PONE-D-23-06603Short Dual Antiplatelet Therapy Duration After Percutaneous Coronary Intervention in High Bleeding Risk Patients: Systematic Review and Meta-analysisPLOS ONE

Dear Dr. Turgeon,

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.

==============================Please address each reviewers' comment individually in the response letter indicating where in the manuscript you have provided revisions. 

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Please submit your revised manuscript by Jun 09 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

R. Jay Widmer

Academic Editor

PLOS ONE

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Additional Editor Comments:

In general, the reviewers were fairly positive regarding the paper and its primary finding/message. However, there are serious concerns regarding the methods, statistics, and protocols used in the meta-analysis and how those might apply to the discussion. Furthermore, improved graphics and figures could be incorporated. Please make every effort to utilize these comments to improve the manuscript as written.

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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: Yes

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

Reviewer #1: Yes

Reviewer #2: No

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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: Dr. Bainey and co-authors present a meta-analysis of short vs. standard antiplatelet therapy in HBR patients. Inherent limitations is the study level design.

My comments are as follow:

- Figure S1 is not clear, there is some overlap between column 1 and 2. How can a RCT have higher risk of bias in domain 2 than post-hoc analyses? Please consider reviewing.

- Many studies on DAPT duration in HBR are non-randomized. I would understand their exclusion if you had included only RCT. However, this is not the case, as sub-analyses of previous RCT (possibly even non pre-specified) were included as well).

- You should provide definitions of bleeding and ischemic events. The fact that they are not consistent across studies needs to be taken into account.

- Publication bias should be assessed using funnel plots.

- Why did you favored BARC bleeding definition over TIMI? Please comment and discuss.

- I think a proper discussion on the literature is largely missing. There are several previous articles that should be cited and discussed in the paper. There is a wealth of papers on short DAPT, if one embark in another article in such topic, the discussion cannot ignore what has already been published, and most importantly should highlight why the work is different. Please refer to the following (which are a few but there are certainly more) and note that some of them are specific for patients at HBR:

1. doi: 10.1093/ehjcvp/pvaa127 - PMID: 33135064

2. doi: 10.1002/ccd.26110. Epub 2015 Aug 26 - PMID: 26309050 

3. doi: 10.1093/ehjcvp/pvac065. Online ahead of print - PMID: 36427063

4. doi: 10.1093/ehjcvp/pvaa001 - PMID: 31942965

5. doi: 10.1093/eurheartj/ehac706 - PMID: 36477292

- It would be really nice to summarize the main finding of the study in a central illustration. The paper lacks figures, which ensure clarity.

Reviewer #2: In this analysis, Bainey and colleagues evaluated the effect of short DAPT (1-3 months) compared to standard DAPT (6-12 months) on bleeding and ischemic events in HBR PCI patients.

After a careful evaluation of the manuscript, these are my concerns.

The authors declared that the methodology outlined in the Cochrane Handbook for Systematic Reviews and Interventions, and reported following the 2020 PRISMA statement. However, the authors did not provide, among the others, the registration information for the review, nor report the reasons for the missing items in the limitation section.

Furthermore, the exclusion criteria (type of the analyses exclude as language, abstract presentation to congresses, and so on) were not detailed in the method section.

Please report in the statistical section how the net clinical benefit (number of events for 1000 patients) has been assessed.

In order to look at the impact of each study on outcomes, the authors should perform an influence analysis at least for the primary outcome.

It could also be interesting to perform a sensitivity analysis based on the type of platform used (resorbable versus non-resorbable polymer)

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-06603R1Short Dual Antiplatelet Therapy Duration After Percutaneous Coronary Intervention in High Bleeding Risk Patients: Systematic Review and Meta-analysisPLOS ONE

Dear Dr. Turgeon,

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.

==============================Please address each comment individually in the response letter indicating where changes have been made in the manuscript. 

==============================

Please submit your revised manuscript by Sep 09 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

R. Jay Widmer

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The reviewers were generally favorable and have a few suggestions regarding the patient selection, treatment type, as well as some comments on tables and figures. Please address these individually in the response letter in a timely fashion, and thank you for your patience on this manuscript revision.

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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 #3: (No Response)

Reviewer #4: 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 #3: No

Reviewer #4: Yes

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

Reviewer #3: I Don't Know

Reviewer #4: 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 #3: Yes

Reviewer #4: 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 #3: (No Response)

Reviewer #4: 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 #3: The authors performed a systemic review and meta-analysis of short DAPT vs. standard DAPT after PCI in patients with high bleeding risk. The following were my comments on this article:

1. The study population of these studies was not truly the entire group of patients with high bleeding risk after PCI. In TWILIGHT study, the eligible patients were required to be free from bleeding or ischemic events within the first 3 months after PCI. In TICO study, the key exclusion criteria included increased risk of bleeding due to prior traumatic brain injury or brain surgery within the past 6 months, internal bleeding within the past 6 weeks, and anemia. In STOPDAPT-2 study, the patients who experienced ischemic or bleeding complications during hospital stay post-PCI were excluded. In Master DAPT, the exclusion criteria included any active bleeding requiring medical attention (BARC > 2) within the first month after PCI. And the eligible patients were required to be free from adverse cardiovascular events during the first month after the index PCI. However, most bleeding complications after PCI occur within the first month of DAPT after PCI (doi:10.3390/jcm9061657). So these studies and the result of this meta-analysis could not apply to all patients with high-risk bleeding. On the contrary, they only represented some relatively “stable” high-risk patients after PCI. Patients with high bleeding risk could consider shortening the duration of DAPT and switching to P2Y12 inhibitor monotherapy if they do not have any ischemic or bleeding events within the first 1-3 months after PCI. The title and conclusion may mislead the readers.

2. The subgroup analysis for ACS vs CCS in patients with HRB had many questionable issues. First, the compare group in Master DAPT might receive suboptimal DAPT for ACS patients after PCI, because all ACS patients in compare group received only 6-months DAPT. SMART-DATE trial (https://doi.org/10.1016/S0140-6736(18)30493-8) had proved that shortening the duration of standard 12-month DAPT to 6-month DAPT in ACS patients would significantly increase the risk of recurrent ischemic events. Second, they were only two trials in this subgroup analysis. Third, STOPDAPT-2 ACS study had failed to attest noninferiority to standard 12-months of DAPT for the net clinical benefit with a numerical increase in cardiovascular events. Fourth, there was a similar observation in TWILIGHT-HBR subgroup analysis. The rate of all-cause death, MI, or stroke was increased in ticagrelor monotherapy (6.5% vs. 5.6%; HR 1.16). When the patient number becomes larger, the number would be statistically significant.

3. The duration of DAPT and the choice of subsequent SAPT(aspirin or specific P2Y12 inhibitors) need to take into discussion together. Since most successful clinical trials were applying P2Y12 inhibitor monotherapy after shortened DAPT, it is not appropriate to mix the results of aspirin monotherapy with P2Y12 inhibitor monotherapy. (Most patients in Master DAPT trial were also receiving P2Y12 inhibitor monotherapy after 1-month DAPT)

4. Since this article is a “systemic review and meta-analysis”, I expect the paragraph of “discussion” and “limitation” should be more words and discussion. The gap between current evidence from previous studies and clinical practice could be considered to add into your discussion.

5. In Table 1. “STOPDAPT-2 Total cohort-HBR” and “STOPDAPT-2 HBR” were presented as separate trials. Does ”STOPDAPT-2 total cohort (STOPDAPT-2 + STOPDAPT-2 ACS)-HBR” include the patients enrolled in “STOPDAPT-2 HBR”? In my understanding, “STOPDAPT-2 Total cohort-HBR” and “STOPDAPT-2 HBR” should be viewed as ONE trial.

6. In Figure 2C, It would be better if the order of each included study could be the same as the order used in most of your analyses. So the “TICO-HBR” should be the first one, and “STOPDAPT-2” be the second one.

Reviewer #4: This is a revised submission on short DAPT duration after PCI. Reviewer comments have been adequately addressed.

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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 #3: Yes: Wen-Han Feng

Reviewer #4: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Short Dual Antiplatelet Therapy Duration After Percutaneous Coronary Intervention in High Bleeding Risk Patients: Systematic Review and Meta-analysis

PONE-D-23-06603R2

Dear Dr. Turgeon,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

R. Jay Widmer

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 #3: All comments have been addressed

Reviewer #4: 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 #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #3: Yes

Reviewer #4: Yes

**********

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 #3: Yes

Reviewer #4: 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 #3: Yes

Reviewer #4: 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 #3: (No Response)

Reviewer #4: The revision and rebuttal to the reviewers comments have been reviewed.

Comments have been adequately responded to in the revision.

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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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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 #3: Yes: Wen-Han Feng

Reviewer #4: No

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