Polypharmacy occurrence and the related risk of premature death among older adults in Denmark: A nationwide register-based cohort study

Anna Vera Jørring Pallesen; Maria Kristiansen; Rudi G. J. Westendorp; Laust Hvas Mortensen

doi:10.1371/journal.pone.0264332

Peer Review History

Original SubmissionJune 1, 2021
20 Jul 2021 Decision Letter - Omid Beiki, Editor PONE-D-21-15519 Polypharmacy occurrence and the related risk of premature death among older adults in Denmark: A nationwide register-based cohort study PLOS ONE Dear Dr. Pallesen, 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. Please submit your revised manuscript by Sep 03 2021 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. 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Reviewer #1: 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: This paper uses a nationwide register to describe the epidemiology of polypharmacy in Denmark. The paper finds that polypharmacy is common, and associated with several important factors including aging, multimorbidity and socioeconomic factors. It also describes the incidence of polypharmacy, which is poorly reported in the literature, and assesses the association with mortality. The paper is clearly written and easy to read. The background is well laid out and sets out the aims in a clear and justified manner. The methods seem, in general, appropriate. The results are well structure and easy to follow. The discussion is appropriate, although I think the interpretation needs to be cautious. Data are not available due to the confidential nature of the national dataset used. I have a number of comments that would benefit from consideration by the authors: 1. Abstract - the final sentence concludes that the strong association with mortality infers a need for moniotoring and policy to reduce polypharmacy. This implies a causal association which I do not believe is convincingly supported by the evidence presented. 2. Methods - I am not familiar with the overlap weighting approach used, and I suspect many other readers will not be either. Could the authors expand on this a little, in terms of elaborating on what the benefits of this particular approach are, without the reader needing to resort to reading the references given? 3. Results - The presentation of prevalence over time is, at least initially, confusing - I was left trying to work out why the prevalence drops to 2.4 from a mean of 3.5 in 2013. I was relieved that the discussion concurred with my own conclusions, in that the later years represent younger people entering the study. However, it did make me wonder how useful this is - I would suggest that the analysis focuses on 2013 only in 2013. 4. Results - The presentation of polypharmacy incidence is very nice, given this is not well reported. As is acknowledged by the authors, the 2013 values are less interpretable, and I wonder if tables 3 and 4 should focus on 2014-2017 only, dropping 2013 and changing the reference category accordingly. 5. Discussion: mortality and strengths/limitations sub-sections. The authors state "This strength makes the estimate ...the most reliable ... to describe the association between polypharmacy and mortality." I don't disagree that the association is clearly described, but I do think there are important points that are not considered. Firstly, severity of disease is not accounted for - people may have similar morbidities, but very different degrees of severity of those different morbidities, with severity thus being associated with both mortality and with polypharmacy. Clearly, most studies using routine data cannot readily account for severity as it is not captured in coded records. Nevertheless - this should be acknowledged here and in the strengths/limitations section (at present, the authors state "we may not have adjusted for all potential confounders" - severity is clearly one of these). Secondly, the authors appear to have only measured morbidity using a simply dichotomy (0/1 OR 2+ conditions) based on 47 chronic conditions. Why was there no adjustment for a more sophisticated measure of multimorbidity that accounted for different numbers, types and weightings of conditions? I apologise if this was done, in which case it should be made clearer. Thirdly, the association between polypharmacy and adverse outcome (hospitalisation) has been shown to vary with the degree of multimorbidity (pubmed.ncbi.nlm.nih.gov/24428591/) but no effect modification was considered here; this is worth discussion as one would expect a similar picture to be seen with mortality. 6. The conclusion states that the findings show "a potential for prevention of inappropriate polypharmacy". I disagree - the authors have made no attempt to quantify the appropriateness or otherwise of polypharmacy in the study. The assumption can certainly be made that much of the polypharmacy experienced by this cohort will be inappropriate, but no data is presented to support this argument. Similarly, the conclusion moves on to discuss prevention and reduce of polypharmacy (similar to the abstract) but the data do not support these arguments as a causal association cannot be assumed. The conclusion here, and in the abstract, should be toned down accordingly. ******** 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:** Rupert Payne [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". 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Revision 1
3 Sep 2021 Author Response We appreciate the feedback and comments that we have received from the reviewer. In this document we respond to all the comments given and describe the changes that we have made to the manuscript. We hope that these modifications will satisfy the reviewer. Comment 1: Abstract - the final sentence concludes that the strong association with mortality infers a need for monitoring and policy to reduce polypharmacy. This implies a causal association which I do not believe is convincingly supported by the evidence presented. Response 1: Thank you for this feedback, that is a very good point. We understand that on the basis of our study, we cannot draw conclusions on causality. We have edited the abstract accordingly and hopefully to your satisfaction (Line 43-45). Comment 2: Methods - I am not familiar with the overlap weighting approach used, and I suspect many other readers will not be either. Could the authors expand on this a little, in terms of elaborating on what the benefits of this particular approach are, without the reader needing to resort to reading the references given? Response 2: The overlap weighting approach is a relatively new approach – or at least it is not widely used yet. So in that regard, we agree that the description of this method could be expanded. The paragraph on this topic (p. 8, lines 153-159) has been edited according to your feedback. Comment 3: Results - The presentation of prevalence over time is, at least initially, confusing - I was left trying to work out why the prevalence drops to 2.4 from a mean of 3.5 in 2013. I was relieved that the discussion concurred with my own conclusions, in that the later years represent younger people entering the study. However, it did make me wonder how useful this is - I would suggest that the analysis focuses on 2013 only in 2013. Response 3: By design, we look at prevalence at the time of inclusion and as we study polypharmacy in an open cohort, the age structure in the first year will be different than in the subsequent years. All people older than 65 years will enter in 2013, while only 65 year-olds will enter in the later years. To accommodate your point that it might be a bit confusing, we have added a note to the table (p. 14). Additionally, we have added an explanation in the results section (p. 11, lines 190-199) where we explain the difference in age structure and also share results from a descriptive analysis of the mean medication use and prevalence among the 65 year-olds that were included in 2013. This analysis reveal that the mean medication use were 2.4, while 18.6% had polypharmacy and 2.5% had excessive polypharmacy at the time of inclusion. This additional analysis therefore shows that the 65 year-olds in 2013 do not differ from the 65 year-olds included in 2014-2017. We hope that this addition will be satisfactory. Comment 4: Results - The presentation of polypharmacy incidence is very nice, given this is not well reported. As is acknowledged by the authors, the 2013 values are less interpretable, and I wonder if tables 3 and 4 should focus on 2014-2017 only, dropping 2013 and changing the reference category accordingly. Response 4: Thank you for this comment, we are happy that we can report on the incidence of polypharmacy since – as you say – this is not well reported. We investigate incidence among people who were not exposed at the time of inclusion. Due to differences in the age structure as described in the previous response, individuals entering the study population in 2013 differs from individuals entering the study population in any of following years in terms of age. So by design, the differences in incidence rates observed in 2013 compared to the subsequent years are expected. Similar to our response to your previous comment, we have decided to make a note of this difference in Tables 3 and 4 on page 17 and 19. Moreover, to limit the effect of different age structures across the years we adjusted for age in the Cox regression model II (Table 3 and 4). The results show that when adjusting for age as well as sex and multimorbidity, the hazard of polypharmacy is not significantly different across the years of inclusion – only 2017 shows an increased hazard of transitioning into polypharmacy. We have emphasized this on page 25, line 324-327. Comment 5: Discussion: mortality and strengths/limitations sub-sections. The authors state "This strength makes the estimate ...the most reliable ... to describe the association between polypharmacy and mortality." I don't disagree that the association is clearly described, but I do think there are important points that are not considered. Firstly, severity of disease is not accounted for - people may have similar morbidities, but very different degrees of severity of those different morbidities, with severity thus being associated with both mortality and with polypharmacy. Clearly, most studies using routine data cannot readily account for severity as it is not captured in coded records. Nevertheless - this should be acknowledged here and in the strengths/limitations section (at present, the authors state "we may not have adjusted for all potential confounders" - severity is clearly one of these). Secondly, the authors appear to have only measured morbidity using a simply dichotomy (0/1 OR 2+ conditions) based on 47 chronic conditions. Why was there no adjustment for a more sophisticated measure of multimorbidity that accounted for different numbers, types and weightings of conditions? I apologies if this was done, in which case it should be made clearer. Thirdly, the association between polypharmacy and adverse outcome (hospitalisation) has been shown to vary with the degree of multimorbidity (pubmed.ncbi.nlm.nih.gov/24428591/) but no effect modification was considered here; this is worth discussion as one would expect a similar picture to be seen with mortality. Response 5: These are some very valuable considerations for the discussion of methods. We do agree with your argument that the severity of the morbidities are important in terms of the risk of being exposed to polypharmacy as well as the risk of dying. The severity of the disease constitute an indication for both. Our study is based on register data, which – as you also mention – unfortunately do not hold information about the severity of the disease. Nonetheless, it is an important point, which we have highlighted in the discussion line 415-419. Regarding your second point on our use of a binary morbidity variable based on 47 chronic conditions, we chose this purposefully. We were interesting in the exposure to multimorbidity defined as having at least two conditions at the same time. All of the conditions listed most often require drug therapy. And some of the conditions require therapy with multiple drugs. Intuitively, the risk of polypharmacy should be higher among those with multiple conditions. We actually did conduct the analysis with multimorbidity categorized as 0, 1, 2, 3, 4, and 5+. Unsurprisingly, the risk/hazard of being exposed to polypharmacy increased with a larger number of conditions. However, the interpretation of the results were difficult due to very high OR and HR. We decided that a simple binary measure of multimorbidity were better for interpretation. However, we do acknowledge that such a simplification has its limitations. We have elaborated on this in the discussion of strengths/weaknesses in line 419-422. In regards to your last comment, you make a very interesting point that multimorbidity may act as an effect modifier. We propose in the paper, that this is investigated in future research. Please see line 422-426. Comment 6: The conclusion states that the findings show "a potential for prevention of inappropriate polypharmacy". I disagree - the authors have made no attempt to quantify the appropriateness or otherwise of polypharmacy in the study. The assumption can certainly be made that much of the polypharmacy experienced by this cohort will be inappropriate, but no data is presented to support this argument. Similarly, the conclusion moves on to discuss prevention and reduce of polypharmacy (similar to the abstract) but the data do not support these arguments as a causal association cannot be assumed. The conclusion here, and in the abstract, should be toned down accordingly. Response 6: As for your first comment regarding our abstract, we do agree that make too strong conclusions based on the study that we conducted. We are fully aware that we can draw no conclusion on causality based on our study. Therefore, we have edited the conclusion accordingly and toned it down (lines 436-440). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0264332.r002
11 Jan 2022 Decision Letter - Omid Beiki, Editor PONE-D-21-15519R1Polypharmacy occurrence and the related risk of premature death among older adults in Denmark: A nationwide register-based cohort studyPLOS ONE Dear Dr. Pallesen, 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. Please submit your revised manuscript by Feb 25 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, Omid Beiki, M.D., Ph.D. 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: (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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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: No ****** 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 ****** 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: Thank you to the authors for addressing the points I raised. Although I still have some reservations over the manner in which the results are presented, I feel the clarifications that have been made help address these concerns. My only outstanding (minor) remark is the response to my comment 2 (methods). The response was generally fine, but the statement "limitations include that large weights are given for individual participants, large variability in the estimated treatment effect may be observed and bias" seems to be incomplete, although it may be simply a grammatical issue. I think it perhaps should read "limitations include that large weights are given for individual participants, large variability in the estimated treatment effect may be observed, and THERE MAY BE bias"? (if so, bias in what sense?) Or alternatively was the term "and bias" supposed to be deleted and the word "and" added prior to "although"? ****** 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:** Rupert Payne [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.0264332.r003
Revision 2
7 Feb 2022 Author Response Thank you so much for your positive feedback on the revised manuscript. Your suggestions have definitely helped us improve it. The one comment you give to our revised manuscript surely warrants some attention. We acknowledge that the word bias cannot be added without further explanation. We therefore propose another sentence to replace the one in question (p. 8, lines 155-158). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0264332.r004
9 Feb 2022 Decision Letter - Omid Beiki, Editor Polypharmacy occurrence and the related risk of premature death among older adults in Denmark: A nationwide register-based cohort study PONE-D-21-15519R2 Dear Dr. Pallesen, 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, Omid Beiki, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0264332.r005
Formally Accepted
11 Feb 2022 Acceptance Letter - Omid Beiki, Editor PONE-D-21-15519R2 Polypharmacy occurrence and the related risk of premature death among older adults in Denmark: A nationwide register-based cohort study Dear Dr. Pallesen: 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. Omid Beiki Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0264332.r006

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