PONE-D-24-28817Updated Mata-Analysis of Fractional Flow Reserve versus Coronary Angiography for Guiding Percutaneous Coronary Intervention.PLOS ONE

Dear Dr. yin,

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. The topic of this meta analysis is clinically important. However, our reviewers pointed out some loopholes and limitations in the methods, and recommended a more comprehensive review of some existing studies. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 19 2024 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:

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• 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Haipeng Liu

Academic Editor

PLOS ONE

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3. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

A numbered table of all studies identified in the literature search, including those that were excluded from the analyses. 

For every excluded study, the table should list the reason(s) for exclusion. 

If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

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Name of data extractors and date of data extraction

Confirmation that the study was eligible to be included in the review. 

All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.

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If applicable for your analysis, a table showing the completed risk of bias and quality/certainty assessments for each study or outcome.  Please ensure this is provided for each domain or parameter assessed. For example, if you used the Cochrane risk-of-bias tool for randomized trials, provide answers to each of the signalling questions for each study. If you used GRADE to assess certainty of evidence, provide judgements about each of the quality of evidence factor. This should be provided for each outcome. 

An explanation of how missing data were handled.

This information can be included in the main text, supplementary information, or relevant data repository. Please note that providing these underlying data is a requirement for publication in this journal, and if these data are not provided your manuscript might be rejected. 

Additional Editor Comments:

Overall, the topic of this meta analysis is clinically important. However, our reviewers pointed out some loopholes and limitations in the methods, and recommended a more comprehensive review of some existing studies. Please carefully revise according to their comments.

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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: No

Reviewer #2: Partly

Reviewer #3: Partly

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

Reviewer #1: No

Reviewer #2: No

Reviewer #3: 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

Reviewer #3: 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: No

Reviewer #2: Yes

Reviewer #3: No

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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: In this study, Yin et al reported on outcomes of FFR-guided PCI vs Angiography-guided PCI as an updated meta-analysis incorporating recent results from FLOWER MI and FRAME AMI . I have the following comments:

1) Abbreviations should be explained in the main body of the text when they first appear.

2) The DEFER study is the first FFR vs angio-guided PCI study (not FAME) and should be included in the analysis. https://pubmed.ncbi.nlm.nih.gov/11413082/ AND https://pubmed.ncbi.nlm.nih.gov/17531660/

3) This study compared FFR vs angio-guided PCI in NSTEMI and should be included in the analysis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236005/

4) FLOWER MI has 1 year MACE data and should be included in the analysis

5) Why is the main study for FRAME AMI not quoted? Instead a subgroup analysis from a conference abstract was quoted in its place. Please use the FRAME AMI main study data and reference: https://pubmed.ncbi.nlm.nih.gov/36540034/

6) In your first results paragraph comparing MACE rates of FFR-guided PCI vs angio-guided PCI, you stated that FFR PCI was associated with significant reduction of MACE during short term and long terms, with both 95% confidence intervals appropriately below 1.00, but the p values are non-significant (0.476 and 0.126)- is this an error?

7) You should consider doing a subgroup analysis of ACS vs non ACS RCTs

8) Is the meta analysis done with fixed or random effects? Please state

9) Please consider doing a meta-regression analysis; Is there evidence of publication bias?

10) There are many spelling mistakes- please check the manuscript thoroughly for spelling errors: Eg: Your title should be "meta-analysis" not "mata-analysis"

Reviewer #2: This manuscript presents an updated meta-analysis comparing Fractional Flow Reserve (FFR) and Coronary Angiography (CAG) for guiding Percutaneous Coronary Intervention (PCI). It evaluates key clinical outcomes, including Major Adverse Cardiovascular Events (MACE), all-cause mortality, myocardial infarction (MI), and target vessel revascularization, with follow-up periods divided into short-term (≤1 year) and long-term (>1 year). The study concludes that FFR-guided PCI is associated with a lower incidence of MACE in both short and long-term follow-up, though no significant differences are observed for other outcomes compared to CAG-guided PCI.

1. Gender Bias:

With the majority of patients being male, the authors should explore the potential impact of this imbalance on generalizability and explicitly acknowledge it in the limitations.

2. Comparison with Existing Meta-Analyses:

Including a more detailed discussion comparing the current findings with similar meta-analyses would provide important context and help highlight the novelty of the study’s conclusions.

3. In-depth discussion on pathophysiological factors:

Many pathophysiological factors can influence the treatment efficacy of PCA. Especially, microvascular dysfunction can significantly influence the treatment efficacy and prognosis but is challenging to evaluate (10.1631/jzus.B2100425). An in-depth discussion on other pathophysiological factors is expected.

4. Improve Statistical Rigor and Reporting:

a. Clarify Model Selection: The manuscript should specify when and why a particular model (e.g., fixed-effect or random-effect) was chosen. A fixed-effect model assumes that all studies estimate the same effect size, which works well if heterogeneity is low (I² < 50%). In contrast, a random-effect model accounts for between-study variability and is more appropriate when heterogeneity is substantial (I² > 50%). For example, the use of a random-effect model for long-term MI outcomes (I² = 71.8%) should be justified to improve transparency.

b. Interpret Sensitivity Analyses: Although the manuscript mentions a leave-one-out sensitivity analysis, further explanation is needed on why certain studies (e.g., Nunen et al.) introduced heterogeneity and how their exclusion influenced the overall results. This would provide deeper insights into the robustness of the findings and clarify the sources of variation.

c. Assess Publication Bias: The manuscript does not address potential publication bias, which can distort meta-analytic results. Including funnel plots and performing statistical tests (e.g., Egger’s regression test) would improve rigor and ensure that the findings are not skewed by selective reporting.

Reviewer #3: Overall comments:

This review is well-structured and answers an important research question. It needs careful proofing to improve quality of grammar and spelling to be fit for a journal.

There are other overall concerns such as a lack of clear protocol, a half-completed PRISMA checklist, and statements regarding ethics or conflict of interests, leaving much to be desired to satisfy a reader regarding methodological quality of this work in its current form.

Abstract:

Line 1: The title of the review is misspelled. Please change from “mata-analysis”

Line 8: What does “were medical searched” refer to?

Line 14-17: Check spacing and typography when specifying results of meta-analysis. 95% CI, P-values etc. should be written appropriately to avoid confusion.

Line 21: short and long term follow-up seems to be repeated

Introduction:

Lines 32-44: It is important to clearly explain the research gap and why you expect this gap to exist. From what has been written it is not clear why FFR may be superior to angiography, and if guidelines are clear on the gold standard approach what this review will add

Lines 50-55: Just because other reviews did not compare RCTs does not mean their results are not significant, as evidenced by guidelines agreeing with them and recommending FFR. When doing a redo meta-analysis it is important to justify what will be different to the previous ones, and why there is still a research need.

Methods:

Line 60: Was this protocol conducted in line with PRISMA statement? Was there a pre-specified protocol published on a repository such as PROSPERO? It is important to specify whether such methodological standards were met.

Line 63: Mention whether the search strategy is available to the reader

Line 67: This is vague, were any specific types of patients excluded based on comorbidities or indication for PCI?

Line 68: Does this mean you will aggregate results for all types of patients as long as they all receive PCI? Will this reduce generalisability to your results and did you plan to do a subgroup analysis?

Line 74-75: Why is short-term 1 year and beyond this long-term? In the context of PCI and intervention, typically 5 and 10 year results are thought to be long-term.

Line 83: Please clarify which clinical outcomes and baseline characteristics were extracted

Line 84: Why RoB and not RoB2?

Line 88: PRISMA refers not only to statistical analysis, move this to the start of methods.

Line 89-95: This section describes what you did in the meta-analysis but fails to adequately describe anything else regarding your work. How did you process and present the data for your baseline characteristics? How did you determine which variables would be meta-analysed? How did you determine whether heterogeneity was significant? How did you assess for publication bias or quality of evidence? These questions and the overall purpose of the analysis are not clear from what you have written.

Results:

Line 122: What does the range (14.2-36.4%) with diabetes indicate and how was this calculated? Please clarify this in the methods and update results section of manuscript to match.

Line 124: This is the first mention of the protocol, what is this and where can it be found? Please elaborate in results

Line 125: The length of follow-up is not consistent, will results be aggregated across multiple studies with varying length of follow-up? Please report what this average follow-up length is for the reader also.

Line 148: Please mention how many patients were included in each analysis. This would benefit reader for all meta-analysis conducted.

Line 149: PCI has a lower rate of MACE but the p-value is 0.476? This is not significant please verify the number is correct across all meta-analysis.

Line 178: What was the significance of this heterogeneity and how was it determined?

Discussion:

Line 199: Why would you refer to a trial included within your meta-analysis to justify your results are in line with previously established results?

Line 207-208: It would be pertinent to explain how MACE is reduced in FFR when mortality, TVR, and MI were the same in both groups, both clinically and within your study results.

Line 209: But you only included the FAME study at 1-year of follow-up? When there was longer data available? What was the reason for this and mention in methods how you approached trials reporting multiple sets of results (i.e. from different time periods or subgroups).

Line 210: What was the result of this meta-analysis and how was your study similar/different? Compare and contrast number of patients and meta-analysis results more thoroughly.

Line 214: DEFER-DES is included within your meta-analysis, of course your results will match what they did. Please explain why your result was why it was the case and how conducting your meta-analysis added to the result.

Line 219: It is not appropriate to use rhetoric such as “Definitely not!” in a manuscript.

Line 220: Is this not what guidelines have been saying already based on previous analysis? How does your meta-analysis contribute towards existing understanding of FFR and its usage in clinical practice?

Line 222: This section of the manuscript would benefit from significant addition, as it is unclear as to why FFR is superior to CAG clinically from what has been written thus far.

Line 228: Having all the patients receive PCI does not reduce confounding; it simply makes them appropriate to compare since they are all undergoing the same intervention.

Line 229-230: But the 1-year cutoff was used arbitrarily and is not in line with previous literature (see my comment from earlier)

Line 231: This is a limitation of the inclusion criteria which can be rectified – limitations of the study ideally are things out of your control.

Line 234: Has this been justified before? If so, please reference.

Line 236: This manuscript says “thirdly” abruptly. Please complete this section.

Conclusions:

Line 240: Expand on the context of the result and how this study aids practice

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6. 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 #1: No

Reviewer #2: No

Reviewer #3: Yes: Niraj S Kumar

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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.

PONE-D-24-28817R1Updated Meta-Analysis of Fractional Flow Reserve versus Coronary Angiography for Guiding Percutaneous Coronary Intervention.PLOS ONE

Dear Dr. yin,

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 submit your revised manuscript  by Mar 09 2025 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,

Haipeng Liu

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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 #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 #4: No

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

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 #4: Yes

**********

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 #4: Yes

**********

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 #4: The authors discuss that the use of FFR guided PCI compared to angiogrpahy guided PCI. The use of FFR to improve pateint outcomes in chronic coronary syndromes are well established from the previous RCT the authors have included. The use of FFR guided PCI in ACS population is questionable including the results from Flower MI. They are two different populations so agree with the authors separating non ACS vs ACS. However, not sure if this meta-analyses adds to what we already know from the previous RCTs.

One comment I have is that Nunen 2015 and Tonino 2009 are the same patient popuation. If you include both studies into the meta-analysis you will be double counting the FAME study population.

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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 #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.

PONE-D-24-28817R2Updated Meta-Analysis of Fractional Flow Reserve versus Coronary Angiography for Guiding Percutaneous Coronary Intervention.PLOS ONE

Dear Dr. yin,

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 submit your revised manuscript by Jul 19 2025 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,

Haipeng Liu

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.

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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 #5: All comments have been addressed

Reviewer #6: 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 #5: Yes

Reviewer #6: Yes

**********

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

Reviewer #5: Yes

Reviewer #6: 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 #5: Yes

Reviewer #6: Yes

**********

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 #5: Yes

Reviewer #6: Yes

**********

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 #5: This meta-analysis provides a valuable update on the comparative efficacy of FFR-guided versus CAG-guided PCI, with rigorous methodology and clinically relevant subgroup analyses. The study aligns with prior evidence while addressing gaps in long-term outcomes and patient-specific effects. The revisions have successfully corrected the typos, enhanced the overall clarity and coherence of the writing, and significantly improved the quality and robustness of the study.

Reviewer #6: This is an excellent meta-analysis. Some comments have been provided. Introduction, Results and Discussion sections are wonderful. Method section need minor changes. Well done.

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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 #5: Yes: Adan Khan

Reviewer #6: Yes: Shan Ouyang

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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.

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Submitted filename: PONE-D-24-28817_R2.pdf

PONE-D-24-28817R3Updated Meta-Analysis of Fractional Flow Reserve versus Coronary Angiography for Guiding Percutaneous Coronary Intervention.PLOS ONE

Dear Dr. yin,

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 submit your revised manuscript by Aug 30 2025 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.

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Haipeng Liu

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

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.

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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 #6: All comments have been addressed

Reviewer #7: (No Response)

Reviewer #8: (No Response)

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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 #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

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

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: 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 #6: Yes

Reviewer #7: Yes

Reviewer #8: (No Response)

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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 #6: Yes

Reviewer #7: Yes

Reviewer #8: 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 #6: Overall, this is an excellent Meta-Analysis. Especially the result and discussion section. Only minor recommendation in the manuscript for your information.

Reviewer #7: The authors have conducted a meta-analysis to compare FFR vs. Conventional angio for guiding PCI in ACS and Non-ACS patients., where FFR showed benefit in long term outcomes and in Non ACS patients. While the authors have revised the manuscript incorporating feedback from the original reviewers, there are still some additional points which should be addressed before the manuscript can be considered for publication. These are as follows;

Introduction:

While explaining the rationale for the study, the authors write ‘Consequently, we again compare the clinical outcomes of FFR-guided and CAG-guided PCI through even 61 more rigorous quality control and patients’ selection’ The authors should additionally consider documenting how pooling of randomized data at a large scale would give more clinically relevant findings than non-randomized data.

Methods:

In methods, the authors should make a table for the search strategy used for each database and in the next column, specify the number of results that was obtained after the search string was run. This table should be added in supplementary files and referenced in the main manuscript appropriately. This would ensure reproducibility at a broader level.

Cite it appropriately. ‘Due to the limited number of included studies (fewer than ten), funnel plots were not utilized, as 129 their power to detect asymmetry would be insufficient’

From what I know, it is generally advised to use relative risk as an effect size for meta-analysis when all the included studies are RCTs. The authors have used OR instead. Authors should consider giving an explanation for why OR was used. If they decide to switch to RR instead, it should also be explained while being backed up by some strong references.

Explain more from what authors mean by non-ACS? It’s a vague term and demands more explanation. Does it mean Stable CAD patients?

Results:

It would be better if the results of the ROB 2.0 tool can be visually depicted using the Robvis tool. In supplementary files the authors call the traffic light plots ‘ Review of authors’ judgement’ which, theoretically is not wrong, but is a non-formal way of presentation. The authors should consider changing it to ‘Traffic Light Plots for Risk of Bias Assessment for Randomized Controlled Trials or something like this. Additionally, the current plots are from Rob 2 macros, which is obsolete now. Try making them on Robvis which gives clearer and more appropriate images. Make sure to cite the tool.

For the flow diagram, instead of using the self-made flowchart, trying using PRISMA 2020 version and customize it as per study needs.

Discussion:

In the limitations section, the authors have detailed multiple methodological limitations. The authors should focus more on clinical limitations. Heterogeneity, even if mild for some outcomes, should be mentioned. How pooling ACS and Non-ACS patients together negatively impacts clinical interpretation albeit the subgroup analysis.

Additionally, there are similar meta-analysis published in literature. The authors should discuss their findings in light of these already published meta-analyses. Their questions might be little bit different but they are definitely relevant here. Some I could find are: PMID: 25637372, 36115726

The authors may want to discuss if there may be an effect of underlying medications on the pooled results? Is it possible that some medications that these patients may have been currently on, lead to changes in reported parameters?

Rebuttal Letter:

The authors should give a point-to-point response to each comment by the reviewer, with page and line numbers detailed for each change done. Right now, the authors’ responses are vague, generic and difficult to follow.

Missing Content:

The PRISMA checklist is missing. It’s a basic requirement for any Systematic review or meta-analysis and it is considered incomplete without it, as per the Cochrane guidelines. It should be added to supplementary files.

A graphical abstract would be a nice addition.

Reviewer #8: This is a well-structured and clinically relevant meta-analysis of eight RCTs comparing FFR- versus CAG-guided PCI. The stratified analyses by follow-up duration and patient type (ACS vs non-ACS) add important nuance to the interpretation of FFR’s clinical utility. Given that this is a third-round revision, the manuscript appears to have undergone thoughtful improvements, and no major concerns remain. The core methodology, results, and conclusions are sound. I offer a few final suggestions below—largely aimed at enhancing clarity, polish, and alignment between results and tone of conclusions.

1.The manuscript would benefit from moderate language polishing to improve clarity and readability.

2.For outcomes like MI in ACS patients, heterogeneity was high (e.g., I² = 77%). It would strengthen the discussion to briefly address potential sources (e.g., STEMI vs NSTEMI, timing of FFR during acute phases, variability in clinical endpoints).

3.The authors recommend routine use of FFR-guided PCI across clinical practice. Given the null findings in ACS and short-term follow-up, I would suggest softening the language slightly to better reflect the stratified results. Acknowledging that the strongest benefit is in non-ACS and long-term scenarios would improve alignment with the data.

4.Consider ensuring uniform phrasing for “short-term,” “long-term,” “non-ACS,” etc., throughout the manuscript. Some inconsistencies were noted in hyphenation and formatting.

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Reviewer #6: Yes: Shan Ouyang

Reviewer #7: Yes: Jawad Basit

Reviewer #8: No

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Attachments

Attachment

Submitted filename: Manuscript.docx

Updated Meta-Analysis of Fractional Flow Reserve versus Coronary Angiography for Guiding Percutaneous Coronary Intervention.

PONE-D-24-28817R4

Dear Dr. Yin,

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.

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Kind regards,

Haipeng Liu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewer #6:

Reviewer #7:

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 #6: All comments have been addressed

Reviewer #7: All comments have been addressed

**********

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 #6: Yes

Reviewer #7: Yes

**********

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

Reviewer #6: Yes

Reviewer #7: 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 #6: Yes

Reviewer #7: Yes

**********

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 #6: Yes

Reviewer #7: Yes

**********

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 #6: Overall this is an excellent article of meta-analysis in this area. Especially there are some new findings and deep understanding in the discussion section. Well done

Reviewer #7: The authors have thoroughly addressed all of my previous comments, and I have no further concerns. I commend them for their work.

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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 #6: Yes: Shan Ouyang

Reviewer #7: Yes: Jawad Basit

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