PONE-D-22-18899Specialized heart failure clinics versus primary care: Extended registry-based follow-up of the NorthStar TrialPLOS ONE

Dear Dr. Malmborg,

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 Jan 06 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,

Giuseppe Gargiulo, MD, PhD

Academic Editor

PLOS ONE

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When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following financial disclosure: 

"This work was funded by the Danish Heart Foundation (Grant number: 18-R121-A8218). "

  

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 

If this statement is not correct you must amend it as needed. 

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Additional Editor Comments:

This is an interesting study.

It would be interesting to account for additional events during follow-up. Please include an additional analysis comparing groups based on number of HF re-hospitalizations.

Please check figure 1, the titles on the KM curves seem not corresponding to the figure caption.

Please better comment on the borderline P for interaction for AF in Fig 2. Statistical significance could be missing simply due to power issues.

Can the authors provide more information on the reasons for re-hospitalizations during the follow-up?

The rates of device therapy at randomization is very low. It would be important to have info during follow-up.

Please add more details on the initial trial. The paper must be self-standing and the readers/reviewers should not go searching for other info from different prior publications.

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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: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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: No

Reviewer #2: No

Reviewer #3: No

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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

Reviewer #3: 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: PONE-D-22-18899: statistical review

This study compares long-term survival between heart failure patients who have been randomly assigned to follow-up in a specialized HF clinic or primary care. 5-year adherence to prescribed neurohormonal blockade in 5-year survivors is also assessed. Traditional survival analysis methods are correctly exploited to compare the survival trajectories between the two groups and beta regression is correctly considered for comparing adherence proportions. I have nothing to say about this paper: the research question is well posed, statistical methods are appropriate, results are correctly interpreted and possible limitations of the study are nicely remarked in the discussion.

Reviewer #2: In this manuscript, authors report findings from the extended follow-up of a trial conducted in Denmark (NorthStar) that randomized patients with heart failure with reduced ejection fraction (HFrEF) to be followed up in primary care or in a specialized HF clinic once treatment had been optimized.

FU data were obtained using linked electronic health records.

Overall, the manuscript is clear and easy to read till the end.

However, I think that the main limitation of this study, as acknowledged by the authors, is that during a period of up to 10 years many bad things can happen to patients with heart failure, and a substantial proportion of those randomized to a primary care clinic follow-up would have received specialist input due to clinical deterioration which, in my opinion, limits the relevance of these findings.

Authors might add a comment to adherence to beta-blockers, which seems higher that that to RASi.

Reviewer #3: The authors present a very interesting study on the value of specialized heart failure clinics versus primary care. It is a relevant study, but I have some comments:

- Although an NT-proBNP > 1000 pg/mL might identify high-risk patients, an HF hospitalization (43% in the initial study) the previous year might be a marker of higher risk than NTproBNP values.

- The authors use both MRA and ARA. ARA is not defined in the Abbreviation nor Table 1. Interestingly, the use of MRA appears to increase from randomization (33%) to the 5-year follow-up MRA (HFC: 51.9%; PC: 52.0%). It may be associated with the publication of pivotal MRA trials in HF. However, it is surprising that PC prescribed MRA at a relatively high percentage.

- Was CRT or ICD different at 5-year follow-up? The use at baseline is surprisingly low.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-22-18899R1Specialized heart failure clinics versus primary care: Extended registry-based follow-up of the NorthStar TrialPLOS ONE

Dear Dr. Malmborg,

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 Apr 20 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,

Giuseppe Gargiulo, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

The authors provided a properly revised version of the manuscript with almost all points addressed.

There is still 1 of my previous points to be addressed, specifically point 1.4 in which I did not ask for specific new analyses but simply a table or text reporting reasons of re-hospitalizations during follow-up (new acute coronary syndrome, infections, diuretic resistance, worsening of renal function etc.).

Also few points from reviewer 4 should be addressed.

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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 #2: All comments have been addressed

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 #2: Partly

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #2: Yes

Reviewer #3: Yes

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 #2: Yes

Reviewer #3: No

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 #2: Yes

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 #2: Authors performed additional analyses but I still think that the main limitation of this study remains a (very likely) high rate of cross over: as acknowledged, a substantial proportion of those randomized to a primary care clinic follow-up had been admitted with heart failure and would have received specialist input due to clinical deterioration. This, in my opinion, limits

the relevance of these findings that could be, eventually, summarised in a much shorter research letter.

Reviewer #3: All comments have been addressed by the authors. I believe the manuscript can be published in the current form.

Reviewer #4: In this manuscript, Dr. Malmborg and colleagues tried to assess if there is a difference in hospitalization for heart failure or cardiovascular mortality comparing specialized heart failure clinics versus primary care through an extended post-hoc registry-based follow-up study of a randomized controlled trial.

Overall, this is a quite nicely written article, greatly improved already by previous revisions, with a clinical relevance.

However, some relevant issues need to be addressed by the authors:

- Albeit the study was conducted rigorously, the result is in contrast to recent results from registry studies involving far larger numbers of patients (https://onlinelibrary.wiley.com/doi/full/10.1002/ehf2.13848; https://www.internationaljournalofcardiology.com/article/S0167-5273(21)01334-6/fulltext). This should be expanded upon in the discussion section, pointing out why there may be this discrepancy.

- Table 1: The authors report an haemoglobin mean level of 8.6, but only about 20% of patients with anemia. How is this possible? What are the upper letter a in anemia and upper letter b in hyponatremia for?

- Figure 2: On the bottom near the hazard ratio should be specified whether left or right is in favour of HFC or PC

- Please note that the text requires a careful proofreading, since there are several grammar lapses

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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 #2: No

Reviewer #3: No

Reviewer #4: Yes: Christian Basile

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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.

Specialized heart failure clinics versus primary care: Extended registry-based follow-up of the NorthStar Trial

PONE-D-22-18899R2

Dear Dr. Malmborg,

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,

Giuseppe Gargiulo, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All comments were addressed. The manuscript is improved and can now be accepted for publication.

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: Yes

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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

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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 #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 #4: The manuscript was greatly improved, the images are now clearer and as it is I have no further comment.

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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: Yes: Basile Christian

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