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis
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Following Total Knee Arthroplasty
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Mhamad Faour, MD,1
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Nicolas S. Piuzzi, MD,1,2
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David P. Brigati, MD,1
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Alison K. Klika, MS,1
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Michael A. Mont, MD,1
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Wael K. Barsoum, MD,1
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Authors:
Carlos Higuera Rueda, MD1
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Department of Orthopaedic Surgery Cleveland Clinic Foundation Cleveland, Ohio
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Instituto Universitario del Hospital Italiano de Buenos Aires Buenos Aires, Argentina Correspondence to:
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Mhamad Faour, MD. Cleveland Clinic Foundation 9500 Euclid Ave. A-41 Cleveland, Ohio 44195 216-444-4954 [email protected]
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Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prophylaxis
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Following Total Knee Arthroplasty ABSTRACT:
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Aspirin is an effective prophylactic agent for venous thromboembolism (VTE) after total knee
5
arthroplasty (TKA). However, the optimal prophylactic dose of aspirin has not been established.
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The aim of the study was to compare two aspirin regimens with regard to the incidence of: 1)
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symptomatic deep venous thrombosis (DVT), 2) pulmonary embolism (PE), 3) bleeding, and 4)
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mortality within 90 days following TKA. We retrospectively identified 5,666 patients who
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received aspirin twice daily (BID) for 4 to 6 weeks following TKA. A total of 1,327 patients
10
received 81-mg BID and 4,339 patients received 325-mg BID aspirin. Postoperative
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complications collected were: VTEs (DVT and PE), bleeding (gastrointestinal or wound
12
bleeding) and mortality.
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The incidence of VTE was 0.5% in 325-mg group and 0.7% in 81-mg group (p=0.02).
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Symptomatic DVT was 1.4% in the 325-mg aspirin compared to 0.3% for 81-mg aspirin
15
(p=0.0009). After accounting for confounders, regression model showed no correlation between
16
aspirin dose and VTE incidence (Odds Ratio [OR] = 1.03; 95% Confidence Interval [95% CI]:
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0.45-2.36; p=0.94) or DVT (OR=0.50; 95% CI: 0.16-1.55; p=0.20). The incidence of PE was
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0.2% in high- compared to 0.4% in low- aspirin (p=0.13). Bleeding was 0.2% in 325-mg aspirin
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and 0.2% in 81-mg aspirin (p=0.62) and 90-day mortality was similar (0.1%) between the groups
20
(p=0.56). Low-dose aspirin was not inferior to high-dose aspirin for the prevention of VTE after
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TKA. Low-dose aspirin can be considered a safe and effective agent in the prevention of VTE
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after TKA.
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Level of evidence: III
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Key Words:
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Aspirin; venous thromboembolism; prophylaxis; knee arthroplasty; deep venous thrombosis;
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pulmonary embolism; bleeding.
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INTRODUCTION:
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Venous thromboembolism (VTE) is considered the third most frequent cause for hospital
29
readmission following total knee arthroplasty (TKA) [1]. The risk of VTE has dropped
30
dramatically in modern days (<1%), mostly due to the continuous improvement in perioperative
31
protocols [2–5][6–8]. With such a low incidence and the standardization of multimodal
32
prophylaxis practices, it became difficult to distinguish differences in efficacy of different
33
chemoprophylactic modalities. There is a wide and expanding array of VTE chemoprophylactic
34
agents for patients undergoing TKA. Many well-known challenges associated with these agents,
35
such as the risk of bleeding and wound-related infections, and difficulties with administration,
36
titration, and monitoring, are still under scrutiny in the search for an ideal chemoprophylaxis [9–
37
12].
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Compared to other anticoagulants, aspirin is considered an appealing alternative because
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of its low cost and ease of administration with no need for routine blood monitoring. The
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rationale for the use of aspirin is based on its proven effectiveness and safety to reduce the
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incidence of VTE following total knee and hip arthroplasty and a large body of research that
42
spans over four decades [13–16]. The American Association of Orthopedic Surgeons (AAOS)
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and the American College of Chest Physicians (ACCP) have jointly recommended the use of
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aspirin alone for the prophylaxis of VTE after TKA (recommended dose: 325mg twice daily
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[BID] for 6 weeks after surgery) [17,18]. Since then, accumulating literature has demonstrated
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that aspirin is not inferior to other agents for the prevention of VTEs [10,19]. Additionally, low-dose aspirin (81mg) is reportedly not inferior to high-dose aspirin for
48
the primary and secondary prevention of cardiovascular and cerebrovascular events. The
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literature also demonstrated that low-dose aspirin was more effective than higher doses in
50
preventing cerebrovascular events and mortality following vascular surgery[20]. Since the
51
toxicity of aspirin is reportedly dose-dependent, especially the risk of gastrointestinal (GI)
52
bleeding [21], the least effective dose of aspirin in the prevention of VTE is still unknown and
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the evidence to support the use of low-dose aspirin for VTE after TKA is lacking. To date only
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one study has shown potential benefits to the use of low-dose aspirin when compared to high-
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dose aspirin for VTE prevention following lower extremity joint arthroplasty [22].
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Thus, the aims of this study were to: 1) compare the efficacy of high- and low-dose
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aspirin in the prevention of VTE (deep venous thrombosis [DVT] and pulmonary embolism
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[PE]) following TKA, and 2) compare the adverse events of high- and low-dose aspirin regimens
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in terms of GI and wound-related bleeding and mortality within 90 days following TKA.
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METHODS:
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After institutional review board approval, a query was performed to obtain electronic
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medical records to identify patients who underwent elective primary TKA between 2012 and
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2016. In this retrospective cohort study we identified a total of 9,081 patients who underwent
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TKA in this time period. Then through manual chart review we identified patients who received
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only aspirin following TKA. A total of 3,415 patients were excluded because they received other 3
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modalities of chemoprophylaxis (e.g., Coumadin, enoxaparin) with or without aspirin on the day
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of the procedure, leaving a study cohort of 5,666 patients. All included patients received either 81-mg aspirin BID or 325-mg aspirin BID on the
70
evening of or the next day after the procedure for 4 to 6 weeks depending on the surgeons’
71
preference. In addition, all patients received pneumatic compression stockings after the
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procedure as standard of care. Physical therapy was initiated either on the day of surgery or on
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postoperative day 1 and continued daily throughout the hospital stay.
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From the electronic medical records, patient demographic characteristics, comorbidities,
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and perioperative details were collected by three of the authors (MF, NP, KB). Complications
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occurring within 90 days postoperatively, including symptomatic VTE (DVT and PE), upper and
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lower gastrointestinal (GI) bleeding requiring medical attention and wound bleeding that
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required surgical intervention or change in management protocols, and mortality and cause of
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death were collected through reviewing electronic medical records. Patients were not routinely
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screened for venous thromboembolism. Symptomatic deep venous thrombosis was diagnosed
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using physical examination and confirmed with lower-extremity ultrasound, and pulmonary
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embolism was detected using either computed tomography (CT) or ventilation perfusion (VQ)
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studies in cases of symptomatic VTE following AAOS and ACCP recommendations [18,23].
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Statistical analysis
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All analyses were performed using the R statistical programming language (R version
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3.3.3, Vienna, Austria). All testing was two-sided and considered significant at the 5% level. A
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non-inferiority margin is an amount for which would be borderline clinically relevant. We
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utilized a 0.25 percentage point difference as the non-inferiority margin for the power calculation
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based on Parvizi et al [22]. At 0.80 standard for power, the current study is adequately powered
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to test for non-inferiority given the non-inferiority margin of 0.25%. For the “unadjusted” (univariate) comparisons, categorical variables were compared
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between groups using either Pearson’s chi-squared test or Fisher’s exact test, as appropriate.
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Continuous variables were compared between groups using Welch’s two sample t-test. A
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multivariate mixed effects logistic regression model was considered for each response variable
95
where each response was modeled as a function of aspirin dosage and the covariates. The
96
covariates included in the regression model were: Age, sex, body mass index (BMI), age-
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adjusted Charlson comorbidity index (CCI), and surgeon. All covariates were treated as fixed
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effects except surgeon, which was treated as a random effect.
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Patient characteristics were similar between the 325-mg aspirin group and the 81-
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mg aspirin group (Table 1). The mean age was 68 years in both aspirin groups (p=0.93).
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The mean BMI was 32.6 kg/m2 in the 325-mg aspirin group compared to 32.5 kg/m2 in the
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81-mg aspirin group (p=0.60). Sex distribution was not different between the groups
103
(p=0.82). Age-adjusted Charlson comorbidity index (CCI) was 4.3 in the 325-mg aspirin
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group compared to 4.5 in the 81-mg aspirin group (p=0.03).
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RESULTS
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The incidence of symptomatic VTE in the both groups was 1.3% (74 of 5,666 patients).
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There was a significant difference (p=0.02) in the incidence of VTE between groups: 0.7% in the
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81-mg aspirin group compared to 1.5% in the 325-mg aspirin group (Table 2). The overall 5
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incidence of symptomatic DVT following surgery was 1.1% (65 of 5,666 patients). The
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incidence of symptomatic DVT in the 325-mg aspirin group was 1.4% compared to 0.3% in the
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81-mg aspirin group (p<0.001). As for PE, the overall incidence in the study population was
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0.2% (12 of 5,666 patients). The incidence of PE in the 325-mg aspirin group was 0.2%
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compared to 0.4% in the 81-mg aspirin group (p=0.13) (Table 2).
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The incidence of bleeding in the study population was 0.2% (10 of 5,666 patients). The
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incidence of bleeding after surgery was 0.2% in the 325-mg aspirin group compared to 0.2% in
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the 81-mg aspirin group (p=0.62). In the 325-mg group, 2 patients had wound-related bleeding, 4
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had lower GI bleeding, and 1 had upper GI bleeding. In the 81-mg group, 1 patient had wound
120
hematoma, and 2 patients had upper GI bleeding. Of the 5,666 study patients, 7 (0.1%) died
121
within the first 90 days following surgery, with 6 deaths (n=1 cardiac arrest, n=1 myocardial
122
infarction, n=1 respiratory failure, n=1 cerebral hemorrhage, and n=2 unknown) in the 325-mg
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aspirin group and 1 death due to cardiac arrest in the 81-mg aspirin group (p=0.56).
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Univariate analyses showed significant correlation between aspirin dose and the risk of
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VTE (OR=0.45; 95% CI: 0.22-0.90; p=0.02) and DVT (OR=0.21; 95% CI: 0.07-0.58; p<0.01).
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Furthermore, no correlation was found between aspirin dose and the incidence of PE (p=0.13),
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bleeding (p=0.62), or mortality (p=0.56) within 90 days following TKA (Table 3). After
128
accounting for age, sex, BMI, CCI and surgeon, mixed linear regression model showed no
129
correlation between aspirin dose and the incidence of VTE (OR = 1.03; 95% CI: 0.45-2.36;
130
p=0.94) or the incidence of DVT following TKA (OR=0.50; 95% CI: 0.16-1.55; p=0.20) (Table
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3).
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DISCUSSION:
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For the prevention of cardiovascular and cerebrovascular events, aspirin has been used
134
successfully, with lower doses being as effective as higher doses of aspirin [20,24,25]. In joint
135
arthroplasty, high-dose aspirin has been shown to be effective and safer than other
136
anticoagulation modalities in the prevention of VTE after total knee and hip arthroplasty [10,26–
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29]. However, very few studies have compared the efficacy and safety of different aspirin
138
regimens for the prevention of VTEs following TKA [22,30] and the optimal dose for the
139
prevention following TKA is still yet to be determined. Thus, the aim of this study was to
140
evaluate the efficacy and safety of low-dose aspirin compared to high-dose aspirin in the
141
prevention of VTE after TKA.
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This retrospective study has a number of limitations and strengths. This cohort
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comparative study may be limited by the retrospective design, and the discrepancies in patient
144
characteristics and aspirin prescription disparities among surgeons. Furthermore, it was not
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possible to evaluate patient adherence to taking aspirin after they were discharged from the
146
hospital. However, to the best of our knowledge this is the largest cohort reported in TKA, and
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all patient medical records were carefully reviewed by the authors to identify the outcomes of
148
interest and identify patients who received aspirin only after surgery. In addition, mixed linear
149
regression model was used to account for the differences in patient characteristics as well as
150
surgeon prescribing patterns. Furthermore, post hoc analysis of the study population showed that
151
our study was powered to detect non-inferiority difference between low-dose and high-dose
152
aspirin. However, it was not powered to detect superiority effect of low-dose vs high-dose
153
aspirin.
154
important outcomes such as the incidence of periprosthetic joint infection which have been
155
correlated to chemoprophylactic agents after TKA [10,22].
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Our study was also limited in the outcomes assessed and did not evaluate other
7
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This study showed similar findings to what have been previously reported in the literature
157
that aspirin is an effective treatment for the prevention of VTE after TKA[10,26,29,31]. High-
158
dose aspirin demonstrated similar efficacy and safer profile in the prevention of VTE following
159
TKA compared to other anticoagulants. Gesell et al evaluated if aspirin can be safely used for
160
adjuvant chemoprophylaxis in patients who have a low thromboembolic risk. They compared the
161
efficacy and safety of high-dose aspirin (325mg BID) in 1,016 patients to warfarin in 1,001
162
patients undergoing TKA and found no significant difference in rates of VTE (aspirin: 25
163
patients [2.5%] vs warfarin: 22 patients [2.6%]; p=0.7), PE (aspirin: 11 patients [1.1%] vs
164
warfarin: 9 patients [0.9%]; p=0.68), and 90-day mortality (aspirin: 1 patient [0.1%] vs
165
warfarin:1 patient [0.1%]; p=0.5) between the two groups. They also found higher rate of wound
166
related complications in the warfarin group (p=0.03) [2].
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The literature evaluating the use of low-dose aspirin in the prevention of VTE following
168
TKA is very scarce. One previously published study by Parvizi et al examined, in a prospective
169
crossover design, the efficacy and adverse event profiles of low-dose (81-mg BID) vs high-dose
170
aspirin (325-mg BID) regimens for patients undergoing total hip and knee arthroplasty[22]. They
171
found that low-dose aspirin was not inferior to high-dose aspirin in the prevention of VTE. The
172
results of our study corroborate with the findings of Parvizi et al study. We showed that low-
173
dose aspirin was non-inferior to high-dose aspirin in the prevention of VTE following TKA[22].
174
The incidence of VTE in this study is considered very low compared to the incidence reported in
175
the literature [2,32–34]. The low incidence of VTE can be attributed, in addition to aspirin use, to
176
other multimodal protocols employed perioperatively to minimize the risk of VTE including
177
spinal anesthesia [3], pneumatic compression during inpatient stay [5,16] as well as early
178
mobilization after the procedure [4].
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The study also showed no significant difference in the incidence of bleeding (GI and
180
wound) between the two doses. Despite the risk of GI bleed being dose-dependent as previously
181
reported, the incidence of GI bleeding was very low in this study population and we did not
182
detect any significant difference when comparing high versus low aspirin doses. The incidence
183
of bleeding reported in this study (0.13%) included both wound-related and GI bleeding. Parvizi
184
et al reported 0.3% incidence rate of GI bleeding alone in their study comparing two aspirin
185
regimens for the prevention of VTE [22]. Feldstein et al prospectively compared the incidence of
186
GI side effects of different regimens of aspirin following total knee and hip arthroplasty in 643
187
patients. They found that 81-mg aspirin BID was associated with significantly less GI distress
188
and nausea compared with 325-mg BID aspirin dose. They also reported an overall GI bleeding
189
was 0.9%, with 2/282 (0.7%) in the aspirin 325-mg group, vs 4/361 (1.1%) in the aspirin 81-mg
190
group (p = 0.7). [30]. Jones et al, in a prospective study comparing low-dose aspirin (150mg
191
daily) to Enoxaparin for the prevention of VTE in 327 patients undergoing total knee and hip
192
arthroplasty, demonstrated that low-dose aspirin was associated with lower risk of wound
193
discharge after TKA and similar efficacy in the prevention of VTE when compared to
194
Enoxaparin [35]. In addition, the study reported 0.12% overall 90-day mortality rate after TKA
195
which was lower than what has been reported in the literature [36].
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The optimal dose and frequency of administration of aspirin for the prevention of VTE
197
following total joint arthroplasty has yet to be discerned. One potential challenge to the use of
198
aspirin as a prophylactic agent for VTE is aspirin resistance also known as the aspirin response
199
variability. There is increasing evidence that some patients may exhibit low response to the anti-
200
platelet effects of aspirin (also referred to as aspirin resistance) during the early post-operative
201
period in cardiac surgery, which is associated with an increased risk of cardiovascular
9
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events [37–39]. The mechanism of post-operative aspirin low response remains uncertain but
203
might be related to an increased rate of platelet production post-operatively, as a consequence of
204
an initial consumptive thrombocytopenia, leading to an excess of platelets unexposed to aspirin
205
postoperatively. Li et al reported aspirin response variability in patients after total hip and knee
206
arthroplasty, with one-half of the patients (6 of 12 patients) exhibiting post-operative aspirin low
207
response [40]. Studies testing diverse aspirin treatments showed that twice-daily low doses were
208
more effective than once-daily higher aspirin doses on surrogate end points of platelet inhibition
209
[41]. Consequently, additional studies will need to evaluate the ideal dosage and administration
210
frequency of aspirin in the prevention of VTE after total joint arthroplasty.
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Furthermore, aspirin is known to cause gastrointestinal side effects, primarily
212
dyspepsia or peptic ulcer[42]. Enteric-coated aspirin has been developed to decrease the
213
risk of gastrointestinal side effects [43]. However, clinical trials have shown that enteric
214
coating can significantly reduce the antiplatelet effect of aspirin [44–46]. Therefore,
215
enteric-coated aspirin might not be bioequivalent to plain aspirin, entailing the risk of
216
insufficient thrombosis prophylaxis [47]. In addition, a recent review of the literature
217
demonstrated that there seems to be no effect of enteric-coating on the incidence of
218
clinically relevant dyspepsia or gastrointestinal bleeding compared to plain aspirin [48].
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Since higher doses of aspirin (325mg twice daily) are associated with higher
220
gastrointestinal complications; enteric-coating does not provide clinically significant
221
reduction in gastrointestinal bleeding; and low-dose aspirin was not inferior to high-dose
222
aspirin in the prevention of VTE after TKA as was demonstrated in this study, low-dose
223
(81mg) plain aspirin twice daily can play an important role in conjunction with other
224
perioperative measures in the prevention of VTE after total joint arthroplasty. Future 10
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225
studies need to assess the difference between a single-dose aspirin and aspirin twice daily
226
for the prevention of VTE after total joint arthroplasty. In conclusion, low-dose aspirin can be considered a safe and effective agent in the
228
prevention of VTE since it was not inferior to high-dose aspirin for the prevention of VTE after
229
TKA. With the overall low incidence of VTE, the role of chemoprophylaxis may be considered
230
minimal in the perioperative prevention in low risk patients. Future studies should identify the
231
optimal aspirin regimen for the prevention of VTE following TKA and evaluate the efficacy of
232
other non-chemoprophylactic agents with and without the additional use of chemoprophylaxis.
233
Furthermore precise patient VTE risk stratification is needed in order to establish the optimal
234
multimodal perioperative VTE prevention approach.
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Table 1: Population characteristics 325 mg aspirin (n=4,339)
81 mg aspirin (n=1,327)
p-value
RI PT
Factor
0.82
Sex Female
2,588 (59.7%)
Male
1,751 (40.3%)
Age (Mean ± SD) BMI (kg/m2) (Mean ± SD)
32.6 ± 6.7
Age-adjusted CCI (Mean ± SD)
4.3 ± 2.2
68 ± 10
0.93
32.5 ± 6.7
0.60
4.5 ± 2.2
0.07
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BMI-Body Mass Index; CCI-Charlson comorbidity Index.
540 (40.7%)
SC
68 ± 10
787 (59.3%)
Table 2: Incidence of complications within 90 days of total knee arthroplasty
Venous Thromboembolism Deep Venous Thrombosis
Bleeding
AC C
Mortality
EP
Pulmonary Embolism
325 mg BID aspirin (n=4,339) 65 (1.5%)
81 mg BID aspirin (n=1,327) 9 (0.7%)
0.02
61 (1.4%)
4 (0.3%)
<0.001
7 (0.2%)
5 (0.4%)
0.13
7 (0.2%)
3 (0.2%)
0.62
6 (0.1%)
1 (0.1%)
0.56
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Complication
p-value
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RI PT
Table 3: Multivariate and univariate analyses of aspirin dosage and outcomes after total knee arthroplasty. Outcomeα Events Adjusted OR P-value Unadjusted OR P-value ¶ ¶ (95% CI)* (95% CI) 74 1.03 (0.45 – 2.36) 0.94 0.45 (0.22 – 0.90) 0.02 VTE 65 0.50 (0.16 – 1.55) 0.20 0.21 (0.07 – 0.58) DVT <0.001 β 12 N/A N/A 2.34 (0.74 – 7.39) 0.13 PE β 10 N/A N/A 0.54 (0.06 – 4.52) 0.56 Mortality β N/A N/A 1.40 (0.36 – 5.43) 0.62 7 Bleeding
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VTE-Venous Thromboembolism; DVT-Deep Venous Thrombosis; PE-Pulmonary Embolism. ¶ The ORs given are between 81-mg aspirin group and the 325-mg aspirin group as a reference. *Adjusted Odds ratio in the regression model reported after accounting for age, gender, CCI, BMI, and surgeon as confounders. Surgeon was used as a random effect in the regression model. α Outcomes are measured within 90 days following TKA β Multivariate regressions were not generated due to the high risk of small sample bias due to the low number of events observed for those outcome measures.