Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Riediger et al. present a very interesting work on effect aspirin has in VTE prevention in ortho. The INTRO nicely presents the paradoxical findings in ortho surgery. There are a couple of minor additions/edits this reviewer suggests making manuscript even more appealing to readers: 

1. This works describes multiple doses from 81 QD to 325 mg BID. Add a sentence discussing benefits/risks of these doses. Many surgeons prefer to use 81 mg to minimize GI distress. Some discussion (a couple of sentences) around that would be helpful for readers.
2. In one of the instances, authors mention "PRISMA 2025". Is that a typo? 
3. Figure 2 states "RISMA". Correct the typo. 
4. There two lines for Figure 1 title. Correct. 

Overall, very nice work tackling the aspirin paradox in ortho. 

Author Response

We sincerely thank the reviewer for the careful evaluation of our manuscript and for the positive overall assessment of our work addressing the role of aspirin in orthopaedic venous thromboembolism prophylaxis. We greatly appreciate the constructive comments, which helped improve the clarity and methodological consistency of the manuscript. All suggested revisions have been implemented in the revised version.

Comment 1:
“This work describes multiple doses from 81 mg QD to 325 mg BID. Add a sentence discussing benefits/risks of these doses. Many surgeons prefer to use 81 mg to minimize GI distress.”

Response:
Thank you for this valuable suggestion. We have expanded the Discussion and Conclusions sections to explicitly address aspirin dose heterogeneity and its clinical implications. The revised manuscript now states that lower aspirin doses (e.g., 81 mg daily) may reduce gastrointestinal adverse effects and are increasingly favoured in contemporary arthroplasty pathways; however, currently available evidence does not permit definitive conclusions regarding optimal aspirin dose or dosing frequency because no adequately powered trial has demonstrated superiority of one dosing strategy over another.

Comment 2:
“In one instance, authors mention ‘PRISMA 2025’. Is that a typo?”

Response:
We thank the reviewer for identifying this inconsistency. The manuscript has been corrected throughout to consistently refer to the PRISMA 2020 statement.

Comment 3:
“Figure 2 states ‘RISMA’. Correct the typo.”

Response:
Corrected as suggested. Figure 2 now consistently states “PRISMA 2020 flow diagram”.

Comment 4:
“There are two lines for Figure 1 title.”

Response:
Thank you for identifying this formatting issue. The embedded title within Figure 1 has been removed, and the figure has been reformatted to comply with standard journal formatting requirements.

Once again, we thank the reviewer for the encouraging and constructive feedback, which substantially improved the clarity and presentation of the manuscript.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This structured review addresses a timely and clinically important question regarding the role of aspirin in orthopaedic thromboprophylaxis. The manuscript provides a useful synthesis of recent randomised trials and major guidelines. However, several methodological, reporting, and interpretative issues should be addressed. 

Major Concerns

1. Generalizability and evidence gaps (pharmacotherapy context): The conclusions should state more explicitly that the current evidence applies primarily to standard-risk patients. Key trials (EPCAT II, PREVENT CLOT, CRISTAL) excluded high-risk populations such as those with prior VTE, active malignancy, or thrombophilia. As a former clinical pharmacist, I note that formulary decisions and individualised prescribing require clearer acknowledgment that extrapolation to elderly hip fracture patients or those with multiple comorbidities remains unsupported by high-level evidence. Please revise the conclusions to include a direct statement on this limitation.

2. Applicability to contemporary fast-track arthroplasty: The manuscript notes that trial conditions may not reflect modern short-duration prophylaxis pathways, but this point remains underdeveloped. Given that fast-track protocols with early discharge are now common, the lack of RCTs directly comparing ultra-short anticoagulant regimens with prolonged aspirin represents a major evidence gap. I recommend adding a short paragraph in the Discussion (or a dedicated subsection in Future Directions) to explicitly state whether the authors consider this a practice-limiting gap and how future research should address it.

3. Aspirin dose heterogeneity – explicit conclusion needed: While dose variability (81–325 mg daily) is acknowledged in the text, the manuscript does not clearly conclude that an optimal aspirin dose cannot be identified from current evidence. From a clinical pharmacy perspective, this is crucial: guidelines vary, and practitioners need to know whether any dose has demonstrated superiority. Please add an explicit statement in the Discussion and Conclusions that the available evidence does not permit a definitive recommendation on optimal dosing.

4. Efficacy vs. effectiveness and diagnostic bias: The distinction between efficacy (trial conditions) and effectiveness (real-world) could be sharpened. Specifically, smaller trials relied on ultrasonography rather than venography, and many were underpowered to detect differences in symptomatic VTE. This may bias results toward apparent equivalence. A brief clarification of this potential bias – and its implications for interpreting "non-inferiority" claims – would substantially improve methodological transparency.

5. Discrepancy between stated and tabulated RCT numbers: The Results section (3.1. Overview of Included Evidence) states that "Nine randomised controlled trials (RCTs)" were included. However, Table 1 lists ten distinct study rows (EPCAT II, CRISTAL, PREVENT CLOT, Kulshrestha, Zhou, Hongnaparak, Colleoni, Jiang, Zou, Lotke). Please clarify this inconsistency. If one of these is not an RCT, reclassify it; otherwise, correct the text to state that ten RCTs were included.

6. Sixteen additional Level I–II studies not described: The Abstract and Methods indicate that 16 additional Level I–II studies were included, but the Results section provides no systematic description of these studies (neither in text nor in a table). Their characteristics, key findings, and limitations should be summarised. Similarly, the four major guidelines are named but not systematically compared. I strongly recommend adding a supplementary table summarising the key recommendations, patient populations, and strength of evidence for each guideline, as this would be of high practical value to clinicians and formulary committees.

7. Risk of bias assessment (ROB 2) – insufficient reporting: The manuscript states that the Cochrane ROB 2 tool was used and summarises results in Figure 3. However, for a clinical pharmacy audience, it is essential to see domain-level assessments (randomisation, deviations, missing outcome data, outcome measurement, selective reporting) for each of the nine RCTs. Please provide this as a supplementary table or figure. Additionally, consider using the standard ROB 2 traffic-light plot, which is more informative than the current summary figure.

Minor Concerns (Reporting and Presentation)

8. Figure 1 has two titles: The legend states "Figure 1. Hierarchical summary..." but the figure itself appears to contain an embedded title. Please remove the internal title to comply with standard formatting.

9. Ambiguous reference to "Figure 2": The text mentions "two large trials" and then "Figure 2" in a way that is unclear. Please check that each figure is cited sequentially and unambiguously. Currently, there is only one PRISMA flow diagram (labelled Figure 2), but the text refers to "Figure 2" in at least two separate sections – ensure the citations are correct.

10. Heading formatting error (2.1 Eligibility Criteria): The subheading "2.1. Eligibility Criteria" appears incorrectly placed after a paragraph ending with "Supplementary Table S2.2.1." Please separate the heading from the preceding text and ensure consistent numbering.

11. Typographical and spacing issues: In the Methods section, "terms and Boolean combinations" is not clearly separated from the subsequent heading "2.1 Eligibility Criteria". Similarly, in Table 1, the column "Primary outcome" is missing entries for several rows (e.g., Zhou). Please review the entire document for consistent spacing and table completeness.

12. Justification for meta-analysis inclusion window (2021–2025): The Methods state that only meta-analyses published 2021–2025 were included. Please provide a brief justification for this time restriction (e.g., to align with contemporary practice or post-EPCAT II/CRISTAL). Without this, it appears arbitrary.

13. Referencing anomaly in Table 1: In Table 1, the "Study" column uses numbers in brackets (e.g., Zhou [27], Jiang [27], Zou [27]). These appear to denote references, but multiple distinct studies share the same reference number. Please correct this so each study has a unique citation. If these studies are from the same primary reference, specify the original source clearly.

Conclusion

This review addresses an important clinical question and has the potential to inform guideline implementation and formulary decisions. However, the above issues – particularly the discrepancy in RCT count, the lack of descriptive synthesis for the 16 additional studies and four guidelines, the incomplete ROB 2 reporting, and the need for clearer statements on generalisability and dose uncertainty – should be addressed. From a clinical pharmacy perspective, explicit guidance on patient selection, dosing ambiguity, and the efficacy–effectiveness gap would substantially enhance the manuscript's practical utility. I recommend major revision.

Author Response

We sincerely thank the reviewer for the comprehensive and highly constructive critique of our manuscript. We particularly appreciate the detailed pharmacotherapy-focused perspective and the emphasis on methodological transparency, generalisability, and contemporary fast-track arthroplasty practice. The manuscript has been extensively revised accordingly.

Major Comment 1:
“Conclusions should state more explicitly that the current evidence applies primarily to standard-risk patients.”

Response:
We fully agree and have substantially revised the Abstract, Discussion, and Conclusions sections to explicitly acknowledge that the currently available evidence primarily applies to standard-risk arthroplasty patients. We now specifically state that high-risk populations such as patients with prior VTE, thrombophilia, active malignancy, severe obesity, or prolonged immobilisation remain underrepresented in contemporary RCT evidence. Additional cautionary statements regarding extrapolation to elderly hip fracture populations have also been added.

Major Comment 2:
“Applicability to contemporary fast-track arthroplasty remains underdeveloped.”

Response:
Thank you for this important observation. We substantially expanded the Introduction, Discussion, and Future Directions sections regarding modern ERAS and fast-track arthroplasty pathways. The revised manuscript now explicitly discusses that contemporary fast-track pathways have demonstrated substantially lower symptomatic VTE rates than historical cohorts and that no adequately powered RCT currently compares ultra-short anticoagulant regimens with prolonged aspirin prophylaxis. We now explicitly identify this as a major evidence gap and future research priority.

Major Comment 3:
“An explicit conclusion regarding aspirin dose heterogeneity is needed.”

Response:
We agree and have added explicit statements to both the Discussion and Conclusions sections indicating that currently available evidence does not permit definitive recommendations regarding optimal aspirin dose, dosing frequency, or duration of prophylaxis. We additionally discuss that lower-dose aspirin regimens may reduce gastrointestinal adverse effects, although no adequately powered study has demonstrated superiority of one regimen over another.

Major Comment 4:
“Efficacy vs. effectiveness and diagnostic bias should be clarified.”

Response:
We appreciate this important methodological point. We expanded the Methods, Results, and Discussion sections to explicitly discuss that several smaller RCTs relied predominantly on ultrasonography rather than venography and were underpowered for symptomatic VTE endpoints. We now specifically state that this methodological limitation may bias findings toward apparent equivalence between aspirin and anticoagulant strategies.

Major Comment 5:
“Discrepancy between nine and ten RCTs.”

Response:
Thank you for identifying this inconsistency. The manuscript has been corrected throughout. The final structured synthesis now consistently includes ten randomised controlled trials, including the historical Lotke et al. trial, which has now been fully incorporated into the Results section, Table 1, and reference list.

Major Comment 6:
“Sixteen additional Level I–II studies are insufficiently described.”

Response:
We agree and have substantially expanded the Results section. The revised manuscript now systematically summarises the additional Level I–II studies addressing perioperative risk modifiers, fracture-related thrombosis, hypercoagulability, ERAS pathways, and blood management strategies. In addition, supplementary material summarising guideline recommendations and evidence characteristics has been added.

Major Comment 7:
“ROB 2 reporting is insufficient.”

Response:
Thank you for this important suggestion. Figure 3 has been completely redesigned using a study-level ROB 2 traffic-light format modelled after standard Cochrane/BMJ risk-of-bias presentations. The revised figure now includes domain-level assessments for each RCT, including randomisation, deviations from intended interventions, missing outcome data, outcome measurement, selective reporting, and overall bias assessment.

Minor Comment 8:
“Figure 1 has two titles.”

Response:
Corrected as suggested. The embedded figure title has been removed.

Minor Comment 9:
“Ambiguous Figure 2 references.”

Response:
All figure citations have been revised sequentially and clarified throughout the manuscript.

Minor Comment 10:
“Heading formatting error.”

Response:
Corrected. The Methods section formatting and numbering have been revised for consistency.

Minor Comment 11:
“Typographical and spacing issues.”

Response:
The manuscript has undergone extensive formatting and language revision. Table 1 entries and spacing inconsistencies have been corrected throughout.

Minor Comment 12:
“Justification for meta-analysis inclusion window.”

Response:
We added an explicit methodological justification in the Methods section. Meta-analyses were restricted to 2021–2025 to reflect contemporary arthroplasty practice following EPCAT II and CRISTAL and to avoid incorporation of outdated prophylaxis pathways.

Minor Comment 13:
“Referencing anomaly in Table 1.”

Response:
All reference inconsistencies have been corrected. Each study in Table 1 now carries a unique and accurate citation.

We sincerely thank the reviewer again for the exceptionally detailed and constructive comments, which substantially strengthened the methodological transparency and clinical applicability of the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript provides a structured evidence-based review of aspirin for venous thromboembolism prophylaxis in orthopaedic surgery, with particular emphasis on arthroplasty and trauma populations. The topic is clinically relevant. Overall, the manuscript is interesting. However, several issues should be addressed.

1. Authors were strongly encouraged to register their detailed protocols  before data extraction commences, in a public registry such as PROSPERO  (https://www.crd.york.ac.uk/prospero/). Authors must include registration information in the Methods section.

2. Manuscript states that nine RCTs, four guidelines, and sixteen additional Level I–II studies were included. However, Table 1 appears to list ten trial entries rather than nine. 

3. The manuscript alternates between "randomised" and "randomized".

4. In the legend for Figure 2, the text reads "RISMA 2020 flow diagram". This should be corrected to PRISMA 2020.

5. Methods section states that the review follows the PRISMA 2025 statement, whereas the manuscript later refers to the PRISMA 2020 checklist and Figure 2 is labeled as a PRISMA 2020 flow diagram. This should be corrected and made consistent.

6. Figure 3 only summarizes the number of trials classified as low risk, some concerns, or high risk. A study-level ROB 2 table should be provided, including judgments for each ROB 2 domain and the rationale for each rating. 

7. In first paragraph, authors mention epidemiology of venous thromboembolism. Authors should cite more recent literature, such as PMID: 39759425.

8. The reported search terms are relatively broad and may not be sufficient for a reproducible systematic search. The authors should provide the full database-specific search strategies in the main text or supplementary material, including all Boolean operators, MeSH/Emtree terms, date limits, language restrictions, and filters applied. 

Author Response

We sincerely thank the reviewer for the thoughtful and constructive assessment of our manuscript. We greatly appreciate the detailed methodological suggestions and have carefully revised the manuscript accordingly.

Reviewer Comment 1:
“Authors were strongly encouraged to register their detailed protocols in PROSPERO.”

Response:
Thank you for this important suggestion. Because the present work represents a structured evidence-based review integrating randomised trials, guideline interpretation, and perioperative contextual studies rather than a formal quantitative meta-analysis, no prospective PROSPERO registration was performed. This has now been explicitly stated and clarified in the Methods section.

Reviewer Comment 2:
“Manuscript states nine RCTs, whereas Table 1 lists ten.”

Response:
We appreciate the reviewer identifying this inconsistency. The manuscript has been corrected throughout to consistently state that ten randomised controlled trials were included. The historical Lotke et al. study has now been fully integrated into the structured synthesis and reference list.

Reviewer Comment 3:
“The manuscript alternates between ‘randomised’ and ‘randomized’.”

Response:
The manuscript has been standardised throughout using consistent British English spelling (“randomised”), in accordance with journal style.

Reviewer Comment 4:
“Figure 2 states RISMA instead of PRISMA.”

Response:
Corrected as suggested.

Reviewer Comment 5:
“PRISMA 2025 versus PRISMA 2020 inconsistency.”

Response:
We thank the reviewer for identifying this error. The manuscript has been corrected throughout to consistently refer to PRISMA 2020.

Reviewer Comment 6:
“Figure 3 should provide study-level ROB 2 assessments.”

Response:
Figure 3 has been completely redesigned into a study-level ROB 2 traffic-light plot using a standard Cochrane/BMJ-style format. Domain-level assessments are now provided for all included RCTs.

Reviewer Comment 7:
“Please cite more recent epidemiological literature.”

Response:
Thank you for this valuable suggestion. Recent epidemiological literature regarding contemporary VTE burden after arthroplasty has now been incorporated into the Introduction section.

Reviewer Comment 8:
“Provide full reproducible search strategy.”

Response:
We agree and have substantially expanded the methodological reporting. Detailed database-specific search strategies, including Boolean operators, MeSH/Emtree terms, and search restrictions, are now provided in Supplementary Table S2. In addition, the completed PRISMA 2020 checklist has been included as Supplementary Table S1.

We sincerely thank the reviewer for the valuable comments, which significantly improved the methodological transparency and reporting quality of the manuscript.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

current version is much better than former.

Author Response

We thank the reviewer for the re-assessment of our manuscript and for the positive feedback.

We appreciate the reviewer’s constructive comments during the initial review process, which have helped us improve the manuscript substantially. We are pleased that the reviewer considers the revised version to be significantly improved and we hope that the manuscript is now suitable for publication.