PONE-D-24-28766Comparison of frailty instruments for predicting  mortality and prolonged hospitalization in acute coronary syndrome patientsPLOS ONE

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Additional Editor Comments:

According to Reviewers' decision, the manuscript needs a major revision.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

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

Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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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: In this prospective multicenter study of 1174 patients over 70 years old hospitalized with acute coronary syndrome, four frailty assessment tools and a cognitive function test were evaluated for their ability to predict mortality and prolonged hospitalization. All frailty assessment tools were associated with graded increases in mortality risk, with the Edmonton Frail Scale (EFS) achieving the highest c-statistic (0.663) compared to the others. The EFS also showed improved risk discrimination when added to the Euroscore II and GRACE clinical risk scores. For predicting prolonged hospitalization (>10 days), the EFS again had the highest c-statistic (0.649). The study concludes that the EFS is the most effective tool for discriminating the risk of mortality and prolonged hospitalization compared to other frailty assessments and the GPCog cognitive test.

The study is commendable for its focus on a highly relevant issue—assessing frailty in older patients with acute coronary syndrome. The clinical relevance is clear, as frailty is an important predictor of outcomes in elderly patients, and its accurate assessment can significantly influence management strategies. Additionally, the statistical methodology employed is robust and appropriate for the study design, ensuring reliable and valid results.

However, there are several points that warrant further consideration:

- From a methodological viewpoint, the inclusion of the GPCog cognitive test may not be necessary. Limiting the comparison to frailty assessment tools alone would make the study more streamlined and interpretable.

- The Katz index is primarily a measure of disability, which is a distinct phenomenon than frailty. The ADL levels are not highly discriminative in the studied population, and it is unclear whether the tables reference lost or maintained ADLs. So, it can be omitted from the analysis.

- In Figure 1, for the calculation of Cox regression for the EFS, I would like to see the following scoring: 0-5 = Not Frail; 6-7 = Vulnerable 8-9 = Mild Frailty; 10-11 = Moderate Frailty; 12-17 = Severe Frailty

- It should be noted that none of the frailty assessment tools used were specifically developed for acute settings, and there is a lack of evidence regarding their reproducibility in this context. This limitation should be explicitly mentioned.

- Although the methods state that the evaluations were conducted when patients were clinically stable, it is important to clarify whether the Clinical Frailty Scale refers to the level of frailty before the acute coronary syndrome event or at the time of the ACS. Given that the CFS reflects overall clinical judgment, there is a potential for overestimating frailty in patients assessed during this acute phase.

- In the discussion, it is essential to highlight the multidimensional contribution of frailty to cardiovascular diseases. Please refer to and discuss the findings of Testa et al. (2020), which address physical versus multidimensional frailty in older adults with and without heart failure: "Testa G, Curcio F, Liguori I, Basile C, Papillo M, Tocchetti CG, Galizia G, Della-Morte D, Gargiulo G, Cacciatore F, Bonaduce D, Abete P. Physical vs. multidimensional frailty in older adults with and without heart failure. ESC Heart Fail. 2020 Jun;7(3):1371-1380. doi: 10.1002/ehf2.12688. Epub 2020 Apr 3. PMID: 32243099; PMCID: PMC7261566."

Overall, this study makes a significant contribution to understanding frailty in elderly patients with acute coronary syndrome, and these considerations can further refine its impact and applicability.

Reviewer #2: The study evaluated the relative strengths of 4 frailty assessment instruments and a test for cognitive function for predicting mortality and prolonged hospitalization in acute coronary syndrome patients. 1174 patients >70 years of age hospitalized with an acute coronary syndrome were enrolled. All-cause mortality over the 5 years and hospitalization for >10 days in the next year was determined from national administrative data. Edmonton Frail Scale (EFS), Fried Criteria (Fried), Clinical Frailty Scale (CFS), Katz score (Katz), a dementia screening test (GPCog), the GRACE and Euroscore2 clinical risk scores were completed during hospital admission. During a median follow-up of 5.1 years there were 353 deaths. Frailty assessed using all instruments was associated with graded increases in mortality risk. Harrell’s C-statistic for mortality were EFS was 0.663, Fried 0.648, CFS 0.640, Katz 0.593, and GPCog 0.608 (p<0.001 for all). For patients with an EFS score 9 (n=197) compared to 2 (n=331) the hazard ratio (HR) for mortality, adjusted for age and sex, was 5.0 (95% CI: 3.4-7.4). C-statistics for hospitalization >10 days (n=267, 22%) were EFS 0.649, Fried 0.628, Katz 0.602, CFS 0.584, and GPCog 0.552, (p<0.001 for all). In models which included the Euroscore II and GRACE risk scores the EFS improved incremental risk discrimination for both mortality and prolonged hospitalization more than other frailty instruments.

The topic of the study is of interest. I have some suggestions. ADL are measure of disability and I think not appropriate to use Kats index as measure of frailty, similarly GPCog measure one of the frailty domain. The AUC found in your analysis could also be evaluating stratifying the sample by age (i.e. 70-80 and > 80). It should be of interest to evaluate the results of a cox regression analysis on your outcome to verify the effect of the different instruments of frailty. Why measure in this setting Euroscore II?

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Reviewer #1: No

Reviewer #2: Yes: Francesco Cacciatore

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Comparison of frailty instruments for predicting  mortality and prolonged hospitalization in acute coronary syndrome patients

PONE-D-24-28766R1

Dear Dr. Stewart,

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.

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Barry Kweh

Academic Editor

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Additional Editor Comments (optional):

The authors have clarified methodological queries, refined as well as broadened their discussion and improved the overall structure of their manuscript.

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

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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: 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

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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: I am pleased to report that all the revisions I had previously requested have been satisfactorily addressed. The changes made have significantly enhanced the clarity and depth of the manuscript, ensuring that the scientific merit and reliability of the findings are well represented.

The revisions have adequately resolved the issues raised during the initial review, and I believe that the manuscript is now improved. The discussion is clearer, the methodology is more robust, and the overall presentation aligns well with the journal's standards.

Reviewer #2: The authors have adequately addressed the comments raised in the previous round of review. I found the manuscript improved and now it is suitable for pubblication in this form.

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Reviewer #1: No

Reviewer #2: No

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