PONE-D-21-35110Changes in BNP levels from discharge to 6-month visit predict subsequent outcomes in patients with acute heart failurePLOS ONE

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(This work was supported by the Japan Agency for Medical Research and Development [18059186] (Drs T. Kato, Kuwahara, and Ozasa))

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Reviewers' comments:

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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: 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: Yes

Reviewer #2: Yes

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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: To the Authors

General Considerations

The aim of this study was to investigate the association between changes in BNP from discharge to 6-month visit and subsequent clinical outcomes in patients with acute HF. Authors enrolled 446 patients with available paired BNP data at discharge and 6-month index visit, classified according to the tertiles of BNP concentrations: low (≤-44 %, N=149), middle tertile (>-44 % and ≤22 %, N=149) and high (>22 %, N=148). The main results of this study were that % changes in BNP among the 3 groups of HF patients were associated with a subsequent risk for a composite of all-cause death and hospitalization for HF. Authors concluded that changes in BNP levels may help to manage patient with HF.

There is an extensive literature supporting the clinical relevance of changes of BNP levels in monitoring patients with an acute episode of HF (249 articles in PubMed using the key words: acute heart failure, BNP changes; 101 articles using the key words: acute heart failure, BNP changes, outcome). Authors should better indicate in Introduction (or Discussion) sections of the revised manuscript the originality of this article compared to other previous studies or to other more recently published (for example: Bettencourt P et al. JACEP Open 2021;2:e12448).

I have some specific points to address to the Authors in order to further improve the scientific message of this article.

Specific Points

1. BNP assay. Authors compare 3 different groups of HF patients divided according to the levels of BNP. It is well known that there are several assay methods for BNP showing very large systematic differences (up to folds) in the concentrations measured in healthy subjects and HF patients (for reviews about this issue: Clerico A et al. Clin Chim Acta 2015;443:17-24; Clerico A. et al. Future Cardiol 2016:12:573-84)). Authors should add a specific paragraph in the revised manuscript reporting the analytical characteristics and performances and reference interval values measured in a healthy population (compared to age and sex to HF patients) with the BNP method used in this study. The international guidelines by IFCC (International Federation of Clinical Chemistry) recommend that the BNP concentration should be reported as ng/L (not pg/mL) (Apple FS et al. Circulation 2007;116;e95-e98).

2. Table 1, BNP at discharge. An interesting data reported in Table 1 is that patients included in the first tertile have a BNP discharge values significantly lower than the other two tertiles. These results should be discussed more in detail in the revised manuscript. Authors should better explain this reverse association between elevated BNP at discharge and better final outcome.

3. A limitation of this study is that the measurement of cardiac troponins using high-sensitivity assays (i.e., hs-cTnI and hs-cTnT methods) was not performed in this study. Several recent studies have demonstrated that hs-cTnI and hs-cTnT may have a better risk stratification both in apparently healthy subjects and patients with cardiac disease (including HF) than natriuretic peptides (BNP or NT-proBNP) (Farmakis D et al. Eur Heart J 2020;41:4050-6; Clerico A et al. Clin Chem Lab Med 2020;59:79-90; Harrison N et al. Curr Heart Fail Rep 2019;16:21-31; Rosa GM et al. Eur J Clin Invest 2019;49:e13044; Perna ER Minerva Carioangiol 2016;64:165-80; Aimo A et al. Circulation 2018;137:286.297; Aimo A et al. Int J Cardiol 2019;277:166-172). This important point should be discussed by the Authors.

Reviewer #2: In the present paper, Shiba and colleagues aim to investigate "the association between the changes in BNP levels and subsequent clinical outcomes in patients with AHF". The Authors collect data from the Kyoto Congestive Heart Failure (KCHF) registry (n=446) whe received BNP testing at discharge after an AHF episode and at 6 month. They report that the incidence of the primary end-point (a composite of all-cause death or hospitalization for HF) was significantly higher in patients with stable/increased BNP vs those with decreasing BNP levels.

The message of the paper is rather clear, and the conclusions are supported by the provided evidence. Still, some major points, as listed below, need to be addressed.

Major points

- How did the Authors select the variables to be included in the multivariable model? Why did they dichotomized variables such as LVEF or eGFR?

- Further to the pre-specified subgroups, a subset analysis should have been performed in patients with/without atrial fibrillation

- How/when was exactly defined atrial fibrillation? How did the Authors account for eventual changes in background rhythm

- The cause for AHF should be reported in the study population. Moreover, whether it was a de novo vs an acutely decompensated HF should be also mentioned.

Minor points

- In the methods section, end-stage renal disease was defined according to eGFR, while exsclusion criteria were based on serum creatinine. Please clarify.

- The number of events in the whole population and in subgroups according to BNP changes should be clearly reported in the Methods section.

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Reviewer #1: No

Reviewer #2: No

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Changes in BNP levels from discharge to 6-month visit predict subsequent outcomes in patients with acute heart failure

PONE-D-21-35110R1

Dear Dr. Kato,

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,

Claudio Passino, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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 #1: Yes

Reviewer #2: Yes

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

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

Reviewer #1: Yes

Reviewer #2: 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 #1: Authors revised the manuscript in accordance of suggestions made by the two Reviewers. The scientific message of the article is significantly improved now.

Reviewer #2: The Authors have properly addressed all the comments raised in the previous revision, and the manuscript has now significantly improved.

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

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Reviewer #1: No

Reviewer #2: No