COVID-19 outcomes in patients taking cardioprotective medications

Fritha J. Morrison; Maxwell Su; Alexander Turchin

doi:10.1371/journal.pone.0275787

Peer Review History

Original SubmissionMarch 17, 2022
26 May 2022 Decision Letter - Masaki Mogi, Editor PONE-D-22-07504COVID-19 Outcomes in Patients Taking Cardioprotective MedicationsPLOS ONE Dear Dr. Turchin, 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. ============================== The manuscript by Turchin et al. has been evaluated by two Reviewers and should be revised according to the Reviewers' comments. Carefully read the suggestions and respond them appropriately. ============================== Please submit your revised manuscript by Jul 10 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 3. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. 4. Thank you for stating the following in the Competing Interests/Financial Disclosure* (delete as necessary) section: “AT has received research funding from Astra Zeneca, Edwards, Eli Lilly, Novo Nordisk and Sanofi; has equity in Brio Systems; and has served as a consultant for Covance and Proteomics International. None of the other authors have any competing interests.” We note that one or more of the authors are employed by a commercial company: name of commercial company. 1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. 2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests) . If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf. [Note: HTML markup is below. Please do not edit.] 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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 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 ****** 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: No ****** 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: Dr. Alexander Turchin et al conducted a retrospective observational study with a large number of COVID19 patients. They investigated whether patients taking four classes of cardioprotective medications - aspirin, metformin, renin angiotensin aldosterone system inhibitors (RAASi) and statins – have a lower risk of adverse outcomes of COVID-19, and showed lower mortality in patients taking metformin, RAASi, or statins in comparison with those not taking them. The manuscript is well written, and provides an important contribution. I have only few comments on their manuscript. As already mentioned by the authors, my main concern is the influence of confounders. The patients who discontinued taking medication have usually poor compliance with medications and healthy lifestyle. In the Discussion section, the authors mention that the mechanism of benefit from RAASi in COVID19 is based on the reduction in ACE2. With my understanding, RAASi does not decrease the expression of ACE2. Furthermore, in the beginning of COVID19 pandemic, it was suggested that RAASi might increase ACE2 and increased ACE2 expression by preexisting RAASi treatment may affect the virus susceptibility. Later, this hypothesis have been rejected. The mechanism of the benefit of RAASi in COVID19 is thought to be derived from anti-inflammatory effects. COVID-19 could cause the imbalanced RAAS and drugs of ACE inhibitors and ARBs balancing RAAS may have the potential benefit on the lung protection in COVID-19. Reviewer #2: Morrison et al have conducted a retrospective cohort study analysing primary care patients (n=13,585) at a single healthcare delivery system who had a positive reverse transcription-polymerase chain reaction [RT-PCR] result for SARS-CoV-2 between March 2020 and March 2021. The main purpose of the study was to assess whether the intake of four classes of cardioprotective medications -aspirin, metformin, renin angiotensin aldosterone system inhibitors (RAASi) and statins– have a lower risk of adverse outcomes of COVID-19. The authors conclude that cardioprotective medications were not associated with a consistent benefit in adult COVID-19 patients, and only the regular intake of aspirin aspirin had a significantly higher risk of hospitalization in both bivariate and multivariable analyses. Major issues, 1) The conclusions in the text are unfocused on the present data and should be rephrased. 2) The authors should clarify whether RT-PCR was repeated in the same patients and swab performance (collection timing, procedure, and method of transport) was the same for all patients. 3) The authors should add information regarding magnitude of viral load, medications and outcome of patients. 4) Previous studies have described a relationship between comedications (instead of single medication) and outcome of frail patients (please see Heart Fail Rev. 2021; 26(2): 371–380, GeroScience. 2020 Aug; 42(4): 1021–1049). The authors should mention the above studies and discuss their results in the light of them. 5) The authors should clarify the relationship between nasopharyngeal SARS-CoV-2 viral load at first patient's hospital evaluation and outcome of COVID19 patients. Evidences on this issue are controversial. Previous study has demonstrated that nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome (please see Sci Rep. 2021 Jun 21;11(1):12931), but other study showed that initial viral load is an incremental predictor of mortality (Mayo Clin Proc Innov Qual Outcomes. 2021 Oct;5(5):891-897). 6) In the light of recent report, extra caution is a d vis e d when reviewing prescriptions of individuals with significant polypharmacy or with renal/hepatic impairment (Clin Pharmacol Ther. 2022 May 14.doi: 10.1002/cpt.2646.). Therefore, the authors should add a perspective regarding drug-durg interactions in COVID19 patients with significant polypharmacy or with cardiac/renal/hepatic impairment. 7) Background should be improved. Therefore, the authors should discuss their results in the light of the following unmentioned studies (please see Eur J Epidemiol. 2022 Feb;37(2):157-165; Clin Res Cardiol. 2021 Jul;110(7):1041-1050; Am J Hypertens. 2022 May 10;35(5):462-469; Metabolism . 2022 Jun;131:155196. ). What about direct oral anticoagulants or vitamin-K antagonists or antiplatelet therapy or steroids or angiotensin II receptor blockers or other anti-diabetic drugs? What type of statins? Indeed, recent unmentioned RCT demonstrated that atorvastatin increased hospitalization days and imposed negative effects on symptom improvement in hospitalized patients with COVID-19 (J Med Virol. 2022 Jul;94(7):3160-3168.) 8) The authors mention potential future anti-COVID19 drugs (monoclonal antibody treatments and antiviral drugs). However, emerging evidences on DNA/RNA aptamers anti-ACE2 (Pharmacol Res. 2022 Jan;175:105982.) or anti-receptor binding domain of SARS-CoV-2 spike protein (Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2112942118. ) promise new development and should be mentioned by the authors. ****** 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: Yes:** Yasushi Matsuzawa 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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0275787.r001
Revision 1
8 Sep 2022 Author Response EDITOR We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. RESPONSE We have added Table 4 that includes the data that was previously not shown as advised by the Editor. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. RESPONSE We have included a full ethics statement in the Methods section (at the end of the Study Cohort subsection). Thank you for stating the following in the Competing Interests/Financial Disclosure* (delete as necessary) section: “AT has received research funding from Astra Zeneca, Edwards, Eli Lilly, Novo Nordisk and Sanofi; has equity in Brio Systems; and has served as a consultant for Covance and Proteomics International. None of the other authors have any competing interests.” We note that one or more of the authors are employed by a commercial company: name of commercial company. 1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. RESPONSE We wanted to clarify that Phase V Technologies did not provide any financial support for the study. We would like to amend our Competing Interests statement to read as follows: AT has received research funding from Astra Zeneca, Edwards, Eli Lilly, Novo Nordisk and Sanofi; has equity in Brio Systems; and has served as a consultant for Covance and Proteomics International. MS is an employee of Phase V Technologies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the other authors have any competing interests. Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.” If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. RESPONSE We wanted to clarify that Phase V Technologies did not provide any financial support for the study. We would like to amend our Financial Disclosure Statement to read as follows: This research was funded in part by contract # ME-2019C1-15328 from Patient-Centered Outcomes Research Institute (http://www.pcori.org). The funder only provided financial support in the form of the authors’ (FJM, MS, AT) salaries and research materials and did not play any role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Phase V Technologies did not provide any financial support for the study and did not play any role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The specific roles of the study authors are articulated in the ‘author contributions’ section. 2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. RESPONSE We would like to amend the Competing Interests statement as outlined above. REVIEWER # 1 In the Discussion section, the authors mention that the mechanism of benefit from RAASi in COVID19 is based on the reduction in ACE2. With my understanding, RAASi does not decrease the expression of ACE2. Furthermore, in the beginning of COVID19 pandemic, it was suggested that RAASi might increase ACE2 and increased ACE2 expression by preexisting RAASi treatment may affect the virus susceptibility. Later, this hypothesis has been rejected. The mechanism of the benefit of RAASi in COVID19 is thought to be derived from anti-inflammatory effects. COVID-19 could cause the imbalanced RAAS and drugs of ACE inhibitors and ARBs balancing RAAS may have the potential benefit on the lung protection in COVID-19. RESPONSE We appreciate the Reviewer’s suggestion and have made changes in both Introduction and Discussion sections in accordance with the Reviewer’s recommendation. REVIEWER # 2 The conclusions in the text are unfocused on the present data and should be rephrased. RESPONSE We have amended the Conclusions section as recommended by the Reviewer. The authors should clarify whether RT-PCR was repeated in the same patients and swab performance (collection timing, procedure, and method of transport) was the same for all patients. RESPONSE We would like to clarify that this a real-world evidence study, and therefore all test results that were analyzed were performed for patient care, and not specifically for this study. Consequently it is unlikely that testing procedures have been exactly the same in all patients. We have included this information in the Limitations section of the paper. The authors should add information regarding magnitude of viral load, medications and outcome of patients. RESPONSE We regret that the information about the viral load was not available for analysis. We have included this in the Limitations section of the manuscript. Multiple patient outcomes (hospitalization, ICU admission, artificial ventilation and death) are already included in the analysis. Previous studies have described a relationship between comedications (instead of single medication) and outcome of frail patients (please see Heart Fail Rev. 2021; 26(2): 371–380, GeroScience. 2020 Aug; 42(4): 1021–1049). The authors should mention the above studies and discuss their results in the light of them. RESPONSE We have included a discussion of and references to the papers recommended by the Reviewer. The authors should clarify the relationship between nasopharyngeal SARS-CoV-2 viral load at first patient's hospital evaluation and outcome of COVID19 patients. RESPONSE We regret that the information on nasopharyngeal SARS-CoV-2 viral load was not available for analysis. We have included this in the Limitations section of the manuscript. In the light of recent report, extra caution is advised when reviewing prescriptions of individuals with significant polypharmacy or with renal/hepatic impairment (Clin Pharmacol Ther. 2022 May 14.doi: 10.1002/cpt.2646.). Therefore, the authors should add a perspective regarding drug-drug interactions in COVID19 patients with significant polypharmacy or with cardiac/renal/hepatic impairment. RESPONSE We have included this in the Limitations section of the manuscript. Background should be improved. Therefore, the authors should discuss their results in the light of the following unmentioned studies (please see Eur J Epidemiol. 2022 Feb;37(2):157-165; Clin Res Cardiol. 2021 Jul;110(7):1041-1050; Am J Hypertens. 2022 May 10;35(5):462- 469; Metabolism . 2022 Jun;131:155196. ). What about direct oral anticoagulants or vitamin-K antagonists or antiplatelet therapy or steroids or angiotensin II receptor blockers or other anti-diabetic drugs? What type of statins? Indeed, recent unmentioned RCT demonstrated that atorvastatin increased hospitalization days and imposed negative effects on symptom improvement in hospitalized patients with COVID-19 (J Med Virol. 2022 Jul;94(7):3160-3168.) RESPONSE We appreciate the Reviewer’s suggestion and have included discussion of all of the studies referenced above in the Introduction and / or Discussion sections of the manuscript. The authors mention potential future anti-COVID19 drugs (monoclonal antibody treatments and antiviral drugs). However, emerging evidences on DNA/RNA aptamers anti-ACE2 (Pharmacol Res. 2022 Jan;175:105982.) or anti-receptor binding domain of SARS-CoV-2 spike protein (Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2112942118. ) promise new development and should be mentioned by the authors. RESPONSE We have included information on DNA / RNA aptamers being developed for treatment of COVID in the manuscript as advised by the Reviewer. Thank you for your thoughtful feedback, and we appreciate the opportunity to revise our manuscript. Please do not hesitate to contact us should you have any further questions. Yours sincerely, Alexander Turchin, MD, MS Attachments Attachment Submitted filename: CVmedsCOVIDoutcomes-PLOSOne-ResponseToReviewers01-v01.docx https://doi.org/10.1371/journal.pone.0275787.r002
13 Sep 2022 Decision Letter - Masaki Mogi, Editor PONE-D-22-07504R1COVID-19 Outcomes in Patients Taking Cardioprotective MedicationsPLOS ONE Dear Dr. Turchin, 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. ============================== Minor revisions are necessary for the present form. See the comments. ============================== Please submit your revised manuscript by Oct 28 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. 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). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Masaki Mogi Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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: (No Response) ******** 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: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 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: 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 #2: 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: The authors have well revised their manuscript according to my comments. I do not have any more comments on it. Reviewer #2: The authors partially answered the questions put forward by this reviewer. However, the suggestion on the use of DNA/RNA aptamers remains. The authors should better mention and discuss perspective of aptamers directed toward ACE2 (Pharmacol Res. 2022 Jan;175:105982.) and those directed toward the coronavirus spike protein (Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2112942118.). ****** 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: Yes: Yasushi Matsuzawa 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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0275787.r003
Revision 2
16 Sep 2022 Author Response The authors partially answered the questions put forward by this reviewer. However, the suggestion on the use of DNA/RNA aptamers remains. The authors should better mention and discuss perspective of aptamers directed toward ACE2 (Pharmacol Res. 2022 Jan;175:105982.) and those directed toward the coronavirus spike protein (Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2112942118.). RESPONSE We have added a discussion of DNA / RNA aptamers being developed for treatment of COVID in the manuscript (in the Discussion section) as advised by the Reviewer (including the references recommended by the Reviewer). Attachments Attachment Submitted filename: CVmedsCOVIDoutcomes-PLOSOne-ResponseToReviewers02-v01.docx https://doi.org/10.1371/journal.pone.0275787.r004
26 Sep 2022 Decision Letter - Masaki Mogi, Editor COVID-19 Outcomes in Patients Taking Cardioprotective Medications PONE-D-22-07504R2 Dear Dr. Turchin, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Masaki Mogi Academic Editor PLOS ONE Additional Editor Comments (optional): 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: 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 ****** 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 ****** 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: (No Response) ****** 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 ******** https://doi.org/10.1371/journal.pone.0275787.r005
Formally Accepted
29 Sep 2022 Acceptance Letter - Masaki Mogi, Editor PONE-D-22-07504R2 COVID-19 Outcomes in Patients Taking Cardioprotective Medications Dear Dr. Turchin: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Masaki Mogi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0275787.r006

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