PONE-D-19-22709

A cross-sectional evaluation of warfarin anticoagulation services in Uganda and South Africa

PLOS ONE

Dear Dr. Cohen,

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 points raised during the review process.

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Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

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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: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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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

Reviewer #3: No

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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: SUBMISSION SUMMARY:

Semakula and colleagues present an interesting and important cross sectional study examining the demographics and time in therapeutic range (TTR) of patients receiving warfarin at five anticoagulation clinics in Uganda and South Africa. In particular, they report on facility characteristics, indications for anticoagulation, patient characteristics and comorbidities, and anticoagulation care quality metrics.

GENERAL IMPRESSIONS:

Overall, the investigators explore an important clinical question, namely the indications for warfarin as well as TTR attainment in several anticoagulation clinics in Sub Saharan Africa. The manuscript could be strengthened, however, by further clarification and enumeration of the methods, both in the rationale for the timeframe and patient selection procedure as well as statistical methods. Furthermore, since individual level data were gathered from the chart review, multivariable regression analyses could be performed to determine which variables may be associated with better TTR, thus exploring many of the speculative mechanisms for poor treatment quality brought up by the authors in the Discussion section.

COMMENTS BY SECTION:

* Title:

- Consider clarifying the title to avoid misunderstanding that the evaluation was performed on a nationwide scale (e.g. “A cross-sectional evaluation of warfarin anticoagulation services in five clinics in Uganda and South Africa”).

* Abstract:

- Page 3 (Line 55): Consider using more specific language than “INR control”. This is acceptable clinical wording, but the conclusion suggested by this manuscript specifies inadequate TTR attainment is the finding, which may be a more precise description of the reported outcome.

* Introduction:

- Page 4 (Line 68): Citation needed.

- Page 4 (Line 70): Citation needed.

* Methods:

- Page 5 (Line 81): Was there a reason that a 7 month data collection period was selected? It seems that 12 months would be a more relevant/representative timeframe, particularly since there are seasonal variations in hospitalization rates and causes, which may impact the generalizability of the findings. If there was not a specific reason for the selected time interval, this should be reported as a limitation of the study.

- Page 5 (Line 93): Please describe the rationale and specific procedure for the convenience sample. Were patients enrolled consecutively? Were they enrolled following a clinic visit? Was there any random selection procedure of charts? Enrollment alphabetically could potentially introduce complicating factors such as overrepresentation of certain families, ethnic groups, etc.

- Page 5 (Line 94): If a hypothesis of this paper is to assess for potential medication interactions between warfarin and TB/HIV drugs, perhaps it would make more sense to select and query the percentage of patients taking medications known a priori to affect warfarin metabolism. Examples of such medications (NNRTIs and rifampicin) are brought up by the authors in the Discussion section (Page 11) but are not reported as included among drugs queried in the study design.

- Page 5 (Line 96): “Statistical and data analysis” is redundant. The subheading can be changed to “Statistical Analysis” or “Data Analysis”.

- Page 5 (Line 98): Please specify which summary statistics were used (e.g. median, IQR, etc.).

- Page 5 (Line 99): Please name what software packages were used for statistical analysis and figure generation.

- Page 5 (Line 99): This study could be strengthened by performing regression analyses, which could potentially identify factors that may be associated with substandard TTR attainment. Was there a reason this was unable to be performed?

- Page 6 (Line 104): Please include the basis for waiving of informed consent from patients.

- Page 6 (Line 109): Please include the basis for waiving of informed consent from staff.

* Results:

- Page 6 (Lines 111-117): The descriptions of the audited clinics and interviewed individuals could be included in the Study Design and Sites subsection rather than the Results section, since these were known prior to the acquisition of study data.

- Page 8 (Line 133, Line 136): Please clarify the analyses were performed in “Ugandan sites” and “South African sites” rather than “Uganda” or “South Africa”.

* Discussion:

- Page 10 (Line 166): Please clarify how regular patient follow-up and regular INR monitoring were confirmed in this present analysis (e.g. what percentage of patients in the program actually made it to monthly follow-up appointments or INR monitoring visits).

- Page 11 (Lines 189-193): See above in Methods section. The authors discuss the potential of NNRTIs or rifampicin to affect warfarin metabolism, but the prevalence of use of these drugs is not explicitly queried in the study design.

Reviewer #2: 1. Authors state that they used a convenience sample. What was this convenience? Was it consecutive patients seen in the clinics? Random? Needs some elaboration.

2. The authors stated that they interviewed service providers (Doctors, nurses, etc.). However that data obtained from these interviews (quantitative or qualitative) are not clearly mentioned or discussed in the results or discussion sections. Most of the data they state in results section could have come from the patients and patient records. This needs to be clarified.

Reviewer #3: Reviewer # comments

Manuscript title: A cross-sectional evaluation of warfarin anticoagulation services in Uganda and South Africa

General feedback: The paper addresses an important topic on warfarin in the lower-income country (Uganda) and middle-income country (South Africa)

However, several methodological issues need to be addressed.

1. Methods:

a. The audit was conducted between 1 January and 31 July 2018. Authors extracted demographic data and clinical data including indication for anticoagulation, comorbidities, concomitant medications and INR results. It would have been essential to state the span over which INR results were collected. Did the authors document all the INR results over the study period (1 January and 31 July 2018)?

b. We selected, through convenience sampling, key members of clinic staff who were involved in anticoagulation care and who indicated their availability and willingness to be interviewed. Interviews were conducted using a structured questionnaire. I would avoid the word interview but rather use questionnaire administration. This was not a qualitative study, but rather the administration of structured questionnaires.

2. Statistical and data analysis

a. Although the authors stated that time in therapeutic range (TTR) over the most recent

three months was calculated using the Rosendaal interpolation method, one would expect more description as to who qualified for analysis. The Rosendaal method uses INR values from patients with at least two valid intervals separated by 56 days (8 weeks) or less, without an intervening hospitalisation. Some authors have used 60-90 days between readings. It is, therefore, essential to state the interval.

3. Results:

a. A lot of the initial sentences in the results section fits more on the method section than as results. For instance, the description of the study setting. Knowing that Mulago is a tertiary hospital or Groote Schuur as a secondary hospital is a piece of basic information that describes a study site, even before data collection. Kindly review this part.

b. Kindly state if valvular heart diseases included mechanical heart valves.

4. Discussion

a. Although the authors pointed out that the cost of INR testing and warfarin is may be prohibitive in anticoagulation control, this was not clear in figure 1. Ugandan site where patients paid for the warfarin/INR service had a similar level of anticoagulation control as the South African site! I expected this observation to feature in the discussion than the way the authors discussed.

b. Similarly, the contribution of HIV was not very evident despite the considerable difference in the prevalence (20% vs 5%). As in (a) above, this was not clearly stated.

c. Although this study is typically descriptive and may not be powered enough to analyse associations, it would have been nice to look at whether the variables which were collected had any influence on the level of anticoagulation control. If this is not done, the discussion on ‘’associated factors’’ will be limited.

d. Study limitations. How about the sample size? Was it enough to answer the primary objective? This is not justified in the manuscript and could feature as a limitation.

e. Conclusion: The findings from our work will inform further research to develop and validate a warfarin dosing algorithm for use in this setting. Was there any evidence to suggest that the absence of a validated algorithm affected anticoagulation control? As some sites had adopted some algorithm, one would expect the authors to have analysed if the lack of an algorithm affected anticoagulation control before having this conclusion.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Julius Mwita

[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.]

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Attachments

Attachment

Submitted filename: Reviewer PlosOne.docx

PONE-D-19-22709R1

A cross-sectional evaluation of five warfarin anticoagulation services in Uganda and South Africa

PLOS ONE

Dear Dr. Cohen,

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 points raised during the review process.

Specifically, 

There are two unclear issues – that you may need to rectify before the paper is accepted for publication.

1. Why no formal sample size estimation was carried out? This is critical and justification is important.
2. I am not sure it is true that there was no sampling frame?  Ideally – the sampling frame should have been the number of patient records available at the sites.  So, the statement that there was no sampling frame may not be entirely true.

We would appreciate receiving your revised manuscript by Jan 18 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.

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,

Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

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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 #2: All comments have been addressed

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: 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 #2: 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 #2: 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 #2: My comments have been fully addressed. I don't have further comments. I think the manuscript adds to the existing knowledge.

Reviewer #3: comments have been addressed.

However, authors are advised to check the whole manuscript for consistency of their wordings. For instance the use of "INR control" continued despite of the fact that authors agreed to replace it. Similarly, the word "interview" still appears in the abstract

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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 #2: 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.

A cross-sectional evaluation of five warfarin anticoagulation services in Uganda and South Africa

PONE-D-19-22709R2

Dear Dr. Cohen,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Joel Msafiri Francis, MD, MS, PhD

Academic Editor

PLOS ONE

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