Effectiveness of Aspirin in Preventing Deep Vein Thrombosis Following Proximal Femoral Fracture Surgery in Japan

Effectiveness of Aspirin in Preventing Deep Vein Thrombosis Following Proximal Femoral Fracture Surgery in Japan | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effectiveness of Aspirin in Preventing Deep Vein Thrombosis Following Proximal Femoral Fracture Surgery in Japan Takao Ohmori, Kazukiyo Toda, Takuya Taoka, Takeshi Ishihara, Yasuo Ito This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4544364/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Feb, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Previous studies have shown that aspirin is effective as a prophylactic agent against venous thromboembolism (VTE) following proximal femoral fractures (PFF). In Japan, there is a lack of evidence regarding its efficacy and safety in this context. Consequently, aspirin is not covered by insurance for the prevention of venous thrombosis. This study aimed to investigate whether continued aspirin use in patients with PFF, who were already taking aspirin for cerebrovascular disease prevention before injury is effective as a prophylaxis for deep vein thrombosis (DVT). We retrospectively analyzed PFF patients (≥ 65 years) who underwent postoperative duplex ultrasonography from January 2010 to December 2023.The study compared patients taking aspirin alone (aspirin group) and those not taking antiplatelet agents or anticoagulants (control group), matched by propensity scores. We enrolled 1064 patients while 161 (15%) were in the aspirin group. After matching, 132 patients were analyzed. DVT incidence was not statistically significant between the aspirin (53) and control groups (57) (OR: 0.72; 95%CI: 0.44–1.20; p = 0.21). Proximal DVT incidence was also similar (OR: 0.83; 95%CI: 0.25–2.73; p = 0.76). Continued aspirin use in PFF patients who were taking aspirin prior to injury did not reduce the incidence of DVT or proximal DVT, indicating no prophylactic benefit. Health sciences/Medical research/Outcomes research Health sciences/Health care/Fracture repair proximal femoral fractures deep vein thrombosis aspirin prophylaxis surgery Figures Figure 1 Introduction Venous thromboembolism (VTE) remains a significant concern, with a reported incidence of 11–40% of patients after proximal femoral fractures (PFF) surgery 1,2 . Therefore, numerous clinical guidelines recommend postoperative thromboprophylaxis to reduce the risk of VTE associated complications and mortality 3,4,5 . Previous studies have shown that aspirin is effective as a prophylactic agent against VTE following PFF 6,7 . The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Prevention of VTE in orthopedic surgery patients recommend aspirin as a prophylaxis for VTE in PFF 3 . However, there is no evidence supporting the preventive effect of aspirin on VTE in patients with PFF in Japan, and the Japanese Orthopaedic Association guidelines do not recommend its use 8 . Consequently, aspirin is not used as venous thromboembolism (VTE) prophylaxis in these patients in Japan. On the other hand, many patients routinely use aspirin for secondary prevention of cardiovascular and cerebrovascular events, particularly those with cardiovascular comorbidities 9 . Therefore, a considerable number of patients with PFF have already been taking aspirin prior to their injury. In our institution, PFF surgery is performed promptly without discontinuation of aspirin, and aspirin is continued postoperatively. This study aimed to investigate the efficacy of continued aspirin use as a prophylaxis for deep vein thrombosis (DVT) in patients with PFF, who were already taking aspirin for cerebrovascular disease prevention before injury. Materials and methods Study design and patient selection We retrospectively collected data from PFF patients (aged ≥ 65 years) who underwent postoperative lower extremity duplex ultrasonography at our institution from January 2010 to December 2023. The postoperative lower limb duplex ultrasound was routinely performed on all patients whenever possible. The patient demographics and characteristics were retrieved from the electronic patient database. The study compared patients who had been taking aspirin alone (aspirin group) and those who had not been taking antiplatelet agents or anticoagulants (control group) prior to their injury. Patients who discontinued aspirin preoperatively were excluded from the analysis. The study design was approved by the appropriate ethics review board. Informed consent was obtained from all patients and relevant persons, and no identifiable information of the participants is included in this study. Outcomes and variables The primary outcome was the incidence of DVT. The secondary outcome was the incidence of proximal DVT, recognized for its clinical significance due to the increased risk of Pulmonary embolism 10 . Proximal DVT was defined as a thrombus involving one or more central veins, including the popliteal, femoral, common femoral, profunda femoris, external iliac, internal iliac, and common iliac veins, as well as the inferior vena cava. Variables associated with VTE incidence were selected according to previous reports. The following variables were included: age, sex, body mass index (BMI), co-morbidities, American Society of Anesthesiology (ASA) score, time to operation, fracture and operation type, operative duration, intraoperative bleeding, blood transfusion requirement, time from operation to lower extremity duplex ultrasonography, and use of other antithrombotic prophylaxis. PFF were categorized into three groups: femoral neck, intertrochanteric, and subtrochanteric. Based on Garden classification 11 , femoral neck fractures were further subclassified into stable (stages 1 and 2) and unstable (stages 3 and 4) patterns. Additionally, Jensen classification 12 was used to subdivide intertrochanteric fractures into stable (types 1 and 2) and unstable (types 3, 4, and 5) patterns. Prevention of VTE in PFF Patients underwent preoperative rehabilitation, including automatic lower extremity movement and wore elastic stockings. Intraoperative and postoperative intermittent pneumatic compression devices were utilized. Patients were mobilized early, and those without contraindications were administered postoperative anticoagulants (Edoxaban, Enoxaparin, Fondaparinux). Statistical analysis Propensity score matching was used to identify patients with similar baseline characteristics. Propensity scores were estimated using a logistic regression model adjusted for patient characteristics. Matching was performed using 1:1 matching with a caliper width of 0.01 of the standard deviation of the logit of the propensity score, and without replacement. The incidences of DVT and proximal DVT in the aspirin and control groups were compared in matched pairs 13 . Logistic regression analyses were used to calculate unadjusted and adjusted odds ratios (ORs) for the incidences of DVT and proximal DVT. Continuous values are presented as median (interquartile range). Continuous and categorical variables were compared between the groups using Mann-Whitney U and chi-square tests with Yates’ correction, respectively. A two-tailed p-value < 0.05 was considered statistically significant. Statistical analyses were performed using R version 3.1.3 (The R Foundation for Statistical Computing, Vienna, Austria; www.R-project.org ). Result Baseline characteristics During the study period, a total of 1231 patients were enrolled. Of these, 1064 underwent lower-extremity duplex ultrasonography, and their data were available. A total of 332 patients (31%) were taking antiplatelet agents or anticoagulants, whereas 161 patients (15%) were administered aspirin only (aspirin group). All patients were administered 100 mg of aspirin daily. The control group consisted of 732 patients not taking antiplatelet agents or anticoagulants (Fig. 1). Significant differences were observed in the age, Co-morbidity (brain disease, cardiovascular disease, renal failure, diabetes mellitus, Psychiatric disorder), ASA classification, blood transfusion requirements, and use of other postoperative antithrombotic prophylaxis between the two groups (Table 1 ). A total of 347 patients (39%) were diagnosed with DVT, whereas 39 patients (4%) had proximal DVT. However, no significant differences were observed between the two groups in terms of the incidence of DVT (OR: 1.12; 95%CI: 0.79–1.58; p = 0.54) or proximal DVT (OR: 0.82; 95%CI: 0.34-2.00; p = 0.66) (Table 3 ). Propensity score matching analysis A total of 132 patients were included in the analysis utilizing propensity score matching. The matching procedure considerably enhanced the balance of covariates in the matched cohort, resulting in similar characteristics for all elements of the propensity score between the groups (Table 2 ). The incidence of DVT (aspirin group, 53 patients vs, control group, 57 patients) are numerically reduced in patients taking aspirin, but these was not statistically significant (OR: 0.72; 95%CI: 0.44–1.20; p = 0.21). Similarly, the incidence of proximal DVT (aspirin group, six patients vs. control group, seven patients) was not statistically significant (OR: 0.83; 95%CI: 0.25–2.73; p = 0.76). Aspirin use was not associated with a significantly higher risk of postoperative DVT or proximal DVT (Table 3 ). Discussion In Japan, there is a lack of evidence regarding its efficacy and safety in aspirin on VTE in patients with PFF. Consequently, aspirin is not covered by insurance for the prevention of venous thrombosis. Therefore, we investigated the efficacy of continued aspirin use as a prophylaxis for DVT in patients with PFF, who were already taking aspirin for cerebrovascular disease prevention before injury. The results showed that the continuation of aspirin did not reduce the incidence of DVT or proximal DVT, and no effect on DVT prophylaxis was observed. Aspirin inhibits platelet aggregation 14 ; arterial thrombosis is a platelet-predominant phenomenon, often associated with atherosclerotic damage. In contrast, venous thrombosis is generally considered a disorder of plasma coagulation. Venous thrombi are fibrin-rich and originate from areas with slower blood flow, such as the deep veins of the legs. Platelets are less abundant than arterial thrombi. However, elevated levels of platelet and endothelial activation markers have been reported in patients with VTE, and the efficacy of aspirin in the primary or secondary prevention of VTE is biologically justified 15,16,17,18 . Many studies have investigated the prophylactic effect of aspirin on VTE in orthopedic surgery. While some studies highlighted aspirin's efficacy, others found it to be inferior to other agents 19,20 , emphasizing the necessity for further exploration, particularly for hip or knee arthroplasty. On the other hand, studies have reported that aspirin is as effective as other drugs, and there are also reports of significantly reduced mortality in orthopaedic trauma patients 21,22 . Few studies have examined the prophylactic effects of aspirin on PFF. One such report is the Pulmonary Embolism Prevention Trial 6 , which showed that aspirin predominantly prevented VTE. However, a VTE prophylaxis other than aspirin has not yet been described, and the effects of aspirin alone are unclear. Recent studies have examined the effectiveness of VTE prophylaxis in patients with femoral neck fractures undergoing hip arthroplasty and reported superior reductions compared to other agents 7 . On the other hand, the review analysis of VTE risk in patients with hip and lower limb injuries, including eight studies and 17,698 patients, showed that aspirin significantly did not reduced the risk of DVT compared to placebo (relative risk (RR): 0.47; 95%CI: 0.05–2.65) 23 . While several studies have reported that aspirin is an effective prophylactic agent for VTE, there have been skeptical evaluations and an identification of a lack of high-quality randomized controlled trials supporting its use in this context, necessitating further research 24,25 . Furthermore, most studies on the effects of aspirin have examined its efficacy in treating symptomatic DVT prophylaxis. Therefore, the number of cases was limited (0.7 ~ 4.7%) 6,7,19,20,21 . However, asymptomatic DVT is present in 11–40% 1,2 . This study examined asymptomatic DVT by performing postoperative lower extremity echocardiography, which we believe is a more accurate examination of DVT incidence. Many guidelines recommend the use of aspirin for the prophylaxis of VTE in PFF. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Prevention of VTE in orthopedic surgery patients recommend aspirin as a prophylaxis for VTE in PFF 3 . This is also recommended in European guidelines 5 . Conversely, the Japanese Orthopedic Association Guidelines for the Prevention of VTE do not recommend the use of aspirin 8 , emphasizing the need for future clinical studies on the efficacy and safety of aspirin for the prevention of VTE in Japan. We hope that this study will aid in determining whether aspirin is effective as VTE prophylaxis in PFF surgeries in Japan. The main limitation of our study is that aspirin was used for the secondary prevention of cardiovascular and cerebrovascular events in patients with cardiovascular comorbidities, but not for the prevention of VTE. Additionally, this was a retrospective single-center survey. Further multicenter randomized controlled trials in which aspirin is administered to prevent VTE in Japan are needed. The aspirin dose used in this study was 100 mg daily. Aspirin as a prophylaxis for VTE has been reported in doses of 81–650 mg daily 6,7,19,20,21,22 , and the dose may affect the results. However, there are reports of no difference in the incidence of symptomatic VTE after THA with low-dose (81mg) compared with standard-dose aspirin (325mg) 26 . Conclusion In patients with PFF who were taking aspirin prior to injury, the continuation of aspirin did not reduce the incidence of DVT or proximal DVT, and no effect on DVT prophylaxis was observed. Further subsequent investigations in which aspirin is administered to prevent DVT in Japan are needed. Declarations Competing interests The authors declare no competing interests. Funding No funding was received for conducting this study. Author Contribution T.O. wrote the main manuscript text and T.O. prepared figures 1-3. All authors reviewed the manuscript. Data Availability Data is provided within the manuscript or supplementary information files. References Shin WC. et al. Preoperative Prevalence of and Risk Factors for Venous Thromboembolism in Patients with a Hip Fracture: An Indirect Multidetector CT Venography Study. J Bone Joint Surg Am. 98:2089-2095 (2016). Taoka T. et al. Delayed surgery after hip fracture affects the incidence of venous thromboembolism. J Orthop Surg Res. 18:630. doi: https://doi.org/10.1186/s13018-023-04122-8 (2023). Ytter YF. et al. 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. Chest. 141:e278S-e325S (2012). Sagi HC. et al. Venous Thromboembolism Prophylaxis in Orthopaedic Trauma Patients: A Survey of OTA Member Practice Patterns and OTA Expert Panel Recommendations. J Orthop Trauma. 29:e355-362 (2015). Jenny JY, Pabinger I, Samama CM. European guidelines on perioperative venous thromboembolism prophylaxis: Aspirin. Eur J Anaesthesiol. 35:123-129 (2018). Rodgers A, MacMahon S, Collins R, Prentice C. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 355:1295-1302 (2000). Chisari E. et al. Aspirin Is an Effective Prophylaxis for Venous Thromboembolism in Ambulatory Patients with Femoral Neck Fracture Undergoing Hip Arthroplasty. J Bone Joint Surg Am. 104:603-609 (2022). Japanese Orthopaedic Association. Guidelines for the Prevention of Symptomatic Venous Thromboembolism. Nankodo Co., Ltd. Tokyo (In Japanese) (2017). Gu Q, Dillon C, Eberhardt MS, Wright JD, Burt VL. Preventive Aspirin and Other Antiplatelet Medication Use Among U.S. Adults Aged ≥ 40 Years: Data from the National Health and Nutrition Examination Survey, 2011-2012. Public Health Rep. 130:643-654 (2015). Bikdeli B. et al. Clinical Presentation and Short- and Long-term Outcomes in Patients With Isolated Distal Deep Vein Thrombosis vs Proximal Deep Vein Thrombosis in the RIETE Registry. JAMA Cardiol. 7:857-865 (2022). Garden RS. Low-angle fixation in fractures of the femoral neck. J Bone Joint Surg Br. 43:647–663(1961). Jensen JS. Classification of trochanteric fractures. Acta Orthop Scand. 51:803–10 (1980). Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 46:399–424 (2011). Undas A, Brummel-Ziedins KE, Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 109:2285-2292 (2007). Chirinos JA. et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol. 45:1467-1471 (2005). Undas A, Brummel-Ziedins K, Mann KG. Why does aspirin decrease the risk of venous thromboembolism? On old and novel antithrombotic effects of acetyl salicylic acid. J Thromb Haemost. 12:1776-1787 (2014). Koupenova M, Kehrel BE, Corkrey HA, Freedman JE. Thrombosis and platelets: an update. Eur Heart J. 38:785-791 (2017). Diep R, Garcia D. Does aspirin prevent venous thromboembolism? Hematology Am Soc Hematol Educ Program. 2020:634-641(2020). Anderson DR. et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. N Engl J Med. 378:699-707 (2018). Sidhu VS. et al. Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial. JAMA. 328:719-727 (2022). Haac BE. et al. Aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial. PLoS One. 15:e0235628. doi: https://doi.org/10.1371/journal.pone.0235628 (2020). O'Toole RV. et al. Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture. N Engl J Med. 388:203-213 (2023). Peng S, Zhang M, Jin J, MacCormick AD. The effectiveness of venous thromboembolism prophylaxis interventions in trauma patients: A systematic review and network meta-analysis. Injury. 54:111078. doi: https://doi.org/10.1016/j.injury.2023.111078 (2023). Farey JE, An VVG, Sidhu V, Karunaratne S, Harris IA. Aspirin versus enoxaparin for the initial prevention of venous thromboembolism following elective arthroplasty of the hip or knee: A systematic review and meta-analysis. Orthop Traumatol Surg Res. 107:102606. doi: https://doi.org/10.1016/j.otsr.2020.04.002 (2021). Schutgens REG, Middeldorp S. Aspirin as Thromboprophylaxis in Orthopedic Surgery: A Matter of Perspective. Hemasphere. 7: e933. doi: 10.1097/HS9.0000000000000933 (2023). Faour M. et al. No Difference Between Low- and Regular-dose Aspirin for Venous Thromboembolism Prophylaxis After THA. Clin Orthop Relat Res. 477:396-402 (2019). Tables Tables 1-3 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files TABL1.docx TABL2.docx TABL3.docx Supplementaryimfomation.xlsx Cite Share Download PDF Status: Published Journal Publication published 05 Feb, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 11 Nov, 2024 Reviews received at journal 10 Nov, 2024 Reviewers agreed at journal 23 Oct, 2024 Reviews received at journal 10 Oct, 2024 Reviewers agreed at journal 27 Sep, 2024 Reviewers invited by journal 17 Jun, 2024 Editor assigned by journal 17 Jun, 2024 Editor invited by journal 11 Jun, 2024 Submission checks completed at journal 11 Jun, 2024 First submitted to journal 07 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4544364","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":318528329,"identity":"fafa930b-414d-4106-8575-ec2d6dafd339","order_by":0,"name":"Takao 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Therefore, numerous clinical guidelines recommend postoperative thromboprophylaxis to reduce the risk of VTE associated complications and mortality \u003csup\u003e3,4,5\u003c/sup\u003e. Previous studies have shown that aspirin is effective as a prophylactic agent against VTE following PFF \u003csup\u003e6,7\u003c/sup\u003e. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Prevention of VTE in orthopedic surgery patients recommend aspirin as a prophylaxis for VTE in PFF\u003csup\u003e3\u003c/sup\u003e. However, there is no evidence supporting the preventive effect of aspirin on VTE in patients with PFF in Japan, and the Japanese Orthopaedic Association guidelines do not recommend its use \u003csup\u003e8\u003c/sup\u003e. Consequently, aspirin is not used as venous thromboembolism (VTE) prophylaxis in these patients in Japan.\u003c/p\u003e \u003cp\u003eOn the other hand, many patients routinely use aspirin for secondary prevention of cardiovascular and cerebrovascular events, particularly those with cardiovascular comorbidities \u003csup\u003e9\u003c/sup\u003e. Therefore, a considerable number of patients with PFF have already been taking aspirin prior to their injury. In our institution, PFF surgery is performed promptly without discontinuation of aspirin, and aspirin is continued postoperatively. This study aimed to investigate the efficacy of continued aspirin use as a prophylaxis for deep vein thrombosis (DVT) in patients with PFF, who were already taking aspirin for cerebrovascular disease prevention before injury.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patient selection\u003c/h2\u003e \u003cp\u003eWe retrospectively collected data from PFF patients (aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years) who underwent postoperative lower extremity duplex ultrasonography at our institution from January 2010 to December 2023. The postoperative lower limb duplex ultrasound was routinely performed on all patients whenever possible. The patient demographics and characteristics were retrieved from the electronic patient database. The study compared patients who had been taking aspirin alone (aspirin group) and those who had not been taking antiplatelet agents or anticoagulants (control group) prior to their injury. Patients who discontinued aspirin preoperatively were excluded from the analysis. The study design was approved by the appropriate ethics review board. Informed consent was obtained from all patients and relevant persons, and no identifiable information of the participants is included in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and variables\u003c/h2\u003e \u003cp\u003eThe primary outcome was the incidence of DVT. The secondary outcome was the incidence of proximal DVT, recognized for its clinical significance due to the increased risk of Pulmonary embolism \u003csup\u003e10\u003c/sup\u003e. Proximal DVT was defined as a thrombus involving one or more central veins, including the popliteal, femoral, common femoral, profunda femoris, external iliac, internal iliac, and common iliac veins, as well as the inferior vena cava.\u003c/p\u003e \u003cp\u003eVariables associated with VTE incidence were selected according to previous reports. The following variables were included: age, sex, body mass index (BMI), co-morbidities, American Society of Anesthesiology (ASA) score, time to operation, fracture and operation type, operative duration, intraoperative bleeding, blood transfusion requirement, time from operation to lower extremity duplex ultrasonography, and use of other antithrombotic prophylaxis. PFF were categorized into three groups: femoral neck, intertrochanteric, and subtrochanteric. Based on Garden classification \u003csup\u003e11\u003c/sup\u003e, femoral neck fractures were further subclassified into stable (stages 1 and 2) and unstable (stages 3 and 4) patterns. Additionally, Jensen classification \u003csup\u003e12\u003c/sup\u003e was used to subdivide intertrochanteric fractures into stable (types 1 and 2) and unstable (types 3, 4, and 5) patterns.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePrevention of VTE in PFF\u003c/h2\u003e \u003cp\u003ePatients underwent preoperative rehabilitation, including automatic lower extremity movement and wore elastic stockings. Intraoperative and postoperative intermittent pneumatic compression devices were utilized. Patients were mobilized early, and those without contraindications were administered postoperative anticoagulants (Edoxaban, Enoxaparin, Fondaparinux).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePropensity score matching was used to identify patients with similar baseline characteristics. Propensity scores were estimated using a logistic regression model adjusted for patient characteristics. Matching was performed using 1:1 matching with a caliper width of 0.01 of the standard deviation of the logit of the propensity score, and without replacement. The incidences of DVT and proximal DVT in the aspirin and control groups were compared in matched pairs \u003csup\u003e13\u003c/sup\u003e. Logistic regression analyses were used to calculate unadjusted and adjusted odds ratios (ORs) for the incidences of DVT and proximal DVT. Continuous values are presented as median (interquartile range). Continuous and categorical variables were compared between the groups using Mann-Whitney U and chi-square tests with Yates\u0026rsquo; correction, respectively. A two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed using R version 3.1.3 (The R Foundation for Statistical Computing, Vienna, Austria; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.R-project.org\" target=\"_blank\"\u003ewww.R-project.org\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.R-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline characteristics\u003c/h2\u003e\n \u003cp\u003eDuring the study period, a total of 1231 patients were enrolled. Of these, 1064 underwent lower-extremity duplex ultrasonography, and their data were available. A total of 332 patients (31%) were taking antiplatelet agents or anticoagulants, whereas 161 patients (15%) were administered aspirin only (aspirin group). All patients were administered 100 mg of aspirin daily. The control group consisted of 732 patients not taking antiplatelet agents or anticoagulants (Fig. 1). Significant differences were observed in the age, Co-morbidity (brain disease, cardiovascular disease, renal failure, diabetes mellitus, Psychiatric disorder), ASA classification, blood transfusion requirements, and use of other postoperative antithrombotic prophylaxis between the two groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). A total of 347 patients (39%) were diagnosed with DVT, whereas 39 patients (4%) had proximal DVT. However, no significant differences were observed between the two groups in terms of the incidence of DVT (OR: 1.12; 95%CI: 0.79\u0026ndash;1.58; p\u0026thinsp;=\u0026thinsp;0.54) or proximal DVT (OR: 0.82; 95%CI: 0.34-2.00; p\u0026thinsp;=\u0026thinsp;0.66) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003ePropensity score matching analysis\u003c/h2\u003e\n \u003cp\u003eA total of 132 patients were included in the analysis utilizing propensity score matching. The matching procedure considerably enhanced the balance of covariates in the matched cohort, resulting in similar characteristics for all elements of the propensity score between the groups (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The incidence of DVT (aspirin group, 53 patients vs, control group, 57 patients) are numerically reduced in patients taking aspirin, but these was not statistically significant (OR: 0.72; 95%CI: 0.44\u0026ndash;1.20; p\u0026thinsp;=\u0026thinsp;0.21). Similarly, the incidence of proximal DVT (aspirin group, six patients vs. control group, seven patients) was not statistically significant (OR: 0.83; 95%CI: 0.25\u0026ndash;2.73; p\u0026thinsp;=\u0026thinsp;0.76). Aspirin use was not associated with a significantly higher risk of postoperative DVT or proximal DVT (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn Japan, there is a lack of evidence regarding its efficacy and safety in aspirin on VTE in patients with PFF. Consequently, aspirin is not covered by insurance for the prevention of venous thrombosis. Therefore, we investigated the efficacy of continued aspirin use as a prophylaxis for DVT in patients with PFF, who were already taking aspirin for cerebrovascular disease prevention before injury. The results showed that the continuation of aspirin did not reduce the incidence of DVT or proximal DVT, and no effect on DVT prophylaxis was observed.\u003c/p\u003e \u003cp\u003eAspirin inhibits platelet aggregation\u003csup\u003e14\u003c/sup\u003e; arterial thrombosis is a platelet-predominant phenomenon, often associated with atherosclerotic damage. In contrast, venous thrombosis is generally considered a disorder of plasma coagulation. Venous thrombi are fibrin-rich and originate from areas with slower blood flow, such as the deep veins of the legs. Platelets are less abundant than arterial thrombi. However, elevated levels of platelet and endothelial activation markers have been reported in patients with VTE, and the efficacy of aspirin in the primary or secondary prevention of VTE is biologically justified \u003csup\u003e15,16,17,18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMany studies have investigated the prophylactic effect of aspirin on VTE in orthopedic surgery. While some studies highlighted aspirin's efficacy, others found it to be inferior to other agents \u003csup\u003e19,20\u003c/sup\u003e, emphasizing the necessity for further exploration, particularly for hip or knee arthroplasty. On the other hand, studies have reported that aspirin is as effective as other drugs, and there are also reports of significantly reduced mortality in orthopaedic trauma patients \u003csup\u003e21,22\u003c/sup\u003e. Few studies have examined the prophylactic effects of aspirin on PFF. One such report is the Pulmonary Embolism Prevention Trial \u003csup\u003e6\u003c/sup\u003e, which showed that aspirin predominantly prevented VTE. However, a VTE prophylaxis other than aspirin has not yet been described, and the effects of aspirin alone are unclear. Recent studies have examined the effectiveness of VTE prophylaxis in patients with femoral neck fractures undergoing hip arthroplasty and reported superior reductions compared to other agents \u003csup\u003e7\u003c/sup\u003e. On the other hand, the review analysis of VTE risk in patients with hip and lower limb injuries, including eight studies and 17,698 patients, showed that aspirin significantly did not reduced the risk of DVT compared to placebo (relative risk (RR): 0.47; 95%CI: 0.05\u0026ndash;2.65) \u003csup\u003e23\u003c/sup\u003e. While several studies have reported that aspirin is an effective prophylactic agent for VTE, there have been skeptical evaluations and an identification of a lack of high-quality randomized controlled trials supporting its use in this context, necessitating further research \u003csup\u003e24,25\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFurthermore, most studies on the effects of aspirin have examined its efficacy in treating symptomatic DVT prophylaxis. Therefore, the number of cases was limited (0.7\u0026thinsp;~\u0026thinsp;4.7%) \u003csup\u003e6,7,19,20,21\u003c/sup\u003e. However, asymptomatic DVT is present in 11\u0026ndash;40% \u003csup\u003e1,2\u003c/sup\u003e. This study examined asymptomatic DVT by performing postoperative lower extremity echocardiography, which we believe is a more accurate examination of DVT incidence. Many guidelines recommend the use of aspirin for the prophylaxis of VTE in PFF. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Prevention of VTE in orthopedic surgery patients recommend aspirin as a prophylaxis for VTE in PFF\u003csup\u003e3\u003c/sup\u003e. This is also recommended in European guidelines \u003csup\u003e5\u003c/sup\u003e. Conversely, the Japanese Orthopedic Association Guidelines for the Prevention of VTE do not recommend the use of aspirin\u003csup\u003e8\u003c/sup\u003e, emphasizing the need for future clinical studies on the efficacy and safety of aspirin for the prevention of VTE in Japan. We hope that this study will aid in determining whether aspirin is effective as VTE prophylaxis in PFF surgeries in Japan.\u003c/p\u003e \u003cp\u003eThe main limitation of our study is that aspirin was used for the secondary prevention of cardiovascular and cerebrovascular events in patients with cardiovascular comorbidities, but not for the prevention of VTE. Additionally, this was a retrospective single-center survey. Further multicenter randomized controlled trials in which aspirin is administered to prevent VTE in Japan are needed. The aspirin dose used in this study was 100 mg daily. Aspirin as a prophylaxis for VTE has been reported in doses of 81\u0026ndash;650 mg daily \u003csup\u003e6,7,19,20,21,22\u003c/sup\u003e, and the dose may affect the results. However, there are reports of no difference in the incidence of symptomatic VTE after THA with low-dose (81mg) compared with standard-dose aspirin (325mg) \u003csup\u003e26\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with PFF who were taking aspirin prior to injury, the continuation of aspirin did not reduce the incidence of DVT or proximal DVT, and no effect on DVT prophylaxis was observed. Further subsequent investigations in which aspirin is administered to prevent DVT in Japan are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.O. wrote the main manuscript text and T.O. prepared figures 1-3. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript or supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShin WC. et al. Preoperative Prevalence of and Risk Factors for Venous Thromboembolism in Patients with a Hip Fracture: An Indirect Multidetector CT Venography Study. \u003cem\u003eJ Bone Joint Surg Am.\u003c/em\u003e 98:2089-2095 (2016).\u003c/li\u003e\n\u003cli\u003eTaoka T. et al. Delayed surgery after hip fracture affects the incidence of venous thromboembolism. \u003cem\u003eJ Orthop Surg Res.\u003c/em\u003e 18:630. doi: https://doi.org/10.1186/s13018-023-04122-8 (2023).\u003c/li\u003e\n\u003cli\u003eYtter YF. et al. 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.\u003cem\u003e Chest.\u003c/em\u003e 141:e278S-e325S (2012).\u003c/li\u003e\n\u003cli\u003eSagi HC. et al. Venous Thromboembolism Prophylaxis in Orthopaedic Trauma Patients: A Survey of OTA Member Practice Patterns and OTA Expert Panel Recommendations. \u003cem\u003eJ Orthop Trauma.\u003c/em\u003e 29:e355-362 (2015).\u003c/li\u003e\n\u003cli\u003eJenny JY, Pabinger I, Samama CM. European guidelines on perioperative venous thromboembolism prophylaxis: Aspirin. \u003cem\u003eEur J Anaesthesiol.\u003c/em\u003e 35:123-129 (2018).\u003c/li\u003e\n\u003cli\u003eRodgers A, MacMahon S, Collins R, Prentice C. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. \u003cem\u003eLancet. \u003c/em\u003e355:1295-1302 (2000).\u003c/li\u003e\n\u003cli\u003eChisari E. et al. Aspirin Is an Effective Prophylaxis for Venous Thromboembolism in Ambulatory Patients with Femoral Neck Fracture Undergoing Hip Arthroplasty.\u003cem\u003e J Bone Joint Surg Am. \u003c/em\u003e104:603-609 (2022).\u003c/li\u003e\n\u003cli\u003eJapanese Orthopaedic Association. Guidelines for the Prevention of Symptomatic Venous Thromboembolism. Nankodo Co., Ltd. Tokyo (In Japanese) (2017).\u003c/li\u003e\n\u003cli\u003eGu Q, Dillon C, Eberhardt MS, Wright JD, Burt VL. Preventive Aspirin and Other Antiplatelet Medication Use Among U.S. Adults Aged \u0026ge; 40 Years: Data from the National Health and Nutrition Examination Survey, 2011-2012. \u003cem\u003ePublic Health Rep.\u003c/em\u003e 130:643-654 (2015).\u003c/li\u003e\n\u003cli\u003eBikdeli B. et al. Clinical Presentation and Short- and Long-term Outcomes in Patients With Isolated Distal Deep Vein Thrombosis vs Proximal Deep Vein Thrombosis in the RIETE Registry. \u003cem\u003eJAMA Cardiol. \u003c/em\u003e7:857-865 (2022).\u003c/li\u003e\n\u003cli\u003eGarden RS. Low-angle fixation in fractures of the femoral neck.\u003cem\u003e J Bone Joint Surg Br.\u003c/em\u003e 43:647\u0026ndash;663(1961).\u003c/li\u003e\n\u003cli\u003eJensen JS. Classification of trochanteric fractures. \u003cem\u003eActa Orthop Scand. \u003c/em\u003e51:803\u0026ndash;10 (1980).\u003c/li\u003e\n\u003cli\u003eAustin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. \u003cem\u003eMultivariate Behav Res. \u003c/em\u003e46:399\u0026ndash;424 (2011).\u003c/li\u003e\n\u003cli\u003eUndas A, Brummel-Ziedins KE, Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. \u003cem\u003eBlood.\u003c/em\u003e 109:2285-2292 (2007).\u003c/li\u003e\n\u003cli\u003eChirinos JA. et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. \u003cem\u003eJ Am Coll Cardiol. \u003c/em\u003e45:1467-1471 (2005).\u003c/li\u003e\n\u003cli\u003eUndas A, Brummel-Ziedins K, Mann KG. Why does aspirin decrease the risk of venous thromboembolism? On old and novel antithrombotic effects of acetyl salicylic acid. \u003cem\u003eJ Thromb Haemost.\u003c/em\u003e 12:1776-1787 (2014).\u003c/li\u003e\n\u003cli\u003eKoupenova M, Kehrel BE, Corkrey HA, Freedman JE. Thrombosis and platelets: an update. \u003cem\u003eEur Heart J.\u003c/em\u003e 38:785-791 (2017).\u003c/li\u003e\n\u003cli\u003eDiep R, Garcia D. Does aspirin prevent venous thromboembolism? \u003cem\u003eHematology Am Soc Hematol Educ Program.\u003c/em\u003e 2020:634-641(2020).\u003c/li\u003e\n\u003cli\u003eAnderson DR. et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. \u003cem\u003eN Engl J Med.\u003c/em\u003e 378:699-707 (2018).\u003c/li\u003e\n\u003cli\u003eSidhu VS. et al. Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial. \u003cem\u003eJAMA. \u003c/em\u003e328:719-727 (2022).\u003c/li\u003e\n\u003cli\u003eHaac BE. et al. Aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial. \u003cem\u003ePLoS One. \u003c/em\u003e15:e0235628. doi: https://doi.org/10.1371/journal.pone.0235628 (2020).\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"22\"\u003e\n\u003cli\u003eO'Toole RV. et al. Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture. \u003cem\u003eN Engl J Med.\u003c/em\u003e 388:203-213 (2023).\u003c/li\u003e\n\u003cli\u003ePeng S, Zhang M, Jin J, MacCormick AD. The effectiveness of venous thromboembolism prophylaxis interventions in trauma patients: A systematic review and network meta-analysis. \u003cem\u003eInjury. \u003c/em\u003e54:111078. doi: https://doi.org/10.1016/j.injury.2023.111078 (2023).\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"24\"\u003e\n\u003cli\u003eFarey JE, An VVG, Sidhu V, Karunaratne S, Harris IA. Aspirin versus enoxaparin for the initial prevention of venous thromboembolism following elective arthroplasty of the hip or knee: A systematic review and meta-analysis. \u003cem\u003eOrthop Traumatol Surg Res.\u003c/em\u003e 107:102606. doi: https://doi.org/10.1016/j.otsr.2020.04.002 (2021).\u003c/li\u003e\n\u003cli\u003eSchutgens REG, Middeldorp S. Aspirin as Thromboprophylaxis in Orthopedic Surgery: A Matter of Perspective. \u003cem\u003eHemasphere.\u003c/em\u003e 7: e933. doi: 10.1097/HS9.0000000000000933 (2023).\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"26\"\u003e\n\u003cli\u003eFaour M. et al. No Difference Between Low- and Regular-dose Aspirin for Venous Thromboembolism Prophylaxis After THA. \u003cem\u003eClin Orthop Relat Res.\u003c/em\u003e 477:396-402 (2019).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-3 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"proximal femoral fractures, deep vein thrombosis, aspirin, prophylaxis, surgery","lastPublishedDoi":"10.21203/rs.3.rs-4544364/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4544364/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePrevious studies have shown that aspirin is effective as a prophylactic agent against venous thromboembolism (VTE) following proximal femoral fractures (PFF). In Japan, there is a lack of evidence regarding its efficacy and safety in this context. Consequently, aspirin is not covered by insurance for the prevention of venous thrombosis. This study aimed to investigate whether continued aspirin use in patients with PFF, who were already taking aspirin for cerebrovascular disease prevention before injury is effective as a prophylaxis for deep vein thrombosis (DVT). We retrospectively analyzed PFF patients (\u0026ge;\u0026thinsp;65 years) who underwent postoperative duplex ultrasonography from January 2010 to December 2023.The study compared patients taking aspirin alone (aspirin group) and those not taking antiplatelet agents or anticoagulants (control group), matched by propensity scores. We enrolled 1064 patients while 161 (15%) were in the aspirin group. After matching, 132 patients were analyzed. DVT incidence was not statistically significant between the aspirin (53) and control groups (57) (OR: 0.72; 95%CI: 0.44\u0026ndash;1.20; p\u0026thinsp;=\u0026thinsp;0.21). Proximal DVT incidence was also similar (OR: 0.83; 95%CI: 0.25\u0026ndash;2.73; p\u0026thinsp;=\u0026thinsp;0.76).\u003c/p\u003e \u003cp\u003eContinued aspirin use in PFF patients who were taking aspirin prior to injury did not reduce the incidence of DVT or proximal DVT, indicating no prophylactic benefit.\u003c/p\u003e","manuscriptTitle":"Effectiveness of Aspirin in Preventing Deep Vein Thrombosis Following Proximal Femoral Fracture Surgery in Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-01 19:15:25","doi":"10.21203/rs.3.rs-4544364/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-12T04:32:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-10T19:37:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34100129756571608155330295919755634283","date":"2024-10-23T19:11:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-10T08:30:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215877558591704148522287829206158495760","date":"2024-09-27T22:24:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-17T14:50:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-17T14:45:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-11T10:04:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-11T10:03:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-07T07:30:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ddb09f3e-1ce4-4ff8-9bdc-e587054a616a","owner":[],"postedDate":"July 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33680877,"name":"Health sciences/Medical research/Outcomes research"},{"id":33680878,"name":"Health sciences/Health care/Fracture repair"}],"tags":[],"updatedAt":"2025-02-10T16:12:08+00:00","versionOfRecord":{"articleIdentity":"rs-4544364","link":"https://doi.org/10.1038/s41598-025-88493-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-02-05 15:57:05","publishedOnDateReadable":"February 5th, 2025"},"versionCreatedAt":"2024-07-01 19:15:25","video":"","vorDoi":"10.1038/s41598-025-88493-4","vorDoiUrl":"https://doi.org/10.1038/s41598-025-88493-4","workflowStages":[]},"version":"v1","identity":"rs-4544364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4544364","identity":"rs-4544364","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}