PONE-D-20-21065

Reduced kidney function and the outcomes of fibrinolysis for ST-segment elevation myocardial infarction: A real-world study

PLOS ONE

Dear Dr.  Wu

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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PLOS ONE

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Additional Editor Comments:

The reviewers have expressed conflicting opinions about the priority of your paper. I found the paper of some interest so I think It could be reasonable to give you the chance of improving the quality of your manuscript according to the issues raised by the Reviewers in particular of Reviewer #2

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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: Yes

Reviewer #2: No

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

Reviewer #1: Yes

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: This is an interesting observational analysis from an established network, the Clinical Pathways in Acute Coronary Syndromes program (CPACS-3), a large study of the management of suspected acute coronary syndromes (ACS) in 101 county hospitals without onsite PCI capabilities in China.

The study is quite well presented, analyzed, and interpreted. Fibrinolysis remains an important reperfusion modality for many patients worldwide and these findings may have relevant implications for their management.

I have some suggestions for the author to consider:

MAJOR

� For this research question it may be relevant to specify when the diagnosis of renal insufficiency was performed in relationship to the decision to perform fibrinolysis. Specifically, distinguish patients with known renal insufficiency at the time of fibrinolysis (such as patients on hemodialysis), patients with a new diagnosis of renal insufficiency when creatine was collected (immediately after the fibrinolysis I presume), from patients without renal insufficiency. This may help better understand the results and if, for patients with unknown renal function status, this information should be waited for before deciding fibrinolysis.

� The discussion is well structured in general but might be improved by:

o Shortly speculating as to why an increased failure of fibrinolysis is observed in patients with RKF. Hypofibrinolysis for example has been well documented in patients with renal insufficiency and end-stage renal disease and could be mentioned, and the potential implications for different agents/dosage in this setting.

o What are the authors suggestions for managing these patients in terms of diagnosis (for eg. should we routinely wait creatinine results before performing fibrinolyis ?) and treatments (eg. considerations to accept a delay higher than 120 minutes to urgent angiography and primary PCI in these patients ?) .

MINOR

� Reduced kidney function, RKF, is not a standard acronym. The authors may consider using chronic kidney disease or KDIGO equivalents.

� www.clinicaltrails.gov under Trial registration is misspelled

� Page 11, line 189: “The secondary outcome was all-cause mortality, recurrent MI, stroke, and severe bleeding”. The logic here, as for every composite and correctly reported for the primary endpoint is OR, that is “The secondary outcome was all-cause mortality, recurrent MI, stroke, OR severe bleeding”.

Reviewer #2: In this study the authors analyzed the data from a multicentric registry that involved a considerable number of acute coronary syndrome patients admitted to 101 country hospital in China without the capability to perform primary PCI.

The aim of the study was to assess whether reduced kidney function (RKF) may modify the association between fibrinolytic therapy and in-hospital major adverse cardiovascular events (MACE) – the primary endpoint.

The key results are the following:

1) patients with RKF were more likely to experience in-hospital MACEs compared to those with normal kidney function (19.7% vs 5.6%, respectively)

2) fibrinolytic therapy was associated with a 13% reduction in the primary endpoint in patients with normal kidney function (RR 0.87, 95% CI 0.76-0.99), but not in the those with RKF (RR 1.02, 95% CI 0.87-1.18)

3) Failed fibrinolytic therapy was higher in RFK patients compared to those with normal kidney function (32.8% vs 16.9%)

4) Failed fibrinolysis was not independently associated with the end-point at multivariate analysis (page 14, lines 259-261).

In the discussion (page 17, lines 324-325), the authors comment these results as follows: “in the current study, we found that successful fibrinolysis occurred less frequently in patients with RKF, likely contributing to a higher risk of in-hospital MACE”. The same thought is replicated in the conclusion of the abstract (“RFK modified the association of fibrinolytic therapy with the risk of in-hospital mortality via its negative association with successful fibrinolysis”, page 4, lines 64-65). However, this perspective seems to be contradicted by the results of multivariate analysis showing no independent association between adverse events and failed fibrinolysis and by the fact that in the subgroup with RKF fibrinolytic therapy was not associated with lower incidence of MACE. A possible explanation is that fibrinolytic therapy improves the prognosis in patients with normal kidney function but not in the RKF population (see point number 2) because the latter group is fragile and at-risk of adverse events independently from successful coronary reperfusion.

In my opinion, the most important finding of the study is that patients with RKF have a lower rate of successful fibrinolytic therapy and the authors should speculate in the discussion what led to this significant result (more diffuse coronary artery disease with a higher thrombotic burden in RKF patients?) and to its clinical implications (preference for ptca?).

Lastly, I am in disagreement with the inclusion in the primary endpoint (“in-hospital MACEs”) of patients who died within 1 week after a discharge against medical advice, under the category of all-cause mortality. Apart from being a contradiction itself, it introduces a significant bias since this entity cannot be measured.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-20-21065R1

Chronic kidney disease  and the outcomes of fibrinolysis for ST-segment elevation myocardial infarction: A real-world study

PLOS ONE

Dear Dr. Yangfeng Wu

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.

ACADEMIC EDITOR:  Thank you very much for having revised your paper  whose quality has improved and for having addressed the majority of the Reviewers' comments.  However,  a statistical issue remains to ben solved as highlighted by Reviewer #2. I think that your paper could be considered for publication only if  you will be able to fix this problem and to address the minor comments of Reviewer #1

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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Simone Savastano

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thank you very much for having revised your paper whose quality has improved and for having addressed the majority of the Reviewers' comments. However, a statistical issue remains to ben solved as highlighted by Reviewer #2. I think that your paper could be considered for publication only if you will be able to fix this problem and to address the minor comments of Reviewer #1

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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 #1: All comments have been addressed

Reviewer #2: (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 #1: Yes

Reviewer #2: Partly

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

Reviewer #1: (No Response)

Reviewer #2: I Don't Know

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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: No

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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: The authors have mostly and completely included my comments.

The wording of some sentences, such as the conclusions, may be improved. CKD is indeed and chronic and pre-existing conditions, not a complication. Why don't simply say something such as: "CKD reduced the likelihood of successful fibrinolysis and incresaed the risk of in-hospital MACEs in patients with STEMI (...)".

Reviewer #2: Dear authors, thank-you for your reply. However, there is still one major point that in my opinion needs classification: in the Table 1, a multi variable analysis showed that failed fibrinolysis is not an independent predictor of mace in patients with CKD. In figure 1, another multi variable analysis including the same co-variates gave completely opposite results: this time it seems that CKD has no role in modifying the RR, that it only depends on successful fibrinolysis. I admit I am not a statistician, but I think you should help me and other readers to understand the reason of this.

Another minor comment: if you included mortality post-voluntary discharge because of a cultural habit (Chinese people often desire so), you should state it in the methods section and maybe modify “in-hospital MACE” with “short-term MACE”

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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 #1: No

Reviewer #2: No

[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.

Chronic kidney disease  and the outcomes of fibrinolysis for ST-segment elevation myocardial infarction: A real-world study

PONE-D-20-21065R2

Dear Dr. Yangfeng Wu

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,

Simone Savastano

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you very much for having solved the issues raised by the reviewers. Albeit fibrinolysis is not the principal treatment for acute myocardial infarction worldwide however, it is still wildly used in some countries. I think it could important for readers at lest of those countries.

Reviewers' comments: