PONE-D-21-22546

Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study

PLOS ONE

Dear Dr. Miura,

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PLOS ONE

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- https://www.ahajournals.org/doi/10.1161/CIRCINTERVENTIONS.118.006564

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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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?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: I Don't Know

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General comments:

The authors present analyses where data from an open-label study were pooled with data from a historical randomized trial.

Overall, I think these analyses have merit, though more information is needed to understand why pooling these two trials is reasonable. I believe more needs to be done with the analytic methods as well. Pooling of studies can create bias since data were collected at different times and, potentially, different places. These biases need to be addressed, or at least fully discussed to inform readers, and for me that has not been done here.

Specific comments:

1. (p.4) I believe that you mean that the data…*will be* made available.

2. (p.5) A really key part of these analyses is how comparable the DES+cilostazol patients are to the DEBATE SFA study participants. One part that it completely glossed over are the locations that people are coming from. Were the eight centers from DES+cilostazol ones that were included in DEBATE SFA? If not, are they from similar geographic areas? These sorts of questions should be answered somewhere in the manuscript.

3. (p.7) Please include further information on the sample size. For instance, how was this powered, i.e., using a particular test? What values were assumed, e.g., what effect size?

4. (p.7; Table 3) I think these analyses should be run with proportional hazards regression models (aka Cox models). There is a categorical exposure here so, best that I understand, you are running a bunch of pairwise log-rank tests. That is probably resulting in a higher type I error rate than expected.

5. In addition, the Cox model will allow you to control for other potential confounders which I think needs to be done here. Some of the baseline characteristics in table 1 suggest that including them in a model might have some impact. I am not sure whether any covariates should go into a final model, but this should at least be tried, especially given that these are pooled data.

6. Finally, in the Cox model, I think clustering by center should be accounted for in the model, probably with some sort of marginal model, e.g., via the sandwich estimator. This could also be done with a frailty.

7. You might also consider performing some sensitivity analyses in regards to the pooling, especially in terms of the centers. It's hard for me to know what to recommend here information is lacking. Maybe you could limit the data from DEBATE SFA to those that were in DES+cilostazol. Or maybe some sort of intelligent matching of centers or participants.

8. (Table 1) Significance testing for baseline imbalance in randomized trials been has regarded as unnecessary and potentially misleading (see Altman DG. Comparability of randomised groups. The Statistician 1985; 125-136; Senn, S. Testing for baseline balance in clinical trials. Statistics in Medicine 1994; 1715-1726). I recommend removing the significance testing entirely from table 1.

9. There's no page 15 and then numbering starts on page 16. (It would be nice to have the line numbers throughout the document in future submissions.)

10. (Table 3) I think this table would be easier if the arm names could be used instead of "Group 1" etc.

11. (Figure 2) These survival curves should have confidence bands on them to depict the variability in these estimates. Though, four curves with bands will make this pretty busy. You may need to break these out into panels.

12. (Figure 3) Same comment as figure 2, though with just two curves, panels shouldn't be needed.

Reviewer #2: I read with interest the manuscript #PONE-D-21-22546 by Dr Miura and colleagues entitled “Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study”.

This is a prospective, open-label, multicenter study evaluating the efficacy of cilostazol in improving the patency of DESs and determine whether BNS or DESs with or without cilostazol are more effective in improving the 12-month patency after EVT for FP lesions.

The manuscript is well written and the topic is of interest.

However, the manuscript presents several issues:

- In the “outcome assessments” sub-section, concerning the peak systolic velocity (PSV) ratio cut-off used for ISR determination, authors state “we changed definition of PSV from >2.0 to > 2.5 because that of almost all trial was > 2.5”. First, authors should at least cite the studies they are referring to. Second and most important, in the DEBATE in SFA trial, it seems that the primary end point was evaluated using a peak systolic velocity ratio <2.0, as stated in the “Outcomes Assessment” section of that study1. Since the PSV was used to determine restenosis, the primary outcome of this study, this represents a major issue of the manuscript. Please Clarify.

- When comparing cohorts with historical control data, statistical methods including a propensity score matching would improve the quality of the analysis.

- In the “Results” section, authors state that “no significant differences were found in the 12-month patency rate among the DES with cilostazol, DES, BNS with cilostazol, and BNS groups (94.2% vs. 82.8% vs. 93.1% vs. 77.6%, respectively, p = 0.007) (Figure 2)”; however, in the Figure 2 description is reported that “the 12-month patency rate differed significantly among the four groups (DES with cilostazol: 94.2% vs. BNS with cilostazol 93.1% vs. DES without cilostazol 82.8%, BNS without cilostazol 77.6%, p = 0.0007) with different p value. Please clarify.

References:

1. Miura T, Miyashita Y, Soga Y, Hozawa K, Doijiri T, Ikeda U, et al. Drug-eluting versus bare-metal stent implantation with or without cilostazol in the treatment of the superficial femoral artery. Circ Cardiovasc Interv. 2018;11(8): e006564. doi: 10.1161/CIRCINTERVENTIONS.118.006564.

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Reviewer #1: No

Reviewer #2: No

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Cilostazol Effectiveness in Reducing Drug-Coated Stent Restenosis in the Superficial Femoral Artery: The ZERO Study

PONE-D-21-22546R1

Dear Dr. Miura,

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,

Salvatore De Rosa

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors edited their manuscript addressing the majority of the reviwers' comments, improving the overall quality.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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