Direct Oral Anticoagulants’ Consumption and Expenditure in the COVID-19 Pandemic in Russia and Clinical Practice Guidelines for Their Use

Round 1

Reviewer 1 Report

Dear authors,

thank you for your interesting and clinically relevant manuscript. Although , the manuscript need several minor modifications:

1. the term INCIDENCE is not adequately used (mixed with number of cases and prevalence);

2. the chapter Introduction need to be shortened and focused to the other parts of the manuscript;

3. the part of the Introduction in which CYPs are mentioned should be removed (not necessary for understanding);

4. all mentioned appendixes are missing;

5. search strategy is not described properly (it is not according to PRISMA);

6. PRISMA flow diagram should be inserted in the manuscript as well as search strategy used as per individual database and reasons for exclusion;

7. regarding AGREE II instrument, its validity and Cochrane alpha should be provided;

8. it is not clear and adequate to connect consumption data and clinical recommendations (need better explanation or exclusion from the manuscript);

9. All figures could be included in tables;

10. Explanation for apixaban increase in consumption (vs. rivaroxaban decreasing) is missing;

11. Study limitations should be more extensive.

Author Response

Dear editors and reviewers,

 Thank you very much for your comments and suggestions, which helped us to improve our manuscript “DIRECT ORAL ANTICOAGULANTS CONSUMPTION AND EXPENDITURE IN COVID-19 PANDEMIC IN RUSSIA AND CLINICAL PRACTICE GUIDELINES FOR THEIR USE” by Elena A. Baybulatova, Mikhail S. Chenkurov Elina A. Korovyakova, Sergey K. Zyryanov and Liliya E. Ziganshina

Dear Reviewer,

Thank you very much for your comments and suggestions, which helped us to improve our manuscript.

Please find below our answers point by point.

Reviewer 1

Point 1:

«Dear authors, thank you for your interesting and clinically relevant manuscript. Although, the manuscript need several minor modifications:

1. «the term INCIDENCE is not adequately used (mixed with number of cases and prevalence)»

Authors’ answer:

Dear Reviewer,

Thank you, the word “incidence” was used 5 times in the manuscript. We used “occurrence” on the page 2, Line-70 and “incidence rate” on the page 3, Line-114 in the first two cases and “number of people” on the page 5, Line-224; on the page 5, table 1 and “number of cases” on the page 5, Line-226 in the other three cases of the use of the word “incidence” and highlighted in yellow with track-changes.

Point 2:

Authors’ answer:

Dear Reviewer,

2. 2. « the chapter Introduction need to be shortened and focused to the other parts of the manuscript;»

Dear reviewer, thank you for your comments. The chapter Introduction has been shortened and the changes were highlighted in yellow with track-changes on the page 2-4.

Point 3:

Authors’ answer:

Dear Reviewer,

3. «the part of the Introduction in which CYPs are mentioned should be removed (not necessary for understanding)»

Dear reviewer, thank you for your comments, it has been removed and the changes were highlighted in yellow with track-changes on the page3, Lines 101, page 12, Line 471-472.

Point 4:

Authors’ answer:

Dear Reviewer,

4. «all mentioned appendixes are missing»

Dear reviewer, thank you for your comments.

  All appendixes have been placed at the end of the article for the convenience of your review on the pages 26-48.

Point 5:

Authors’ answer:

Dear Reviewer,

5. «search strategy is not described properly (it is not according to PRISMA)»

 Dear reviewer, thank you for your comments.

Detailed descriptions of the search strategy are provided in Appendices 3,4,5, which are located on pages 29-35.

Point 6:

Authors’ answer:

Dear Reviewer,

6. «PRISMA flow diagram should be inserted in the manuscript as well as search strategy used as per individual database and reasons for exclusion»

Dear reviewer, thank you for your comments.

Figure 1. PRISMA flow diagram have been inserted in the part “Results of the searches” page 9. The search strategy is presented in page 7, line 298-317 and Appendix 3 (page 29-31). Reasons criteria are provided in Appendix 4 (page 32-33).

Point 7:

Authors’ answer:

Dear Reviewer,

7. «regarding AGREE II instrument, its validity and Cochrane alpha should be provide»

Dear reviewer, thank you for your comments.

AGREE II Instrument is a well-known, reliable and widely accepted instrument for guideline appraisal and development, it was fully validated before introducing into practice (your reference), so we used it for the purpose of this study.

Point 8:

Authors’ answer:

Dear Reviewer,

8. «it is not clear and adequate to connect consumption data and clinical recommendations (need better explanation or exclusion from the manuscript)»

Dear reviewer, thank you for your comments.  

Our analysis of the actual consumption of DOACs during the pandemic in the Russian Federation and the DDD recommended by Russian clinical guidelines allowed us to assess the adequacy of prescribing DOACs to patients with COVID-19 in the Russian Federation, as well as the dynamics and structure of DOAC consumption from 2020 to 2022.

Point 9:

Authors’ answer:

Dear Reviewer,

9. «All figures could be included in tables»;

Dear reviewer, thank you for your comments.

All figures is included in the tables:

Table 1. Population of the Russian Federation and the number of cases of COVID-19 in the period from 2020 to 2022 (page 5);

Table 5. Gross national consumption of apixaban and rivaroxaban in the Russian Federation in 2020-2022 (number of DDDs per year) (page 13);

Table 6. DDDs/а case of COVID-19 of apixaban and rivaroxaban in the Russian Federation (2020 to 2022) (page 13);

Table 7. Estimated number of people taking a CPG recommended course of apixaban and rivaroxaban in the Russian Federation in 2020-2022 based on the assumption that only COVID-19 patients were responsible for gross national consumption (page 14);

Table 8. Number of people taking apixaban and rivaroxaban in the Russian Federation in 2020-2022 (15 DDD, 30 days) and (22,5 DDD, 45 days) (page 15);

Table 9. Dynamics of the cost of 1 DDD in the Russian Federation from 2020 to 2022 during the pandemic of a new coronavirus infection (page 20).

Table: DDDs/а case of COVID-19 of apixaban and rivaroxaban in the Russian Federation (2020 to 2022) (Appendix 2, page 28);

Table: Estimated number of people taking a CPG recommended course of apixaban and rivaroxaban in the Russian Federation in 2020-2022 based on the assumption that only COVID-19 patients were responsible for gross national consumption. (Appendix 2, page 28);

Appendix 6.  Sales data and expenditures for National DOAC consumption calculations in 2020-2023 (page 32);

Appendix 8. Comparison of the assessment of seven CPGs for treating COVID-19 with AGREE II (page 45).

Point 10:

Authors’ answer:

Dear Reviewer,

10. «Explanation for apixaban increase in consumption (vs. rivaroxaban decreasing) is missin»;

Dear reviewer, thank you for your comments.

We expanded the explanations of changes in DOAC consumption patterns in the article (page 20, line 720-747).

According to our data, at the beginning of the pandemic in the Russian Federation, the consumption of apixaban and rivaroxaban was comparable; by 2022, the structure of DOAC consumption changed: the consumption of apixaban increased and the consumption of rivaroxaban decreased. Our results coincide with the data obtained in the study by Petrukhina I.and al. [32], where sales statistics were studied in the pharmacy market segment of the Samara region to assess the volume and structure of consumed cardiovascular and antithrombotic drugs during the COVID-19 pandemic, including DOACs. We can speculate that one of the reasons for the increased consumption of apixaban was due to its lower price compared to rivaroxaban.

We calculated the dynamics of the cost of one package of apixaban and rivaroxaban from 2020 to 2022. There was a trend towards an increase in the cost of DOACs, with the cost of one package of rivaroxaban exceeding the cost of apixaban.

Table. Dynamics of the cost of 1 DDD in the Russian Federation from 2020 to 2022 during the pandemic of a new coronavirus infection.

We also believe that the increase in apixaban consumption is associated with the receipt of new information about the effectiveness and safety of the drug, which indicates the greater effectiveness and safety of apixaban compared to rivoraxaban.

For example, in this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban [34].

Also in a systematic review and meta-analysis that examined the effectiveness and safety of apixaban in more than 3.9 million people with atrial fibrillation [35] apixaban was associated with a better overall safety and effectiveness profile compared to VKAs and other DOACs.

Other studies have found similar results [36, 37].

Currently, data on the effectiveness and safety of various drugs from the DOAC group in patients with COVID-19 are insufficient and contradictory, so this issue requires further study.

Point 11:

Authors’ answer:

Dear Reviewer,

11. Study limitations should be more extensive.

Dear reviewer, thank you for your comments.

Another limitation is that clinical guidelines for the treatment of COVID-19 were assessed by three appraisers, rather than four as recommended by the AGREE II guideline. (page 22. Line 813-815).

Reviewer 2 Report

Extensive research has been carried out on "DIRECT ORAL ANTICOAGULANTS CONSUMPTION AND EXPENDITURE IN COVID-19 PANDEMIC IN RUSSIA AND CLINICAL PRACTICE GUIDELINES FOR THEIR USE".

However, I have some suggestions and questions:

- In the abstract, correct the spelling of "stakeholder".

- Line 130 - development of CRs....

Provide abbreviation for CR.

- Provide abbreviations for DDD, NOAC during first time use.

Why do you use the abbreviation "NOAC" in some places, when you commonly use DOAC? Even I could not find the abbreviation for NOAC in the list of abbreviations.

- You mentioned to see the Appendices, but I could not see the appendices even as a supplementary file.

- What search terms you used to retrieve the data? Mention that in the methods sections.

- Line 286 - Results of the searches.

Depict in the form of figure for easy understanding, instead of writing as a text.

-  In table 3, what does E1, E2, E3 indicate?

Author Response

Dear editors and reviewers,

 Thank you very much for your comments and suggestions, which helped us to improve our manuscript “DIRECT ORAL ANTICOAGULANTS CONSUMPTION AND EXPENDITURE IN COVID-19 PANDEMIC IN RUSSIA AND CLINICAL PRACTICE GUIDELINES FOR THEIR USE” by Elena A. Baybulatova, Mikhail S. Chenkurov Elina A. Korovyakova, Sergey K. Zyryanov and Liliya E. Ziganshina

Dear Reviewer,

Thank you very much for your comments and suggestions, which helped us to improve our manuscript.

Please find below our answers point by point.

Reviewer 2

Point 1:

«However, I have some suggestions and questions:

1. «In the abstract, correct the spelling of "stakeholder"».

Authors’ answer:

Dear Reviewer,

Thank you for your comments. The typo has been corrected on the page 1 and in yellow highlight with track-change.

Point 2:

2. «Line 130 - development of CRs....Provide abbreviation for CR».

Authors’ answer:

Dear reviewer,

thank you for your comments. Abbreviations for CRs (clinical recommendations) was provided –page 3, Line 146 in yellow highlight. When shortening the introduction, this abbreviation was removed.

Point 3:

3. «Provide abbreviations for DDD, NOAC during first time use».

Authors’ answer:

Dear reviewer,

thank you for your comments. Abbreviations for DDD was provided:

 DDD (defined daily dose) – page 1, Abstract, in yellow highlight.  

NOAC (new oral anticoagulants) – page 2, line 74, in yellow highlight.

Point 4:

4. «Why do you use the abbreviation "NOAC" in some places, when you commonly use DOAC? Even I could not find the abbreviation for NOAC in the list of abbreviations».

Authors’ answer:

Dear reviewer,

thank you for your comments, the abbreviation "NOAC" was placed in the list of abbreviations;

"NOAC" was sometimes indicated in the text because the abbreviation was used as the search term in

the eLIBRARY search strategy.

Point 5:

5. «You mentioned to see the Appendices, but I could not see the appendices even as a supplementary file».

Authors’ answer:

Dear reviewer,

thank you for your comments.  All appendixes have been located at the end of the article for the convenience of your review on the pages 26-48.

Point 6:

6. «What search terms you used to retrieve the data? Mention that in the methods sections».

Authors’ answer:

Dear reviewer,

thank you for your comments. The search strategy was detailed described in an appendix 3 on the pages 29-31 and it was briefly described in the section “Search strategy” on the page 7, line 298-317 in yellow highlight.   

Point 6:

6. «Line 286 - Results of the searches», «Depict in the form of figure for easy understanding, instead of writing as a text».

 Authors’ answer:

Dear reviewer,

thank you for your comments.  Figure 1. PRISMA flow diagram has been inserted in the part “Results of the searches” on the page 9.

Point 7:

7. «In table 3, what does E1, E2, E3 indicate?»

Authors’ answer:

Dear reviewer,

thank you for your comments. The symbols E1, E2, E3 were replaced with the names of the researchers in table 3 on the page 11 and   highlighted with track-changes.

Table 3. Sample data set for the domain Scope and Purpose.