PONE-D-22-20118Effect of alteplase, benzodiazepines and beta-blocker on post-stroke pneumonia: exploration of VISTA-AcutePLOS ONE

Dear Dr. Phan,

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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: 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: 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: No

Reviewer #3: Yes

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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: The paper by Phan et al. deals with the use of a multivariate, machine learning-based approach to find predictor of risk for post-stroke pneumonia. This paper falls into a large an interesting field and has some added value to the matter. The paper highlights the conundrum that curative interventions for stroke as alteplase has no impact on pneumonia, Similarly also thrombectomy didn’t provide a significant impact on pneumonia

However, I find some critical points that I think are worthy to be taken into account. I think that authors should discuss in more detail the role of NIHSS in the discussion. This result in fact falls in line with similar results that reinforced the validity of this new paper. In several studies NIHSS resulted as the stronger predictors, and also in a nomogram (Willeke F Westendorp et al Eur Stroke J. 2018 Jun;3(2):136-144) and recently confirmed by an independent group with a different statistical method (Tommaso B Jannini et al T B Jannini Neurol Sci. 2022 Feb; 43(2):1167-1176). In particular, the result that NIHSS equal or superior to 10 is a predictor of pneumonia is very interesting since Toscano et al Eur Neurol. 2015;74(3-4):171-7. Found that a similar NIHSS is predictive of persistent dysphagia, which is a risk factor for stroke related pneumonia.

In this line I think that the decision of not including dysphagia among predictors hampers the analysis, and it should be mentioned in the limitation section. As far as I know the field of multivariable statistics, these approaches tend to provide some data mining. They are very much influenced by the covariates that are chosen to be inserted. In particular, if big and strong predictors are excluded, small and less relevant covariates can appear as valid predictors in absence of a better parameters. In the paper by Jannini et al. 2022, the scale used to diagnose dysphagia (GLOBE vs WST) was predictive of the occurrence of pneumonia

I would recommend to add a line in which authors acknowledge that the absence of dysphagia as a predictor can modify the results but that the fact that drugs, with exception of BDZ, do not influenced pneumonia when analyzed without a strong predictor as dysphagia is a reinforcing aspect that medication has a small role in determine pneumonia. In the conclusion, since authors suggest more research, if they want, they could suggest to use a single validated scale to record dysphagia so that it can be used as covariate of multivariable analysis.

Reviewer #2: This paper from Phan et al. explored the effect of alteplase on post-stroke pneumonia occurrence. Collaterally, the effect of other drugs, such as benzodiazepines and beta-blockers, was explored. The study pointed out two interesting results: the first one is the neutral effect of alteplase on post-stroke pneumonia occurrence, and the second one is the protective effect of benzodiazepines on post-stroke pneumonia occurrence.

The statistical analysis seems to be sophisticated and difficult to catch by a non-expert.

In addition to all the limitations listed by the authors, my major concerns are about the methodology.

• First, the effect of alteplase is demonstrated not only by the low NIHSS after thrombolysis, which could simply reflect a low baseline NIHSS, but also by the delta NIHSS (24h NIHSS-baseline NIHSS). Therefore, more conveniently, the effect of alteplase could be unmasked by the delta NIHSS which really reflects the effect of alteplase (efficacy, reperfusion, no reflow…). Since this datum seems to have been collected by authors, the analysis should be re-run in this way to be reliable.

• This is a retrospective study of prospectively collected individual patient data (VISTA-Acute trial) and this could be counted as another limitation. Pneumonia has been assessed retrospectively extracting data on adverse events from a larger database and details on the type of dysphagia screen used are lacking. The management of patients could therefore be very heterogeneous among different centers limiting the significance of the effect of alteplase on post-stroke pneumonia occurrence. A possible way to minimize this heterogeneity could be to insert the variable ‘center’ in the analysis to unmask a possible ‘center-’ effect.

Page 3 line15, replace ‘pneumia’ with ‘pneumonia’

Page 3 line 22, replace ‘devised’ with ‘divided’

Abstract- lines2-3: the sentence does not make sense. It must be reworded.

Reviewer #3: Phan et al. prepared a manuscript aiming to investigate the “Effect of alteplase, benzodiazepines and beta-blocker on post-stroke pneumonia: exploration of VISTA-Acute”.

1. The abstract is concise explaining the work clearly and briefly.

2. Introduction: The strong relationship between stroke severity and pneumia. Change to pneumonia. VISTA, explain in the introduction.

3. Methods: I suggest the authors to analyze more the terms used for collecting pneumonia participants and if possible, the ICD-10 codes. Here in, the authors need to describe more about the groups of this study.

4. Outcomes: 5653 patients. Pneumonia frequency 614. Try to start with the highlight of this study.

5. Statistical analysis: Well detailed.

6. Discussion: The main findings in our study are that RTPA and beta-blockers had a minimal effect on the proportion of people having pneumonia following stroke. Is this in line with other studies? This finding on stroke severity and age is consistent with other studies on stroke associated pneumonia, references. “Our finding suggests a small effect of benzodiazepine on pneumonia”. One of the common complications in the acute phase in AIS patients is short/long- duration epileptic seizures causing pneumonia which usually can be treated with benzodiazepines. Patients with psychomotor anxiety also receive medication in acute phase.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Effect of alteplase, benzodiazepines and beta-blocker on post-stroke pneumonia: exploration of VISTA-Acute

PONE-D-22-20118R1

Dear Dr. Phan,

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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Massimiliano Toscano, M.D., PhD

Academic Editor

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Additional Editor Comments (optional):

The authors followed all the recommendations given and answered all the doubts raised by modifying the text as required. The manuscript has been improved and, as far as I am concerned, the paper is now suitable 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 #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: 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: 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: Dear authors, you have fully addressed my comments. I endorse the publication of the present study.

Reviewer #2: (No Response)

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Reviewer #1: No

Reviewer #2: No

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