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PONE-D-21-07035

Long term follow up of direct oral anticoagulants and warfarin therapy on stroke, with all - cause mortality as a competing risk, in people with atrial fibrillation: sentinel network database study.

PLOS ONE

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429 Care (CLARHC) Oxford, the NIHR Oxford Biomedical Research Centre (BRC, UHT), and the NIHR

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 "The work was supported by an unconditional grant to SdeL. Grant number DSJP3700 by Daiichi Sankyo Limited. URL: https://www.daiichi-sankyo.co.uk.The funder had no role in  study design, data collection and analysis, decision to publish, or preparation of the manuscript"

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4.Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the author of this manuscript has the following competing interest: Simon de Lusignan is the Director of the Oxford RCGP RSC and has received funding through his University for studies from Eli Lilly, Astra-Zeneca, Sanofi, GSK, Seqirus and Takeda; and been member of advisory boards for influenza for Seqirus and Sanofi. FDRH has received occasional fees from Bayer and Boehringer Ingelheim for speaking or consulting on atrial fibrillation related stroke risk. All other authors have declared no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work."

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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: No

Reviewer #2: Yes

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

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Reviewer #1: No

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: The authors conducted a large study investigating mortality and stroke in patients with newly diagnosed atrial fibrillation treated either with DOAC or warfarin. Routinely obtained data of the RCGP database were used. This is an interesting study. I have three major comments which should be addressed to improve the manuscript before publication.

1. While reading the manuscript, it remains unclear why the study was conducted and what the results mean (in the context of previous literature). The clinical problem or the unsolved scientific question leading to this study is not clearly stated. Thus, it is also not clear how to interpret the results.

2. The authors used elaborated statistical techniques to analyze the data. However, it is not explained how these techniques help to answer the research questions raised. This issue increases the problem of how to interpret the results of this study. Besides, please reword the results (results section, table headings, figure legends) in a way that the results answer the research question.

3. The authors used a database of routinely obtained data to do the analysis. A large number of pitfalls are possible in this kind of study that might lead to biased results or wrong interpretations. The authors already spend some efforts to convince the reader that the results are valid. But I strongly believe that the authors must give more details how the outcomes (stroke, death), and co-variates are recorded and how completeness of these measurements is ensured. Besides, incomplete data are a major risk of these kind of studies and the authors must elaborate on this in the limitations part of the manuscript.

4. The authors did not discuss the results in context of previous literature. What did other studies find? Why are the results different? It is the methodology, I guess. Please add a comprehensive paragraph on this issue referring to all key studies comparing the risk of stroke and mortality between DOAC and Warfarin in patients with atrial fibrillation.

Some detailed comments as examples:

1. Title: What is a ‘sentinel network database study’? Please describe early in the manuscript or even in the abstract.

2. Abstract: It appears that the abstract is not formatted according to PLOS one.

3. Abstract/ Background: Please describe the clinical problem or the unresolved scientific question that leads to the present study.

4. Abstract/ Methods: The population is not fully described. Please add more information on the inclusion criteria.

5. Abstract/ Results: You state the statistical methods and results, but it is hard to follow what this means in terms of the research question. I suggest rewording it in a way that a reader can follow who is less familiar with statistical concepts.

6. Abstract/ Results: what does long-term mean? Please state the observation time.

7. Abstract/ Results: Patient characteristics are not given. Please state at least age and sex.

8. Abstract/ Results: Outcomes (incidence rates of stroke, death are not given)

9. Abstract/Conclusions: You did not find a difference in hazards of stroke between DOAC and Warfarin. This is in contrast to a number of previous studies. Why? It’s the methodology I guess. Please clarify this already in the abstract.

Reviewer #2: In this study, the authors analyzed a retrospective cohort of 12619 primary care patients with a first-time diagnosis of atrial fibrillation who were treated with either DOAC or warfarin and performed a competing risk analysis between stroke and all-cause mortality. They conclude that there is no significant difference of hazard between anticoagulants for stroke but all-cause mortality DOACs performed better. While this study is certainly of interest some points need to be addressed before publication:

Major Comments:

(Page 4, Line 3): It is appreciated that the authors thoroughly describe all analysis, however, the background section of the abstract is lacking a sentence about the context of the study (Why did you perform this study?)

(Page 5, Lines 54-57): While reading this part of the introduction, I did not clearly understand the authors' research question. The authors might want to change the wording here

(Page 6,) Thank you for describing the database in such detail. However, some information would still improve the understandability. Are comorbidities entered in the database by the physician or derived from the UK read codes? Is the smoking status also recorded by the physician?

(Page 8): While the statistical analysis is described in-depth, I still wonder how you handled missing data for the primary analysis. You write that you performed a sensitivity analysis with multiple imputations, but did you perform a complete-case analysis for the primary analysis? Please consider describing this more in detail.

(Page 10): The authors might want to include the median observation time of the two groups (DOAC vs. Warfarin).

(Figure 2): I am not sure if the figure legend here is correct. The legend text suggests that there should be more than one curve (e.g. “curve separation”) but the figure just shows one curve.

Minor comments:

(Page 5, Line 54-57) Although I am not a native English speaker, the first sentence seems to miss a verb. The second sentence seems to have an “and” after all-cause mortality too much.

(Page 7): The authors might want to consider moving the flow chart from Figure S1 from the supplementary material to the main article. In my opinion, it would improve readability.

(Page 7, Line 90): A small typo. I think the “to” is too much here.

(Page 8 Lines 109-113): The authors might want to revise the wording in these sentences. It remains unclear to me.

(Table 1): You present here an expansive table. In my opinion, including the number of missing values per covariate would further improve the table. Also, the third column (“Difference in proportion”) is quite hard to understand. You might want to write in the table legend that the p-values are for the comparison of Warfarin to DOAC patients.

(Page 15, Line 238): Probably just a typo but the upper confidence interval of the eGFR is according to table 3 0.92, not 4.00.

(Figure 3 & Figure 4): It might be helpful to show the sub-distribution in one figure to make the graphs easier to compare.

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Reviewer #1: Yes: Michael Nagler

Reviewer #2: No

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Long term follow up of direct oral anticoagulants and warfarin therapy on stroke, with all-cause mortality as a competing risk, in people with atrial fibrillation: sentinel network database study.

PONE-D-21-07035R1

Dear Dr. de Lusignan,

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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Kind regards,

Michael Nagler, M.D., Ph.D., MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: