Abstract
Background
Many orthopaedic surgeons routinely prescribe aspirin (ASA) as prophylaxis for venous thromboembolism (VTE) following hip fracture surgery (HFS). The purpose of this study is to assess the effectiveness of aspirin to other agents in preventing VTE and mortality following hip fracture surgery.
Methods
Following PRISMA guidelines, we performed a search for HFS studies from 1998 to 2023 reporting comparisons between aspirin and other chemoprophylaxis methods for VTE (DVT – deep vein thrombosis; PE – pulmonary embolism). SPSS Meta-analysis function was used to calculate Mean Effect Size Estimate (MESE) and 95 % Confidence Intervals for each outcome. Reverse Fragility Index (RFI) and Fragility Quotient (FQ) were calculated for each study.
Results
Of the 847 articles screened, 4 studies with 5 comparisons met the search criteria to be included for analysis. A total of 1194 participants were included in these studies. There was a decreased risk of mortality seen with use of aspirin compared to other agents (MESE = 0.86, 95 % CI: [0.07–1.66]; p=.03). There was no increased risk of DVT or PE with use of aspirin (both p>.4). The overall RFI and FQ for all 19 outcomes were 12 (IQR: 6.5–15) and 0.080 (IQR: 0.027–0.110), respectively. Ten studies (52.6 %) reported a loss-to-follow-up (LTF) greater than the overall RFI.
Conclusions
Aspirin demonstrates similar protective effects on prevention of VTE compared to other agents and may have significant protective effects on overall mortality following surgical intervention for hip fractures. However, the current evidence concerning its use in this arena is less than robust, with more than half of the studied outcomes considered statistically fragile.
Keywords: Aspirin, Hip fracture, Deep vein thrombosis, Venous thromboembolism, Mortality
Highlights
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Aspirin demonstrated non-inferiority in preventing VTEs, as well as possible beneficial effects in preventing mortality.
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Although the results from these studies are encouraging, the strength of their statistics hinders their clinical application due to the fragility of the p-values and high loss-to-follow-up.
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Future studies should utilize fragility indices and quotients to further characterize their strength of their statistical findings.
1. Introduction
Venous thromboembolism (VTE) is a potentially fatal yet common condition, occurring in 0.1 % of individuals under 25 years old and 1 % of those over 75 years old.1, 2, 3 VTE encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). Risk factors for VTE include age over 40, obesity, history of VTE, prolonged bed rest (>5 days), lower extremity fracture, and major surgery.4 Patients with hip fractures have a significantly higher risk of VTE, with a 37 % chance of developing DVT and a 6 % chance of PE.4, 5, 6 Without VTE chemoprophylaxis, major surgeries such as total knee arthroplasty (TKA) and total hip arthroplasty (THA) have DVT rates of 60–85 % and 50–60 %, respectively.7 Therefore, routine use of mechanical and chemoprophylaxis is crucial to prevent VTE due to its high incidence.
Current literature indicates that chemoprophylaxis can reduce the risk of VTE by 10–80 %.8 Various types of VTE chemoprophylaxis are available, including aspirin (ASA), low-molecular-weight heparin (LMWH), dabigatran, and direct oral anticoagulants (DOAC).9 Cost and safety are key considerations in choosing the appropriate prophylaxis. Aspirin, a generic antiplatelet agent, is a safe and cost-effective option for VTE prophylaxis.10,11 In contrast, rivaroxaban is 300 times more expensive than aspirin 12. Despite the higher cost, some medical and cardiovascular groups prefer rivaroxaban due to its perceived benefits.13,14 Given that a VTE event costs $36,918, selecting cost-effective chemoprophylaxis after hip fracture surgery (HFS) can reduce the financial burden of VTE and minimize the risk of serious complications to the same degree as more expensive alternatives.15
To establish aspirin as a cost-effective and non-inferior alternative to traditional chemoprophylaxis, the statistical fragility of current literature must be evaluated. Statistical fragility assesses the strength of significance in clinical study findings for a particular intervention or topic.16 The fragility indices (FI) and fragility quotients (FQ) are tools that quantify the significance of findings; higher FI and FQ values indicate stronger trustworthiness of the findings, which may improve surgeons' confidence in utilizing the tested clinical practice guidelines.17, 18, 19
A previous systematic review and meta-analysis examined various thromboprophylactic agents but did not assess associations with mortality and compared agents to a placebo rather than a prominent alternative.20,21 This study aims to answer: Is aspirin non-inferior to other chemoprophylactic agents in preventing VTE and mortality following hip fracture surgery? Recent large RCTs suggest that aspirin is non-inferior to LMWH in preventing VTE in orthopedic trauma patients.22 Additionally, several retrospective studies associate aspirin with similar VTE rates compared to traditional chemoprophylactic agents, but the robustness of these results remains unverified.22,23 Our secondary objective is to evaluate the quality of current evidence in hip fracture surgery, focusing on fragility index and quotient as indicators of statistical robustness regarding aspirin's effectiveness in VTE prophylaxis.
2. Methods
2.1. Systematic review registration
The present study abided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was exempt from institutional review board (IRB) approval (Appendix) due to the incorporation of only publicly available data.24 The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO registration identification number: CRD42023476289).
2.2. Study design and eligibility criteria
The PubMed, Cochrane, and Google Scholar databases were queried from 1998 to 2023, for all retrospective and prospective studies related to the use of aspirin for venous thromboembolic prevention following hip fracture procedures. Search terms utilized were: “hip fracture aspirin”, “hip fracture thromboprophylaxis”, OR “venous thromboembolism hip fracture.” In order to meet inclusion, dichotomous outcomes must have been reported for the development of DVTs between comparison groups. Reasons for exclusion included non-cohort studies, animal studies, crossover studies, and studies reporting non-dichotomous outcomes.
2.3. Identification of studies
We screened all studies included in the search for the use of aspirin in comparison with other VTE chemoprophylaxis regimens. We confirmed the methods and results of each study were written in English language and fit within our criteria.
2.4. Article review process and data procurement
The abstracts of each article were reviewed independently by two authors (V.M. and A.A.), followed by a more detailed review of each methodology. Studies comparing multiple chemoprophylactic agents were analyzed as unique comparisons. Study data were extracted into a spreadsheet and data was separated into like variables.
2.5. Methodological quality and bias assessment
The Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) Version 2.0 tool was used to evaluate study bias.25 Using this tool, potential study biases are classified as low to serious risk. The potential types of biases, as well as overall bias, were assessed and recorded. Two independent observers (A.A. and V·H.M.) assessed all included studies. Any discrepancies were resolved by consensus by a third reviewer (T.K·W.).
2.6. Study characteristics
We collected the following information from each article: title, publication year, location of study, patient sample size, type of fracture studied (femoral neck, intertrochanteric, subtrochanteric, pertrochanteric), type of fixation or arthroplasty method studied [total hip arthroplasty (THA), hip hemiarthroplasty (HA), multiple screws or pins, sliding hip screw (SHS), intermedullary nail (IMN)], number of patients lost to follow-up, duration of study (weeks), demographics [age, sex (percent female), body mass index (BMI; kg/m2)], study outcomes [deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding event (MBE), readmission, and mortality], VTE chemoprophylaxis regimen, reported P value, and estimated blood loss (if available). We then filled out a 2 × 2 contingency table for each dichotomous, categorical study outcome.
2.7. Calculation of fragility index and fragility quotient
Using the method previously described, FI was calculated for all relevant dichotomous outcomes reported in each study.16 Using the true n number for each variable of those receiving aspirin and those receiving another chemoprophylactic agent, we compared values using the Fisher exact test. Using the group with fewer events, we continued to add n+1 to the calculated P value until it reached non-significance (P > .05) and labeled the value the fragility index (FI). The reverse was done if the first calculated P value was not statistically significant, and the resulting value was labeled the reverse fragility index (RFI). Then, we obtained the fragility quotient (FQ) for all outcomes by dividing the fragility or reverse fragility index by the sample size of the corresponding study.
2.8. Statistical analysis
We analyzed descriptive statistics for each study and outcome within our study. Primary outcomes included the rate of DVTs. Secondary outcomes included rates of PEs, major bleeding events, readmission, and mortality. Frequency distributions and summary statistics were calculated for all variables. Statistical fragility data was compared between groups using chi-squared and t-tests.
Meta-analysis was conducted if the majority of studies were available for an outcome. Measures of heterogeneity used were Cochrane Q and resulting I2, in addition to the 95 % confidence intervals (CIs). We incorporated all findings of the sensitivity analyses in GRADE (i.e., imprecision).
Mean effect size estimates (MESE) were calculated from final means with standard deviations for the both the intervention (ASA) and control (other chemoprophylactic agent) groups. A negative value signified a protective effect for the intervention group. Data were analyzed in February 2024. All analyses were performed using SPSS software (IBM Corp. IBM SPSS Statistics for Windows, v28.1.1. Armonk, NY, USA). Statistical tests were two-tailed with significance set to p < 0.05.
3. Results
3.1. Study inclusion
Out of 847 studies screened, 4 studies with a total of 5 unique comparisons met the inclusion criteria and were included in the analysis (Fig. 1, Supplemental Table 1). Among these comparisons, 1276 patients with hip fractures were enrolled. Follow-up data were available for 1194 patients (93.6 %). Of these, 728 patients (61.0 %) received aspirin for VTE chemoprophylaxis following surgery (Table 1). Nineteen events were identified, all of which were nonsignificant (P > 0.05). In total, 31 patients (2.6 %) developed a DVT postoperatively, 17 patients (1.5 %) developed either a PE or MBE, and 29 patients (2.4 %) died (Table 2).
Fig. 1.
Prisma flowchart.
Table 1.
List and proportion of chemoprophylactic agents in analysis.
| Type of Intervention | Number of Patients | Proportion of Total |
|---|---|---|
| Aspirin | 728 | 61.0 % |
| Rivaroxaban | 192 | 16.1 % |
| Clopidogrel | 102 | 8.5 % |
| Other (either Warfarin, LMWH, Rivaroxaban, Heparin or Clopidogrel from Chisari et al) | 172 | 14.4 % |
Table 2.
List and rate of outcomes in analysis.
| Type of Outcome (# of comparisons) | Number of Patients | Rate of Outcome |
|---|---|---|
| Deep Vein Thrombosis (n = 5) | 31 | 2.6 % |
| Pulmonary Embolism (n = 4) | 9 | 0.9 % |
| Major Bleeding Event (n = 2) | 8 | 1.1 % |
| Readmission (n = 3) | 85 | 17.8 % |
| Mortality (n = 5) | 29 | 2.4 % |
3.2. Methodological bias of studies
The risk of bias in the included studies was generally acceptable, with a low risk of bias in most domains (Supplemental Table 2). Only one study showed a serious risk of bias in any domain. The interobserver reliability for bias assessment was excellent (ICC: 0.94, 95 % CI: 0.89 to 0.98).
3.3. Effect of aspirin on deep vein thrombosis
All four studies reported the relationship between postoperative anticoagulation and the development of DVT. The test for heterogeneity was significant, with moderate heterogeneity observed (I2 = 6 %). Aspirin use was not significantly associated with the development of DVT compared to other prophylactic agents [Mean Effect Size Estimate (MESE) = −0.11, 95 % CI: −0.74 to 0.97; Z = 0.26; p = 0.80] (Fig. 2).
Fig. 2.
Effect of aspirin on development of deep vein thrombosis.
3.4. Effect of aspirin on pulmonary embolism
Nine studies reported the relationship between postoperative anticoagulation and the development of PE. The test for heterogeneity was significant, with moderate heterogeneity observed (I2 = 0 %). Aspirin use was not significantly associated with the development of PE compared to other prophylactic agents [MESE = 0.48, 95 % CI: −0.74 to 1.70; Z = 0.78; p = 0.44] (Fig. 3).
Fig. 3.
Effect of aspirin on development of pulmonary embolism.
3.5. Effect of Aspirin on Mortality
All four studies reported the relationship between postoperative anticoagulation and mortality. The test for heterogeneity was significant, with moderate heterogeneity observed (I2 = 0 %). Aspirin use was associated with decreased mortality compared to other prophylactic agents [MESE = 0.86, 95 % CI: 0.07 to 1.66; Z = 2.13; p = 0.03] (Fig. 4).
Fig. 4.
Effect of aspirin on mortality.
3.6. Statistical fragility analysis
For the 19 nonsignificant outcomes reported, the number of events needed to change significance (RFI) was 12 (IQR: 6.5–15; Table 3). The fragility quotient (FQ) for nonsignificant outcomes was 0.080 (IQR: 0.027–0.110). Of these 19 outcomes, 5 (26.3 %) were primary and 14 (73.7 %) were secondary.
Table 3.
Overall outcomes.
| Type of Outcome | Value | IQR |
|---|---|---|
| Total Reverse Fragility Index (n=19) | 12 | 6.5–15 |
| Total Fragility Quotient (n=19) | 0.080 | 0.027-0.110 |
| Reverse Fragility Index when RFI > LTF (n=9) | 12 | 7.5–18.5 |
| Fragility Quotient when RFI > LTF (n=9) | 0.053 | 0.035-0.077 |
| Reverse Fragility Index when RFI < LTF (n=10) | 12 | 8–12 |
| Fragility Quotient when RFI < LTF (n=10) | 0.090 | 0.025-0.129 |
The RFI for primary outcomes was 12 (IQR: 9–12; Table 4). The FQ for secondary outcomes was 0.049, indicating that reversing 5 out of 100 outcomes could change the significance of the studies. Of the five primary outcomes, three reported loss-to-follow-up (LTF) data greater than the overall RFI of 12. Therefore, 60.0 % of studies reported an LTF value exceeding the overall RFI.
Table 4.
Fragility analysis of deep vein thrombosis.
| Type of Outcome | Value | IQR |
|---|---|---|
| Reverse Fragility Index (n=5) | 12 | 9–12 |
| Fragility Quotient (n=5) | 0.049 | 0.035-0.072 |
| Number of Studies with RFI < LTF | 3 | 60.0 % |
The FQ for secondary outcomes was 0.095, indicating that reversing 10 out of 100 outcomes could change the study significance. Of the fourteen secondary outcomes, seven reported LTF data greater than the overall RFI of 12.5. Thus, 50.0 % of studies had an LTF value exceeding the overall RFI.
4. Discussion
Venous Thromboembolism (VTE) is a complication of substantial concern to orthopedic surgeons treating geriatric hip fractures. Despite the goals of early mobility with operative fixation or arthroplasty in treating proximal femur fractures, the risk of DVT and PE remain high, especially in an aging population with a high propensity for multiple comorbidities.7 Addition of a cost-effective chemoprophylactic agent to mechanical prophylaxis is of paramount importance. Choosing an agent that maximizes compliance with the highest efficacy and lowest cost has been an area of investigation for some time. A recent large high quality randomized control trial performed by the Major Extremity Trauma Research Consortium (METRC) has suggested the noninferiority of aspirin 81 mg twice daily to the classic use of LMWH in the treatment of orthopedic trauma patients.22 However, this study grouped all extremity fractures including upper and lower extremity injuries. The current available literature on geriatric hip fractures is limited. This population may have a higher risk of VTE than the younger trauma population or those who sustain upper extremity injuries.26,27
With this in mind, the incidence of deep vein thrombosis and pulmonary embolism following surgical intervention for hip fractures are chief concerns of surgeons, hospitals, and third-party payers as they commonly result in readmission and are amongst the leading causes of mortality following hip fracture surgery.28 The risk of death due to pulmonary embolism has been shown to be 0.2 %, with PE comprising 6 % of all in-hospital mortalities after hip fracture operative management.28,29 In our study, while we found aspirin to be non-inferior in preventing both DVTs and PEs, aspirin was also shown to have a protective effect on all-cause mortality compared to other chemoprophylactic agents. Given the effects aspirin has on vascular health in cardiac and neurovascular conditions, in combination with an already elderly population at risk for these complications, aspirin compared to other agents may have a multi-faceted role in avoiding these troublesome events following surgical intervention for hip fractures.
As such, aspirin is an attractive choice for VTE chemoprophylaxis as it is an oral agent, cost-effective, and has a low bleeding risk compared with other anticoagulant agents.14 However, LMWH has been the traditional chemoprophylactic agent of choice with a long track record of efficacy.13 Despite this, it is costly to patients, administered with subcutaneous injection, and may have a lower compliance rate due to its route of administration.30 Other VTE chemoprophylactic agents such as DOACs and dabigatran have been investigated but have significant limitations including increased bleed risk profiles.31
All four comparisons included in this systematic review and statistical analysis were retrospective in nature. To this date, no large prospective randomized trials comparing the efficacy of LMWH and aspirin specifically for hip fracture patients has been undertaken. Chisari et al. performed a large retrospective analysis of 1141 patients who sustained a femoral neck fracture and were subsequently treated with either total hip or hemiarthroplasty.32 However, high-risk patients for VTE were excluded from the analysis. Ginsel et al. studied outcome differences between warfarin and antiplatelet medications in 330 patients operatively treated for femoral neck fractures.33 Collinge et al. investigated 1118 patients with surgical management of hip fractures and found no substantial increase in bleeding risk, VTE, and mortality in patients treated with aspirin as chemoprophylaxis.34 Huang et al. investigated the efficacy of rivaroxaban and aspirin after an initial five-day course of LMWH.35 They found no differences between aspirin and direct oral anticoagulants in bleeding and VTE complications. Despite these promising results, the studies in this review are prone to selection bias, as none were prospective or randomized.
Statistical fragility indices and fragility quotients are useful statistical tools to evaluate the quality of statistical evidence in published trials.16 Our study demonstrates that within the highest quality of evidence currently available, there remains a significant level of uncertainty and statistical fragility regarding the noninferiority of aspirin over other chemoprophylactic agents in the treatment of hip fracture surgery patients. Similarly, studies examining the strength of statistical significance in joint arthroplasty regarding VTE chemoprophylaxis and mortality demonstrated moderately strong fragility indices, however, with most studies reporting high loss-to-follow-up that could impact the interpretation of results.36, 37, 38 Despite the attractiveness of aspirin as a chemoprophylactic agent and its potential impact as a cost-effective prophylactic prevention of VTE, further randomized control trials are required in the geriatric hip fracture population to further bolster the argument for its use in this setting and ensure its efficacy.39
This study has several limitations related to both the methodology of fragility indices and the current literature in this field. While these results offer an effective way to assess the robustness of findings in studies and trials, some argue that their application is limited in scope. Additionally, despite the sound selection of patients and adherence to protocols in the included studies, the literature is notably limited by potential biases. These biases arise from not accounting for confounders and a high loss-to-follow-up, which contribute to the moderate risk of bias observed overall. Statistical fragility was initially designed for evaluating randomized controlled trials and may be affected by confounding variables in non-randomized studies, a factor that should be considered during interpretation.40 Furthermore, the inclusion of only five comparisons within four studies limits the strength of our review, as these studies either did not analyze aspirin as a prophylactic agent or focused solely on patients undergoing hip fracture surgery. Nonetheless, given the high incidence of VTE and the widespread use of aspirin in this context, we hope this study will encourage surgeons and researchers to explore this topic further and derive more meaningful results.
5. Conclusions
Aspirin may be non-inferior to other chemoprophylactic agents for prevention of venous thromboemboli and possibly have protective effects on overall mortality following surgical intervention for hip fractures. However, the current evidence concerning its use in this arena is less than robust, with more than half of the studied outcomes considered statistically fragile. While this should not restrict the utilization of aspirin as a chemoprophylaxis agent, the statistical rigor of current literature is lacking, and future studies examining this topic should emphasize strict follow-up measures to solidify the current literature available.
Guardian/patient's consent
All data analyzed was publicly available and, therefore, consent was not obtained prior to investigation.
Ethical review committee statement
Institutional Review Board approval was not required for use of the deidentified data present in this study.
Funding statement
No funding was obtained for this study.
CRediT authorship contribution statement
Tyler K. Williamson: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Visualization. Victor H. Martinez: Conceptualization, Methodology, Investigation, Data curation, Writing – original draft, Visualization. Adam W. Aziz: Investigation, Data curation, Writing – original draft, Visualization. Travis Kotzur: Investigation, Data curation, Writing – review & editing, Visualization. Luke Verlinsky: Investigation, Data curation, Writing – review & editing, Visualization, Project administration. Frank A. Buttacavoli: Conceptualization, Investigation, Supervision, Resources, Writing – review & editing, Visualization, Project administration.
Declaration of competing interest
Frank A Buttacavoli Heraeus: Paid consultant.
KCI: Paid consultant.
Medtronic: Paid consultant.
Sanara MedTech: Paid consultant.
Zimmer: Paid consultant.
Tyler K Williamson, Victor H Martinez, Adam Aziz, Travis Kotzur, Luke Verlinsky: Nothing to disclose.
Acknowledgments
No acknowledgments are available for this study.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jor.2024.06.039.
Contributor Information
Tyler K. Williamson, Email: tylerwill33tamu@gmail.com.
Victor H. Martinez, Email: vic.martinezz43@gmail.com.
Adam W. Aziz, Email: aaziz@student.uiwtx.edu.
Luke Verlinsky, Email: verlinsky@uthscsa.edu.
Frank A. Buttacavoli, Email: buttacavoli@uthscsa.edu.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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