PONE-D-19-31280

Effect of antithrombotic stewardship on the efficacy and safety of antithrombotic therapy during and after hospitalization

PLOS ONE

Dear Dr Dreijer,

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 comments you will find below.

We would appreciate receiving your revised manuscript by Mar 05 2020 11:59PM. When you are 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,

Christophe Leroyer

Academic Editor

PLOS ONE

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1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed:

https://doi.org/10.1007/s11096-019-00834-2

https://doi.org/10.1016/j.ejim.2019.01.008

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed.

3.  Thank you for stating the following in the Financial Disclosure section:

Stichting Phoenix Schiedam, the pharmaceutical companies (Daiichi Sankyo, Boehringer Ingelheim, Bayer and Pfizer) and the Scientific Committee Reinier de Graaf Gasthuis provided financial support for this study in the form of unrestricted grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

We note that you received funding from a commercial source: Daiichi Sankyo, Boehringer Ingelheim, Bayer and Pfizer.

Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.

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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: 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: Yes

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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

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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: Interesting study with some technical merits.

However, there are major limits that should explained and discussed; additional statistics are required on adjustment analyses:

First: the author did not confirm their primary hypothesis of 9% composite before and 5.5% after intervention and there was no reduction at all based on this prevision. In addition, no multivariable analysis was done (ie, no adjustment on variables differently distributed between the usual and the intervention group): this should be done, because there were strong differences in proportion of DOACs. Was there a predefined statistical plan analysis ? Was the use of segmental regression analysis pre-planned?

Finally, the conclusion should be lowered: the study suggests a potential improvement, but there is no demonstration.

Second: the underlying disease that indicated anticoagulant therapy is not described; this is a major limitation since VTE and atrial fibrillation, for example, are not the same diseases at all and the thrombotic complications are different in terms of frequency and type of event.

Other:

- Table 2: a line with the total composite is needed in each period.

- In the flow chart, authors indicate randomization, which is wrong.

Reviewer #2: This is a truly relevant study. The evaluation is quite complete, including clinical and economic criteria. The implementation of a multidisciplinary team in charge of therapeutic education and medication review may prevent interactions, duplicate medications, and dosing errors. Therefore, we can assume it could reduce the thrombotic and bleeding events. I don’t see any major issue in the manuscript. You will find below a few minor suggestions.

Abstract

line 21: The primary endpoint could be described in the methods section.

Methods

line 171: Some other systemic embolisms could have been included. The decision to only include myocardial infraction and ischemic stroke as arterial thrombosis could be justified.

Discussion

line 373-379: Considering NOACs have limited drug interactions, do not require routine coagulation monitoring with fixed doses, they are easier to use than VKA. Their use does not require a extensive experience.

line 414: It might have been less occurrences of underreporting of the non major bleeding events in the S-Team group. Indeed we can assume that after a therapeutic education, patients might have been more inclined to notify a non major bleeding.

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6. 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 #1: No

Reviewer #2: No

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-31280R1

Effect of antithrombotic stewardship on the efficacy and safety of antithrombotic therapy during and after hospitalization

PLOS ONE

Dear Dr Dreijer,

Please accept my apologies for this delay: our reviewers have been busy these previous days and thank you for resubmitting 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 and thus few minor revisions are needed. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process and you will find below.

We would appreciate receiving your revised manuscript. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Christophe Leroyer

Academic Editor

PLOS ONE

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 #3: (No Response)

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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 #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: 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 #3: Yes

**********

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 #3: 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: all the questions have been addressed. I do not have further comments and the manuscript is suitable for publication

Reviewer #3: The primary aim, as stated, of the prospective nonrandomized clinical trial was to evaluate the efficacy and safety of antithrombotic therapy during and after hospitalization. A group of patients received the intervention protocol while another group served as controls. Although a significant change in the proportion of patients with a thrombotic event was not apparent immediately, by 2 months a significant decrease was observed.

Minor revisions:

1- Abstract: Consider beginning the following sentence with the phrase, The primary aim was to estimate the proportion of patients ... “Primary outcome was the proportion

of patients ... with a composite end point consisting of one or more bleeding episodes or

one or more thrombotic event from hospitalization until three months after hospitalization.”

2- Abstract: Provide more clarity in the following statement. Specifically identify the primary endpoint. “Introduction of the multidisciplinary team had no immediate impact +1.63% (-3.60% to +6.85%) on the primary endpoint, but over time the primary endpoint event rate decreased significantly with -1.83% (-2.58% to -1.08%) per 2 month period.”

3- Line 190: Indicate the statistical testing method which attains 80% power.

4- Line 232: Clarify the type of subgroup analysis performed.

5- Line 282: Clarify that the numbers in parentheses represent the confidence interval.

6- Table 3: Provide a measure of dispersion corresponding to each mean costs.

7- Provide a summary of adverse events to address the safety aim.

8- Identify the sources of funding for the study.

9- The primary aim of the study does not appear to be to determine efficacy and safety, but to compare the proportion of patients in the two groups who develop thrombotic events. Please clarify.

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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 #1: No

Reviewer #3: No

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Effect of antithrombotic stewardship on the efficacy and safety of antithrombotic therapy during and after hospitalization

PONE-D-19-31280R2

Dear Dr. Dreijer,

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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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,

Christophe Leroyer

Academic Editor

PLOS ONE