Adverse drug events leading to emergency department visits: A multicenter observational study in Korea

Min-Gyu Kang; Ju-Yeun Lee; Sung-Il Woo; Kyung-Sook Kim; Jae-Woo Jung; Tae Ho Lim; Ho Joo Yoon; Chan Woong Kim; Hye-Ran Yoon; Hye-Kyung Park; Sang-Heon Kim

doi:10.1371/journal.pone.0272743

Peer Review History

Original SubmissionDecember 20, 2021
11 Feb 2022 Decision Letter - Masaki Mogi, Editor PONE-D-21-39781Adverse drug events leading to emergency department visits: A multi-center observational studyPLOS ONE Dear Dr. Kim, 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 is well assessed by the two reviewers. Major revisions are necessary in the present form. See the reviewers' suggestion carefully and respond them appropriately. Please submit your revised manuscript by Mar 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. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. [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: Yes ****** 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: Yes ****** 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 study is very interesting for the pharmacovigilance area, as it makes a multicentric retrospective study to assess the frequency of adverse events in emergency admission. As mentioned by the author himself, what we have in the literature today with this objective are studies in a single health unit, thus limiting some data and comparisons. The article was well structured and shows interesting results, which can help in better preventive actions to avoid medication errors, which was the most important data of the article. I have some suggestions that may provide more support: 1) it would be interesting to demonstrate how many medications, on average, by age, the subjects took, and thus relate to the influence of polypharmacy on reactions and medication errors; 2) it would be interesting for medication errors to show a table of which medications are involved in these errors and the type of error, thus being able to direct public policies for the prevention of medication errors; 3) I believe that the major limitation of the study is that it was retrospective, and thus having to believe that everything was in the medical records, I suggest putting as a limitation - that the data presented may be greater, since the data were extracted from medical records, in hospitals different, different clinical care teams, and some reactions may not have been recorded, or even not identified, since some signs and symptoms are confused with diseases. Reviewer #2: Title I suggest to indicate the Country where the study was performed (i.e., a Korean multi-center…) Abstract I suggest to use visit instead of admission, seriousness instead of severity, adverse drug event (ADE) instead of side effect, serious instead of severe. Please modify these terms also in the manuscript and tables Statistical analysis performed by the Authors should be added to the Abstract section (where is the multivariate logistic regression reported in the main manuscript?) More detailed results should be added to the Abstract section (where are the interesting ORs reported in table 3?) Methods Which kind of classification system is used by the Author to describe both suspected (causative) medications and observed ADEs? I suggest to detail in this section both ATC and MedDRA classification systems Which kind of algorithm/scale is used by the Author to estimate ADE preventability? There are several approaches, i.e. the Schumock and Thornton criteria, that could be described and used by the Authors Discussion This section should be more extensive and reader-friendly. Authors should perform a point-by-point (demographic, pharmacological and clinical characteristics) comparison between their results and those already published worldwide (i.e., Korea vs Europe, Korea vs United States, Korea vs Canada, Korea vs Australia, etc.) Some examples of similar analysis performed in Europe that could be useful in the aforementioned comparison are reported below: PMID: 32327995, PMID: 33708120, PMID: 34358104 I also suggest to add here some points of strengths (or to better discuss the few points of strengths already mentioned) Which are the clinical implications in conducting this kind of pharmacoepidemiological studies? Why pharmacovigilance and pharmacoepidemiology approaches could be considered a valuable options in the evaluation of drug-safety in a real-life setting such as ED? Figures The quality of figures is relatively low, please make them more readable ****** 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:** Patricia Moriel 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.0272743.r001
Revision 1
29 Mar 2022 Author Response Reviewer 1: The study is very interesting for the pharmacovigilance area, as it makes a multicentric retrospective study to assess the frequency of adverse events in emergency admission. As mentioned by the author himself, what we have in the literature today with this objective are studies in a single health unit, thus limiting some data and comparisons. The article was well structured and shows interesting results, which can help in better preventive actions to avoid medication errors, which was the most important data of the article. Response: Thank you for your positive comments and nice summary. We are submitting a revised manuscript that addresses the concerns raised. A detailed, point-by-point response to these concerns is attached. I have some suggestions that may provide more support: 1) it would be interesting to demonstrate how many medications, on average, by age, the subjects took, and thus relate to the influence of polypharmacy on reactions and medication errors; Response: We absolutely agree with your point of view in that polypharmacy and taking many medications may be associated with increased risk of adverse drug events (ADE). Unfortunately, since we enrolled subjects visiting to emergency department, it was not possible to analyze the medications or prescriptions by the other clinics or hospitals for each patient. Given that polypharmacy is frequently observed especially in older adults, it is speculated that polypharmacy might affect the development of ADE in older adults. We added this point as a limitation of this study (page 18, line299-304). 2) it would be interesting for medication errors to show a table of which medications are involved in these errors and the type of error, thus being able to direct public policies for the prevention of medication errors; Response: Thank you for your comments. We agree with the reviewer’s comments that medication error is an important part to address in this real-world study on pharmacovigilance. However, since we did not analyse the causative drugs related with medication error, it is regrettable to present this data. Instead, we described and presented the medications related with preventable ADE in supplementary Table S2. 3) I believe that the major limitation of the study is that it was retrospective, and thus having to believe that everything was in the medical records, I suggest putting as a limitation - that the data presented may be greater, since the data were extracted from medical records, in hospitals different, different clinical care teams, and some reactions may not have been recorded, or even not identified, since some signs and symptoms are confused with diseases. Response: Thank you for your helpful comments, which have substantially improved the quality of our manuscript. We also agree that the real body of ADE cases would be bigger than we estimated in this study. According to your suggestion, we described the limitation of this study in the discussion section (page 21, line 353-357). Review 2 1. Title I suggest to indicate the Country where the study was performed (i.e., a Korean multi-center…). Response: Thank you for your comments. The title was modified including the country as “Adverse drug events leading to emergency department visits: A multicenter observational study in Korea”. 2. Abstract 1) I suggest to use visit instead of admission, seriousness instead of severity, adverse drug event (ADE) instead of side effect, serious instead of severe. Please modify these terms also in the manuscript and tables. Response: We appreciate the reviewer’s helpful suggestion. We changed certain terms in the abstract and articles based on your suggestions. The word ‘admission’ was changed to the visits except for cases in which an actual ward is admitted. A total of eight ‘severe’ terms were replaced with ‘serious’. The term ‘severe’ was changed to ‘serious’ in statements conveying the severity of ADE in general. However, just as the CTCAE severity grading scale employs the term ‘severity’ rather than ‘seriousness’, the term severity and severity are interchangeable. The term ‘side effect' appears four times in the original manuscript. We used this term to refer to undesirable response due to pharmacologic property of drugs, such as antihistamine-induced sedation, as a part of type A reactions (overdose, secondary effects and drug interactions). Thus, we reserved the term ‘side effects’ for a certain type of ADE. To avoid confusion regarding this issue, we clarified the methods in detail. 2) Statistical analysis performed by the Authors should be added to the Abstract section (where is the multivariate logistic regression reported in the main manuscript?). Response: Thank you for your comment. We added the statistical analysis in the abstract. 3) More detailed results should be added to the Abstract section (where are the interesting ORs reported in table 3?). Response: Thank you for your helpful comments. We detailed the results of the abstract by adding OR and 95% CI in describing the main findings of the multivariate logistic regression analysis presented in Table 3. “Multivariate logistic regression analysis revealed that compared to non- adverse drug event-related cases, adverse drug event-related emergency department visitors were more likely to be female (60.6% vs. 53.6%, p<0.001, OR 1.285, 95% CI 1.025-1.603) and older (50.8 ± 24.6 years vs. 37.7 ± 24.4 years, p<0.001, OR 1.892, 95% CI: 1.397-2.297). Comorbidities such as diabetes, chronic kidney disease, chronic liver disease, and malignancies were also significantly associated with adverse drug event-related emergency department visits.” 3. Methods 1) Which kind of classification system is used by the Author to describe both suspected (causative) medications and observed ADEs? I suggest to detail in this section both ATC and MedDRA classification systems. Response: Thank you for pointing this out, which we did not fully acknowledge in our original manuscript. In this study, the World Health Organization Adverse Reaction Terminology (WHO-ART) was used to describe ADE instead of MedDRA. For the causative drugs, we used the Anatomical Therapeutic Chemical (ATC) Classification System. We modified the description of the methods used in the classification of ADE and causative drugs (page 8, line 124-129). 2) Which kind of algorithm/scale is used by the Author to estimate ADE preventability? There are several approaches, i.e. the Schumock and Thornton criteria, that could be described and used by the Authors. Response: As you mentioned, we used and characterized the preventability of ADEs by the Schumock and Thornton criteria. the description for the criteria of preventability was added in lines 144-145 of the ‘main outcomes of ADEs’ section. 4. Discussion This section should be more extensive and reader-friendly. Authors should perform a point-by-point (demographic, pharmacological and clinical characteristics) comparison between their results and those already published worldwide (i.e., Korea vs Europe, Korea vs United States, Korea vs Canada, Korea vs Australia, etc.). Some examples of similar analysis performed in Europe that could be useful in the aforementioned comparison are reported below: PMID: 32327995, PMID: 33708120, PMID: 34358104. Response: We appreciate the reviewer’s helpful suggestion. We changed the discussion part in the order of incidence, elderly, and female. In addition, our study results were compared with other studies in the order of domestic and foreign studies. According to your comments, we further reviewed the pharmacoepidemiologic studies in Italy and described the summarisez results of the Italian study in the discussion section (page 19, line 320-323). I also suggest to add here some points of strengths (or to better discuss the few points of strengths already mentioned). Which are the clinical implications in conducting this kind of pharmacoepidemiological studies? Why pharmacovigilance and pharmacoepidemiology approaches could be considered a valuable options in the evaluation of drug-safety in a real-life setting such as ED? Response: We absolutely agree with the reviewer’s comments that the pharmacovigilance and pharmacoepidemiology approaches offer great opportunity to suggest what is still needed to improve drug safety around the world. According to the reviewer’s suggestion, we added the strength and importance of the pharmacoepidemiologial study of ADE in real world in lines 319-333 and the conclusion. 5. Figures The quality of figures is relatively low, please make them more readable. Response: The low resolution of the pictures is due to PLOS one's e-submission system. We made the figures through R software with high resolution. Perhaps, when the paper is published, you will be able to see high-resolution pictures. Following this, we attached the PDF version of the high-resolution figures. Attachments Attachment Submitted filename: PONE-D-21-39781_answer reviewer.docx https://doi.org/10.1371/journal.pone.0272743.r002
19 Apr 2022 Decision Letter - Masaki Mogi, Editor PONE-D-21-39781R1Adverse drug events leading to emergency department visits: A multicenter observational study in KoreaPLOS ONE Dear Dr. Kim, 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. ============================== There are small minor revision in the present form. See the reviewers' comments and respond them. ============================== Please submit your revised manuscript by Jun 03 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: 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 #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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 #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 punctually answered the doubts of the reviewers. Most of the suggestions were accepted, some due to the impossibility of obtaining the data were placed as limitations of the study. The new version of the article is clearer, and despite the limitations, which now appear in the article, the results are important mainly because it is a multicentric study. Reviewer #2: Please revise the following sentence: "The MEREAFaPS study group also reported that antiplatelet 321 agents, anticoagulants, and antidiabetics were drugs such as antiplatelet agents and 322 anticoagulants were a common cause of ADE-related ED visits in Italy" ****** 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 #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.0272743.r003
Revision 2
23 Jul 2022 Author Response Manuscript PLOS-D-21-39781R1 Response to reviewers Thank you for giving us the opportunity to submit a revised draft of the manuscript “adverse drug events leading to emergency department visits: A multicenter observational study in Korea” for publication in the PLOS One. We appreciate the time and effort that you and the reviewers dedicated to providing feedback on our manuscript and are grateful for the insightful comments on and valuable improvements to our paper. We have incorporated most of the suggestions made by the reviewers. Those changes are highlighted within the manuscript. Please see below, in red, for a point-by-point response to the reviewers’ comments and concerns. All page numbers refer to the revised manuscript file with tracked changes. Reviewers’ Comments to the Authors: Reviewer 2: Please revise the following sentence: “MEREAFaPS study group also reported that antiplatelet agents, anticoagulants, and antidiabetes were drugs such as antiplatelet agents and anticoagulants were a common cause of ADE-related ED visits in Italy” Author response: Thank you for pointing this out. The reviewer is correct, and we revised the sentence following as “The MEREAFaPS study also reported that antiplatelet agents, anticoagulants and anti-diabetes were also common causes of ADE-related ED visits in Italy” Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0272743.r004
26 Jul 2022 Decision Letter - Masaki Mogi, Editor Adverse drug events leading to emergency department visits: A multicenter observational study in Korea PONE-D-21-39781R2 Dear Dr. Kim, 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: https://doi.org/10.1371/journal.pone.0272743.r005
Formally Accepted
8 Sep 2022 Acceptance Letter - Masaki Mogi, Editor PONE-D-21-39781R2 Adverse drug events leading to emergency department visits: A multicenter observational study in Korea Dear Dr. Kim: 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.0272743.r006

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