Dear Dr. Tajiri,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR:

Thank you for submitting your work to PLOS One. This study addresses an important clinical issue in cancer-associated thrombosis (CAT) management by providing real-world data on the risks of VTE recurrence and bleeding in the DOAC era. While interesting, based on review of your work and taking into account the feedback from reviewers, a major revision is required. I invite you to provide a point-by-point rebuttal addressing the points raised. Some additional feedback have been outlined below:

Major concerns:

The temporal trends in anticoagulation use or outcomes over the study period (2015–2020) are not examined. For example, did DOAC adoption increase over time, and were outcomes better in more recent years?

The authors do not analyse the role of cancer stage or treatment type (e.g., chemotherapy vs. radiation) in VTE recurrence or bleeding risks. These factors likely contribute to the observed differences in outcomes.

The subgroup analyses of cancer type lack adjustments for multiple comparisons. This undermines the reliability of some findings, such as the higher recurrence risk in CNS cancer patients.

The survival analyses focus primarily on differences between cancer and non-cancer groups but do not explore predictors of survival within the cancer group. For example, how does the presence of major bleeding or VTE recurrence impact survival in different cancer subtypes?

Besides, some specific comments are outlined below for authors to consider:

1. In the abstract, details on subgroup findings or the implications of anticoagulation discontinuation, which are important outcomes, are lacking. Please include.

2. The introduction does not clearly differentiate how the study builds upon existing literature, such as the COMMAND VTE Registry studies. The rationale for focusing on cancer patients with DVT diagnosed via ultrasound is not sufficiently justified. A discussion of why asymptomatic cases are important to study would provide more clarity.

3. The study excludes patients with DVT diagnosed before 2015 to focus on the DOAC era but does not clarify whether warfarin use in 9.4% of the cohort is representative of contemporary practice. This could bias the findings. Please explain.

4. While the Fine-Gray subdistribution hazard model accounts for competing risks, the authors does not report sensitivity analyses to test the robustness of its findings. This is critical given the high mortality rate in the cancer group.

5. The study does not mention whether validated bleeding risk scores were used to adjust for bleeding risk in the cancer cohort. This could affect the accuracy of the hazard ratios.

6. Subgroups based on cancer type are analyzed but not adjusted for multiple comparisons. This raises the risk of type I error. This should be addressed.

7. Table 1: While the baseline characteristics are comprehensive, the authors do not report p-values for all comparisons, such as DVT location. Any non-significant findings should still be reported.

8. Table 4: The all-cause mortality data is significant, but the breakdown of causes of death is underexplored in the discussion. For example, the higher rate of cancer-related deaths in the cancer group is expected, but the significance of fatal bleeding events in cancer patients warrants further elaboration.

9. Figure 3 and 5: Subgroup analyses are presented without adjustments for multiple comparisons. The authors should clarify this limitation in the results section.

10. The similar rates of anticoagulation discontinuation between groups are reported without sufficient discussion of the clinical implications. For example, the higher rate of discontinuation due to bleeding in the cancer group suggests a need for better bleeding risk stratification.

11. The discussion does not adequately address the limitations of the study design, particularly the retrospective nature, single-center setting, and the inclusion of asymptomatic DVT cases. Besides, the potential impact of warfarin use in a minority of patients is not discussed in detail. How might this affect the generalizability of the results to a purely DOAC-treated population?

The discussion could expand on the implications of VTE recurrence in patients who discontinued anticoagulation due to bleeding. For instance, should alternative anticoagulants (e.g., low-dose DOACs) or non-pharmacologic strategies be considered in these patients?

Authors should also consider expanding on the VTE/DVT management (see Sun et al PMID: 37175686)

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We look forward to receiving your revised manuscript.

Kind regards,

Sonu Bhaskar, MD PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1:  Thank you very much for providing the opportunity to review the manuscript. It is written in a straight forward manner, with a clear research question, a suitable method and statistics and a clear result. There is littele to discuss or to amend. Results seems reasonable. It would have been interesting to compare the 4 DOAC among each other regarding thrombosis and bleeding. Manybe a follow-up project?

There are very few typos, which can be corrected upon processing.

Reviewer #2:  Introduction:

Problem statement: Not clear. Please spell it out in a stand-alone paragraph.

Study objectives: Not clear. Please spell it out in a stand-alone paragraph. Please spell out the primary and secondary objectives.

Methods:

Line 62 – 63: The registry is a single-center, retrospective cohort study.

Naturally when we do a registry, we either enter data on the spot or later, some may have a follow-up. Therefore, please explain why this registry is retrospective, or otherwise.

Line 74: Among the 17,188 patients enrolled in the TULIPE registry.

These are adult patients only or include children. If adults only, please define the cut-off age.

Line 76 – 78: all the exclusion criteria.

Do all samples have complete data that are required for the study? If yes, then ignore my comment. If no, please add it as an exclusion criteria.

Please specify in methodology that the study data was extracted from the TULIPE registry and divided into different sections: Demographic, clinical, investigations, treatment, outcomes… This corresponds to the results reported latter.

The variables for the study were not stated in the methodology. Please spell it out.

Example: Patient demographic, clinical, laboratory, and treatment data was collected from the registry.

The demographic data include age, gender, BMI…The clinical data include comorbidity, types of DVT, presence of PE… For investigations, it will be better to highlight parameters associated with VTE are selected (this explains why CRP included).

Line 80 – 83: The cancer group was defined as patients with a cancer diagnosis within 6 months prior to the ultrasound; recurrent, regionally advanced, or metastatic cancer; cancer treatment within the previous 6 months; or hematologic cancer not in complete remission (as previously described) [7]

The above definition refers to ‘active cancer’ by Raskob et al. However, they also include cancer within 2 years ‘Patients had to have cancer other than basal-cell or squamous-cell skin cancer that was active or had been diagnosed within the previous 2 years and was objectively confirmed’. Therefore, the cancer group in this study is better renamed as active cancer group.

Line 90 – 91: VTE was defined as new-onset lower extremity venous thrombosis, pulmonary embolism (PE), or Trousseau syndrome, confirmed by imaging.

Please cite the articles to support this definition.

Overall survival was not defined. Let's say patients die at home or transfer care to another centre and die, does this data capture in your study?

Table 3: Anticoagulation therapy beyond the acute phase.

Please define the acute phase in methodology.

Results:

It will be more organized to divide the results into 2 main sections:

1. Baseline: Demographic, clinical, and treatments.

2. Outcomes: VTE recurrence, Bleed, Mortality

So overall results flow is better.

Line 118 – 126: Please specify the value (%) followed by p for the variables with significant differences. It was not stated for this part but mentioned for the remaining parts of the result. Please standardise it.

Line 164 – 165, and Line 202 – 204: The adjusted ratio for VTE recurrence and major bleed was based on age, gender, and BMI.

By right, the adjusted ratio should be based on covariates with p < 0.05 and deemed significant in other studies. Therefore, in my opinion, it should be:

Age, BMI (continuous variables, not BMI as the number is too small), comorbid as a whole, baseline PE, HB level, anticoagulant beyond acute phase, and discontinuation of anticoagulant (even though p not significant, I believe must be related to recurrence of VTE and major bleed in other studies)

Please do the same correction for OS, it was not mentioned in the result.

Discussion:

Line 261 – 264: Chatani et al.'s study included only patients with acute symptomatic VTE, whereas our study enrolled patients diagnosed with DVT via ultrasonography, including asymptomatic cases and those with an unknown onset time. Consequently, our cohort had fewer patients with PE or proximal DVT compared to Chatani et al.’s study.

By right, Chatani et al cancer + acute vs acute compared to current study cancer + scan vs scan (those non-cancer groups unlikely have a routine scan, they scan most likely something going on). The outcome should be worse in Chatani. I would rather argue that Chatani et al include active cancer + cancer 6-24 months vs the current study that includes active cancer, leading to dilution of differences in the former. Please read Chatani et al again and see if justifiable. If so, please write the discussion again.

Line 292 – 294: In this study, the discontinuation rate of anticoagulation therapy at one year was high,

although no significant difference was observed between the cancer and non-cancer groups (52%

vs. 53%, P = 0.444).

I would rather argue that discontinuation for non-cancer is falsely high and leads to no different in result. In the non-cancer group, some patients may have discontinuation at 3 to 6 months due to standard practice, while cancer is often life-long. If the number of patients in non-cancer only takes into those who discontinued prematurely before the appropriate period, the exact number may be smaller.

Line 315 – 325: The development of anticoagulants with a lower bleeding risk and improved

316 adherence is essential. Factor XI (FXI) has emerged as a promising therapeutic target for CAT…

This is the clinical implication of this study, please put in a stand alone paragraph.

Study strength: Not mentioned. Please highlight.

Conclusion:

Maybe mentioned a newer agent to address these issues is required?

Tables:

Table 1:

A BMI of more than 35 can remove as the number too small.

Comorbidities as overall, the p should be presented.

For diseases that cannot recover, like chronic lung, heart disease… Please remove the history of, as the disease is still present. Maybe for VTE only is suitable.

Presentation: DVT should be put above, and PE below.

Table 3:

Ventilator support to be removed. It is irrelevant.

Table 4:

DVT should be above PE. Why DVT only, PE with or without DVT? It is rather confusing.

Could it be divided into DVT and PE? Or DVT, PE, DVT + PE?

Tables 5 and 7: Suggest to correct, including relevant covariates as mentioned in the comment above.

Figures:

Figure 3 and 5: Why these parameters are selected?

TWC and creatinine clearance were not even mentioned in Table 1. Some don’t have between-group significance like gender, or platelet. The cut-off point of these parameters is also not justified.

I would suggest using the parameters selected for the adjusted ratio as mentioned above, such as:

Age, BMI (continuous variables, not BMI as the number is too small), comorbid as a whole, baseline PE, HB level, anticoagulant beyond acute phase, and discontinuation of anticoagulant (even though p not significant, I believe must be related to recurrence of VTE and major bleed in other studies)\

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Reviewer #1: Yes:  Olaf Rose

Reviewer #2: Yes:  Diana-Leh-Ching Ng

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<p>Risk of recurrence and bleeding in patients with cancer-associated venous thromboembolism in the direct oral anticoagulants era: Findings from the TULIPE registry

PONE-D-25-11278R1

Dear Dr. Tajiri,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Sonu Bhaskar, MD PhD

Academic Editor

PLOS ONE

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Thank you for submitting a revised version of your manuscript.

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Reviewers' comments: