Potentially inappropriate medication and attitudes of older adults towards deprescribing.

INTRODUCTION: Multimorbidity and polypharmacy are current challenges when caring for the older population. Both have led to an increase of potentially inappropriate medication (PIM), illustrating the need to assess patients' attitudes towards deprescribing. We aimed to assess the prevalence of PIM use and whether this was associated with patient factors and willingness to deprescribe.
METHOD: We analysed data from the LESS Study, a cross-sectional study on self-reported medication and on barriers and enablers towards the willingness to deprescribe (rPATD questionnaire). The survey was conducted among multimorbid (≥3 chronic conditions) participants ≥70 years with polypharmacy (≥5 long-term medications). A subset of the Beers 2019 criteria was applied for the assessment of medication appropriateness.
RESULTS: Data from 300 patients were analysed. The mean age was 79.1 years (SD 5.7). 53% had at least one PIM (men: 47.8%%, women: 60.4%%; p = 0.007). A higher number of medications was associated with PIM use (p = 0.002). We found high willingness to deprescribe in both participants with and without PIM. Willingness to deprescribe was not associated with PIM use (p = 0.25), nor number of PIMs (p = 0.81).
CONCLUSION: The willingness of older adults with polypharmacy towards deprescribing was not associated with PIM use in this study. These results suggest that patients may not be aware if they are taking PIMs. This implies the need for raising patients' awareness about PIMs through education, especially in females, in order to implement deprescribing in daily practice.

Background

An ageing population with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 long-term medications) poses a worldwide challenge to healthcare organisations, particularly in primary healthcare. As the prevalence of polypharmacy has increased due to high multimorbidity in especially the older population, potentially inappropriate medication (PIM) use has increased as well [1-3]. The single most important risk factor for PIM use is the number of prescribed medications [4]. Medications are considered ‘potentially inappropriate’ when its potential risk outweighs its clinical benefit in an individual [5]. Previous studies have reported a prevalence of PIMs between 40–80% [6-9]. Due to associated negative health consequences (e.g. reduced adherence and quality of life and increased risk of adverse drug reactions and hospitalizations), PIMs are an unnecessary burden to the older population [10-12].

Appropriate prescribing in the older population is challenging. First, older individuals have an increased risk of medication-related harm due to an age-related change in pharmacokinetics and -dynamics, a lower physiological reserve and drug-drug or drug-disease interactions [13-15]. Additionally, they are more susceptible to PIMs due to a lack of evidence regarding the benefits and harms of medications in multimorbid older adults and the frequently observed “prescribing cascade” where new medication is prescribed to treat a side effect of another medication [16]. Lastly, the application of single disease evidence-based guidelines to an individual with multimorbidity results in complex polypharmacy as they do not take into account potential drug- and disease-drug interactions [17,18].

The high prevalence and negative impact of PIMs, as well as the need to individualise therapy illustrates the importance of deprescribing in older individuals. Deprescribing is the process of withdrawal or dose reduction of inappropriate medications, supervised by a healthcare professional. This is endorsed by more recent guidelines, such as the NICE guidelines on multimorbidity and medication optimisation, that were developed to reduce polypharmacy and PIMs by recommending approaches on how to best manage and optimise pharmaceutical treatment in complex older adults [19,20].

Currently, deprescribing tools that assist physicians in detecting PIMs are increasingly being applied in daily practice. An example is the AGS Beers criteria, which is a globally used tool that lists PIMs that should be avoided in most older adults due to increased risk of harm or low/no benefit. Deprescribing can have a considerable positive impact on the health status and treatment burden of the older multimorbid population [21]. It may reduce adverse drug reactions, improve patients’ quality of life and promote medication adherence [22-24]. Understanding patients’ attitudes towards their medications and deprescribing can inform patient-centered care which is a key part of all clinical care [18].

Patients beliefs and attitudes towards deprescribing have increasingly been investigated [1,25-30], but whether these are correlated with appropriateness of their medications has not yet been determined. So far, quantitative research has mostly reported patients’ and clinicians’ attitudes towards deprescribing and investigated its relationship with patient-related factors (such as age). To date, the only medication-related factor that the revised Patients’ Attitudes Towards Deprescribing questionnaire (rPATD) has been related with is the number of prescribed medications, with studies finding inconsistent results. It is not yet known how attitudes towards deprescribing may be related to the suitability of that individual for deprescribing (i.e. whether they are taking a PIM). We hypothesized that patients who use PIMs experience more side effects than patients who do not use any PIMs, which in turn might affect their willingness to deprescribe.

In this study, we investigated whether there is an association of PIM use and willingness to deprescribe in older individuals and which factors influence patients’ attitudes towards deprescribing. Second, we were interested to see how prevalent PIM was in a population of older patients with polypharmacy and which types of PIMs were most commonly used in men and women.

Methods

Design

The current study was nested in the LESS Study [31], which is a cross-sectional anonymous survey-study that evaluates the overall willingness to deprescribe and the barriers and enablers towards the willingness to deprescribe in older Swiss individuals with multimorbidity and polypharmacy. This manuscript reports the results of patients’ attitudes towards deprescribing related to PIMs.

Study population

Sixty-four general practitioners (GPs) from the German-speaking part of Switzerland recruited primary care patients for involvement in this study. All of them were located in different GP offices. Eligible patients were ≥70 years old with multimorbidity and polypharmacy. Multimorbidity was defined as the presence of ≥3 chronic diseases, with chronic diseases being present for at least six consecutive months [32]. Polypharmacy was defined as the concurrent use of ≥5 long-term medications [33,34]. GPs were instructed to consecutively screen eligible patients and recruit 5 participants, reporting the number of patients screened, to reduce the risk of selection bias. The questionnaire was completed by a total of 306 patients, 6 of whom were excluded based on missing information about prescribed medication. Patients anonymously filled in the survey and handed it back to the practice nurse to limit the chance of social desirability bias.

Questionnaire

For this study, we used data from 300 questionnaires on demographic status like age, gender, living situation, help with medication intake, involvement in medication self-management and education level. As for willingness to deprescribe, we used data from the revised Patients’ Attitudes Towards Deprescribing questionnaire (rPATD). This is a validated and reliable tool that has been applied in multiple studies [1,35-38]. It contains 22 questions on a 5-point Likert scale, ranging from “strongly agree” to “strongly disagree” which relate to beliefs and attitudes about their medications and deprescribing [37]. The rPATD was translated into German as previously described [31].

Medication appropriateness

In the present study, we used the self-reported list of prescribed medications and medication dosages for the assessment of PIMs. Self-reported medication is proven accurate and valid for long-term medication in the general population [39,40] and was chosen in this case to specifically focus on which medications patients report they take. The self-reported medication list was checked for inconsistencies (e.g. spelling errors) before analysis of PIMs was performed. In case of uncertainty regarding self-reported medication (e.g. due to poor or unreadable handwriting), in consultation with a GP researcher, the best applicable option was chosen [41]. Next, each medication was coded according to the WHO ATC-coding system. For the assessment of medication appropriateness, a selection of the AGS Beers 2019 criteria was used [42]. The AGS Beers list is the most commonly used tool for assessment of PIMs worldwide [43]. Since data on medical conditions was limited in this study, we used only the criteria that were applicable without clinical information (52 of 97 criteria). A list of the included criteria is added in S1 Appendix. Criteria were excluded based on weak strength of evidence as defined in the AGS Beers list (n = 8) or lack of information (n = 37). Application of a subset of the Beers 2019 criteria is in line with previous studies that used subsets of the Beers criteria for assessing medication appropriateness [29,44-46].

Willingness to deprescribe

Our main outcome was the willingness to deprescribe in relation to medication appropriateness. We therefore analysed data from the rPATD where patients were asked if they are satisfied with their current medications and if they are willing to deprescribe if their doctor said it was possible, along with 20 other questions grouped into four factors: involvement, burden, appropriateness and concerns about stopping, as described elsewhere [1].

Ethics

Ethical approval for this study was obtained from the Ethics Committee of the Canton of Bern, Switzerland (Ref. 2017–02188). All patients provided written informed consent before participating in the study.

Statistical analysis

Before the analysis, consistency checks were performed on the complete data set including the AGS Beers criteria and uncertainties were resolved by consensus of two researchers. Descriptive results were presented in frequencies, proportions, means and standard deviations (SD), and 95% confidence intervals (CI) were appropriate. Hypothesis testing for categorical variables was done using Chi-squared tests and simple linear regression for continuous variables when normally distributed. Patients with at least one PIM in their medication list where grouped to ‘PIM yes’, all others to ‘PIM no’ (exposure).

The individual scores (n = 22) of the rPATD showed a non-normal distribution. For the multivariate model we therefore dichotomized each of the 5-point Likert questions as well as factor scores according to the median as done previously [1]. Individual scores equal to or higher than the median were placed in the “high score” group, whereas scores below the median were placed in the “low score” group. In a multivariate model with different components of the rPATD as the outcome (satisfaction, willingness to stop, involvement, burden, appropriateness, concerns about stopping) [1], we calculated odds ratios (OR) and adjusted for age, gender and number of medications. To account for possible clustering of answers from patients from the same GP, we chose a mixed-effects model with the individual GP as random-effects. In a sensitivity analysis, we repeated the same models but with number of PIMs as the exposure instead of PIM yes vs. no. Significance level was set at <0.05. Data analyses were performed using STATA version 15.2 (Stata Corp, College Station, TX, USA).

Results

For the overall analysis of polypharmacy levels and PIM, 300 participants were included, collectively taking approximately 2700 medications. Seventy-eight percent of all participants used 5–9 regular medications, with the remaining 22% using ≥10 medications (excessive polypharmacy). Participants received on average 8 medications (SD 2.7). More than half of our sample (54%) received at least 1 PIM. The majority received 1 PIM (31.3%), 12.7% received 2 PIMs and 9.7% received ≥3 PIMs up to 7 PIMs. Gender distribution was approximately even, and participants had a mean age of 79.1 years (SD 5.7). The baseline characteristics of participants in each group (no PIM, 1 PIM and >1 PIM) are presented in Table 1. Age, living situation, medication self-management and education level did not significantly differ between participants receiving appropriate medication or PIM. We did, however, find an association of females having more PIM (p = 0.007) than men. Additionally, an association was found between a higher number of prescribed medications and PIMs (p = 0.002). Thus, patients receiving 10 or more medications (i.e. excessive polypharmacy) showed a significantly higher risk of taking PIMs (Table 1).

Table 1

Baseline characteristics of participants stratified by medication appropriateness.

Baseline characteristics	Overalln = 300	No PIMn = 139 (46%)	1 PIMn = 94 (31%)	>1 PIMn = 67 (22%)	p-valuea
Female, n %	139 (46)	55 (40)	42 (45)	42 (63)	0.007
Age, mean (SD)	79.1 (5.7)	79.0 (5.5)	78.9 (6.0)	79.5 (6.0)	0.61
Living alone, n %	100 (34)	49 (36)	27 (29)	24 (36)	0.48
Self-management of medication, n %	257 (86)	120 (87)	83 (88)	54 (82)	0.48
Education level, n %					0.33
Basic education	86 (29)	34 (24)	28 (30)	24 (36)
Apprenticeship	146 (49)	68 (49)	49 (52)	29 (43)
Higher education	68 (23)	37 (27)	17 (18)	14 (21)
Number of medicines, mean (SD)	8.0 (2.7)	7.4 (2.3)	7.8 (2.4)	9.4 (3.5)	<0.001
5–9 medicines	233 (78)	117 (84)	74 (79)	42 (63)
≥10 medicines	67 (22)	22 (16)	20 (21)	25 (37)	0.002

Abbreviations: SD, standard deviation; PIM, potentially inappropriate medication.

ap-value is significant at <0.05.

Fig 1 illustrates the proportion of participants who agreed to the individual questions about satisfaction with treatment and willingness to deprescribe and the proportion of participants with high factor scores stratified by PIM. The majority of participants were satisfied with their current medications (97.1% without PIM vs. 96.9% with PIM; p = 0.90) and were willing to have one or more of their medications deprescribed (74.3% without PIM, 79.9% with PIM; p = 0.25). From the four factor scores, we found more participants with PIM had high burden scores (61% vs. 49%; p = 0.029) and less had high concerns about stopping scores (53% vs. 65%; p = 0.034). The table in S2 Appendix provides more detail about the rPATD factors as shown in Fig 1. However, in the adjusted model the only association remaining was concerns about stopping which was significantly lower in patients with PIM compared to those without PIM (OR 0.55; 95%CI 0.33–0.92; p = 0.023). Moreover, this association disappeared in the sensitivity analysis where number of PIMs was the exposure instead of PIM yes vs. no (OR 0.86; 95%CI 0.69–1.09; p = 0.21).

Fig 1

Proportion of participants who agreed to the individual questions about satisfaction with treatment and willingness to deprescribe and the proportion of participants with high factor scores stratified by PIM.

Involvement, burden, appropriateness and concerns about stopping are factor scores from the rPATD questionnaire [25]. Each of the four factors consisted of 5 questions of which the possible score ranged from 1–5. We grouped the answers of each patient to either ‘yes’ (if the factor score was higher than the median) or ‘no’ (if the factor score was lower than the median). We then calculate the proportion of patients answering “yes”. Abbreviations: PIM, potentially inappropriate medication; rPATD, revised patients’ attitudes towards deprescribing. p-value is significant at <0.05.

The level of agreement to all individual rPATD questions for participants with PIM as compared to participants without PIM is presented in Table 2. There was a statistically significant difference in the proportion of participants who agreed with the question, “If my doctor recommended stopping a medicine I would feel that he/she was giving up on me” in participants taking ≥1 PIM compared to those without PIM (OR 0.49; 95%CI 0.29–0.82); p = 0.006). In the sensitivity analysis with number of PIMs as the exposure, the association became weaker (OR 0.80; 95%CI 0.62–1.02; p = 0.07).

Table 2

Level of agreement to deprescribing in patients with PIM compared to patients without PIM.

rPATD questionsa	Odds ratiob for PIM vs no PIM	95% CI	p-valuec
“Overall, I am satisfied with my current medicines”	1.06	0.25–4.45	0.93
“I like to be involved in making decisions about my medicines with my doctors”	1.22	0.68–2.21	0.51
“I have a good understanding of the reasons I was prescribed each of my medicines”	1.34	0.79–2.29	0.28
“I like to know as much as possible about my medicines”	1.01	0.61–1.65	0.98
“I always ask my doctor, pharmacist or other health care professional if there is something I don’t understand about my medicine”	1.13	0.68–1.89	0.63
“I know exactly what medicines I am currently taking, and/or I keep an up to date list of my medicines”	1.10	0.55–2.18	0.79
“If my doctor said it was possible I would be willing to stop one or more of my regular medicines”	1.60	0.87–2.94	0.13
“I feel that I am taking a large number of medicines”	1.37	0.81–2.30	0.24
“Taking my medicines every day is very inconvenient”	0.89	0.51–1.54	0.67
“I spend a lot of money on my medicines”	0.91	0.54–1.53	0.72
“Sometimes I think I take too many medicines”	1.21	0.73–2.01	0.46
“I feel that my medicines are a burden to me”	0.86	0.53–1.41	0.56
“I would like to try stopping one of my medicines to see how I feel without it”	0.85	0.51–1.40	0.51
“I would like my doctor to reduce the dose of one or more of my medicines”	1.18	0.72–1.92	0.52
“I feel that I may be taking one or more medicines that I no longer need”	1.47	0.91–2.38	0.12
“I believe one or more of my medicines may be currently giving me side effects”	1.14	0.68–1.92	0.61
“I think one or more of my medicines may not be working	0.94	0.13–7.08	0.95
“I have had a bad experience when stopping a medicine before”	0.60	0.35–1.03	0.06
“I would be reluctant to stop a medicine that I had been taking for a long time”	0.71	0.43–1.15	0.16
“If one of my medicines was stopped I would be worried about missing out on future benefits”	0.77	0.48–1.25	0.30
“I get stressed whenever changes are made to my medicines”	0.82	0.50–1.36	0.45
“If my doctor recommended stopping a medicine I would feel that he/she was giving up on me”	0.49	0.29–0.82	0.006

Abbreviations: rPATD, revised patients' attitudes towards deprescribing; PIM, potentially inappropriate medication; CI, confidence interval.

a from [25].

b Odds ratio is adjusted for age, sex, number of medicines and general practitioners.

c p-value is significat at <0.05.

Fig 2 lists types of PIMs according to the 2019 AGS Beers criteria and their frequency by gender. We found proton pump inhibitors and benzodiazepines to be among the most frequent PIMs in our sample. Additionally, we found that certain PIMs differed by gender. Benzodiazepines (p<0.001), nonbenzodiazepines (p = 0.003), combinations of ≥3 CNS-active drugs (p = 0.001) and opioids in combination with benzodiazepines (p = 0.004) were significantly more frequent in females compared to males. Other drugs differed by gender as well including (peripheral alpha-1 blockers and estrogens).

Fig 2

Potentially inappropriate medication stratified by gender.

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; CNS, central nervous system. p-value is significant at <0.05.

Discussion

Summary

In this study, we found PIM to be prevalent (54%) in a consecutive sample of older patients with multimorbidity and polypharmacy in a primary care setting. PIM use was found to be higher in patients with more prescribed medications compared to less. Interestingly, females were more frequently prescribed a PIM, mostly benzodiazepines or other CNS-active drugs, than males. We observed no difference in patients’ attitudes and willingness to deprescribe in patients with or without PIM. Our findings suggest that willingness to deprescribe is equally high in patients with and without PIM. There was also no difference in the adjusted analysis in burden, appropriateness or involvement factor scores, but participants taking PIM had lower concerns about stopping. This may therefore indicate that older adults with polypharmacy are not aware of whether they are taking potentially inappropriate medications or not. Therefore, efforts to increase awareness of the concept of PIM may be beneficial to shared-decision making about deprescribing in regular practice. Our study has also highlighted some areas that could be targeted, such as long term use of benzodiazepines in females.

Comparison with existing literature

The proportion of participants receiving at least one PIM matches previous studies from several countries worldwide, which generally report prevalence’s between 40 and 80% [6-9,47]. We demonstrated that patients receiving 10 or more medications show a significantly higher risk of PIMs. This confirms findings from previous studies that the number of medications is the most important risk factor for PIMs [4,8,48]. Furthermore, we detected a correlation between gender and prevalence of PIMs. It has been previously reported that females receive a higher number of PIMs on average than males [7,47-50]. It has been suggested that this might be due to females being at a higher risk for developing multiple chronic conditions compared to males. This would imply that they are more susceptible to drug-drug and drug-disease interactions, which challenges appropriate prescribing [47]. Yet, the actual reason for this gender-difference is unknown. Similar to previous studies internationally [29,51], proton-pump inhibitors and benzodiazepines were the most common PIMs identified in our study population.

Interestingly, we found that patients’ reported willingness to deprescribe is not related to PIM use according to the 2019 AGS Beers criteria. As investigated in a recent study on PIM and deprescribing interventions that explored factors associated with deprescribing refusal, likewise, PIM use was not associated with acceptance or refusal of deprescribing [29]. Previous qualitative studies on deprescribing, have reported that patients generally lack knowledge of the potential harms of medications and rely on the GP as a central and prominent figure in decision-making [52,53]. These findings suggest that older adults are not aware of whether their medications are appropriate or not. Reported willingness to deprescribe was equally high in our participants with and without PIM. Furthermore, very few of the individual factors had evidence to support a relationship with the use of PIMs, which stems from the fact that the study might not have been sufficiently powered to detect such differences. The factors ‘burden’ and ‘concerns about stopping’ were associated in the unadjusted analyses, but the burden association was lost in the adjusted analyses (likely because of the confounding nature of PIMs being associated with number of medications). Therefore, it is still unclear if and how use of inappropriate medications influences attitudes and beliefs or vice versa. The overall high willingness of older adults with polypharmacy to deprescribe is promising for further implementation of deprescribing in primary healthcare and is in line with prior studies investigating patients’ attitudes towards deprescribing [1,25-30].

Limitations and strengths

We acknowledge several limitations in our study. First, we gathered information on prescribed medications through self-reported medication lists, which might have affected the completeness of the medication lists. The accuracy of self-reported medication data can vary with medication type and duration; with self-reporting generally being more accurate for long-term medications [39,40]. Specifically, certain medication categories (e.g. psychoanaleptics and analgesics) were previously found to be less reliably self-reported [40]. Therefore, by using self-reported medication lists in this study, our results may be an underestimation of the use of PIMs. Second, the prevalence of PIMs in our sample might be underestimated due to the limited generalizability of the Beers criteria, published by the American Geriatrics Society, as they are based on medications commonly prescribed in the United States. Additionally, the Beers criteria capture ‘potentially’ inappropriate medications and so the assessment of appropriateness is not individualised. Third, the recruitment of study participants by GPs could have introduced selection bias. However, since consecutive sampling was used for participant inclusion–as it was not possible to recruit a random sample–the risk of selection bias was minimised. Lastly, since our sample consisted of Swiss older patients, we do not know if our findings are generalizable to other populations. However, as other countries reported similar attitudes towards deprescribing (e.g. 88% willingness to deprescribe in Australia [1], 89% in Italy [25] and 92% in the USA [27]) this increases the confidence in our findings.

To the best of our knowledge, we were the first to investigate the relation between medication appropriateness and patients’ willingness to deprescribe using validated tools. The Beers criteria is the most widely used tool for medication appropriateness and has proven to be accurate in the assessment of PIM [42,43]. The Beers 2019 version is updated according to the latest evidence and includes drug-drug interactions when assessing PIMs. Lastly, we used the rPATD questionnaire, which is validated and has been used internationally to assess willingness to deprescribe [37,54]. We followed international standards with independent forward and back translation to translate the rPATD into German.

Implications for future practice and research

Although we did not detect an association of PIM and willingness to deprescribe, we did see positive trends of patients on PIM towards, for instance, the perception of having more side effects (14%) and taking medication they no longer need (47%). However, since willingness to deprescribe is equal, this implies that patients’ willingness does not seem to be driven by knowledge that they are on a PIM. This again indicates the need to raise awareness about PIMs in older patients with polypharmacy, especially in females. Clinicians should be encouraged to regularly discuss deprescribing and the fact that the risks and benefits of medication use can change over time. Currently, patient education materials are increasingly being developed that will likely add to patients understanding of PIMs [55]. However, the group most at risk for PIM are vulnerable (oldest-) old patients [13-15] that demonstrate highly varying care wishes and needs, thereby challenging clinicians to provide appropriate care. Hence, in addition to our main finding–medication appropriateness being independent of patients’ willingness to have medication deprescribed–this pleads for an even bigger role of shared decision-making in the deprescribing process.

Future studies should further investigate the relationship between enabling factors of deprescribing and medication appropriateness and whether patients’ attitudes and beliefs about medications may change with education [56]. Furthermore, they should focus on what patients consider inappropriate medication and which medications they would be willing to stop. Specific questions about patients’ awareness about PIMs should be included in future research. As we found PIMs to be more prevalent in females compared to males, gender specific causes of PIM should be assessed in future studies. We also suggest focusing on specific classes and/or categories of medications in future research into PIM and willingness to deprescribe as this has not yet been explored and could be informative for translating into practice. Lastly, future studies should apply multiple PIM assessment tools, as well as comprehensive medication reviews determining actual appropriateness.

Conclusion

We found PIM to be prevalent in the older population and patients to be generally willing to deprescribe. Patients’ willingness to deprescribe was found to be irrespective of whether they were taking one or more PIMs. Female gender and increasing number of prescribed medications were positively associated with PIM use. Our results imply that it is necessary to raise awareness among older patients on PIMs, especially in females.

(XLS)

Click here for additional data file.

List of included Beers 2019 criteria.

(TIF)

Click here for additional data file.

Results of the rPATD factor scores.

(TIF)

Click here for additional data file.

14 Jul 2020

PONE-D-20-16955

Potentially inappropriate medication and attitudes of older adults towards deprescribing

PLOS ONE

Dear Dr. Streit,

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 August 15, 2020. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Christine Leong, Pharm. D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This study was sponsored with a grant (PI Prof. S. Streit) from the Swiss Society of General Internal

Medicine (SGAIM) Foundation.

ER is supported by a NHMRC-ARC Dementia Research Development Fellowship."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"This study was funded with a grant (PI Prof. S. Streit) by the Swiss Society of General Internal Medicine (SGAIM). "

[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: Yes

**********

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

Reviewer #1: I Don't Know

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: No

**********

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: No

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: General Comment: From the way the article is written, these authors appear to have assumed that patients are likely to be aware of the PIMs that they are taking. I am very surprised by this assumption. My surprise is compounded when I read this statement in the article's "Comparison with existing literature" section: "This is in line with previous qualitative studies on deprescribing, showing that patients generally lack understanding of potential harms of medicines and showing the GP as a central and prominent figure in decision-making when it comes to deprescribing." So they evidently knew of this to begin with. Because of this, I struggle with their overall framing of the paper.

Nonetheless, the paper makes a useful, modest contribution. They show that people are generally willing to consider deprescribing, and that patients need to be better informed about their medications. They also show that the PIM situation applies more to women than men.

I also think that their hypothesis could in fact be investigated with a revised design, perhaps along the following lines. First, identify a population of older patients who are on PIMs. Second, tell them they are on a PIM. Third, propose deprescribing. Record the response. Then explain the PIM, then propose again and record the response, and compare.

Specific Points to Address:

1. Method section of abstract. Statement should read "...towards the willingness to deprescribe..."

2. First sentence of the "Study population" section is incoherent.

3. Sixth line under "Medication appropriateness", parenthesis should be "poor or unreadable"

4. Same line, "...in team with...": replace "team" with "consultation" of "collaboration".

5. Results section, near top of page 9, "feeling less given up [on] by their physician..." -- ie insert "on"

6. First line of conclusion should be "...generally willing to deprescribe."

Reviewer #2: Thank you for the opportunity to review this manuscript, which reports a study of attitudes towards deprescribing and potentially inappropriate medicines in older adults with multimorbidity and polypharmacy. This paper is well written, and investigates an important, worthwhile and novel question. I have a number of minor comments and requests for clarifications that I hope will improve this already high quality paper.

Background

1. For the sentence "It can reduce the number of side effects, improve patients’ quality of life and promote medication adherence." - this is logical and supported by the evidence for polypharmacy/PIMs' impact on these outcomes. However perhaps any studies that have shown deprescribing impacts on these could be referenced, or the sentence changed to "It may reduce...".

2. The reference to assessment of PIM and deprescribing as "cornerstones" of primary healthcare could be revised. Although their importance may be well recognised, as you suggest their implementation is not optimal.

Methods

3. The Study population section refers to 64 GPs recruiting. Were these all from difference general practices/primary care centres?

4. The same sentence refers to "the German part of Switzerland". Is this the most appropriate description, or would "German-speaking part" be better instead?

5. The same section states "GPs were instructed to consecutively screen and select all eligible patients in a defined timeframe (e.g. 2 weeks)". Can you please clarify was this period the same for all GPs or how was the timeframe defined on an individual basis e.g. was this until a certain number of patients had accrued?

6. In the Medication appropriateness section, there is a sentence on the accuracy of self-report medication. While this is generally true, there are cases from the two studies referenced (and the literature as a whole) of medications with poorer agreement, such as psycholeptics and analgesics. This has implications given these medications feature often in the Beers criteria. I feel this should be expanded on here, and in the study limitations section.

7. It would be helpful to provide a list of the included 52 criteria in the appendix. Also, the "description of the method for counting of medicines" does not actually seem to be included in Appendix 1 at the moment.

Results

8. The sentence "We did, however, find an association of females having more PIM (p=0.007) than men with increasing numbers of PIM." is somewhat unclear and could benefit from rephrasing.

9. Again, reference to "...patients with PIM feeling less given up by their physician" is a little unclear. Perhaps something such as the following may be clearer: "...patients with PIM agreeing less that they felt their physician was giving up on them".

Discussion

10. The Discussion states "Furthermore, very few of the individual questions and factor scores were related with PIM use." It may be worth considering if the study was sufficiently powered to detect such differences. This could be acknowledged by rephrasing that very few of the individual questions and factor scores had evidence to support a relationship with PIM use.

11. The sentence beginning "Patients seem to not..." could be rephrased to say "Our findings suggest that patients seem to not...", just to clarify that this wasn't specifically investigated in this study.

Table 1.

12. I would suggest relabeling the <9 medicines categories to 5-9 medicines to re-emphasise that all patients were on at least 5 medicines.

Appendix 1

13. In the table titled "Results of the rPATD factor scores", it's unclear exactly what the % in the PIM/no PIM columns refer to, and the medians/IQRs. Could these be elaborated on in the table title, or in the table legend?

**********

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: James Conklin

Reviewer #2: Yes: Frank Moriarty

[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.

31 Aug 2020

Dear Dr Leong, dear PLOS ONE Editorial Board,

We were invited to submit a revised version of our manuscript:

“Potentially inappropriate medication use and attitudes of older adults towards deprescribing”

We are very pleased to accept the opportunity to revise and resubmit a revised version of this manuscript and would like to thank you for this chance.

As both reviewers’ comments and suggestions were very valuable, we were happy to im-plement them and feel that they have improved the overall quality of the manuscript.

We wrote a response to the reviewers that is attached below, answering every comment point-by-point. With that, we hope to have sufficiently answered and implemented all ques-tions, suggestions and comments.

We dearly hope to have made the necessary adaptations for convincing you to accept our submission. Again, we want to express our gratitude for the opportunity to improve our manuscript with the relevant and valuable input from the reviewers.

Yours sincerely,

Sven Streit

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, includ-ing those for file naming. 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

Response: Thank you for this reminder. We adapted our manuscript accordingly.

- We changed

o all headings of major sections to bold type 18pt font

o all sub-sections of major sections into bold type 16pt font

o the citing figures from “Figure 1” to Fig 1

o the referencing from . (xx) to [xx].

- We put tables directly after the paragraph in which they are first cited

- We inserted figure captions directly after the paragraph in which they are first cited

2. Thank you for stating the following in the Acknowledgments Section of your man-uscript:

"This study was sponsored with a grant (PI Prof. S. Streit) from the Swiss Society of General Internal Medicine (SGAIM) Foundation.

ER is supported by a NHMRC-ARC Dementia Research Development Fellowship."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submis-sion form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "This study was funded with a grant (PI Prof. S. Streit) by the Swiss Society of General Internal Medicine (SGAIM). "

Response: We removed both sentences from the acknowledgement section of the manuscript.

We would like to update the Funding statement to: “This study was funded with a grant (PI Prof. S. Streit) by the Swiss Society of General Internal Medicine (SGAIM). ER is support-ed by a NHMRC-ARC Dementia Research Development Fellowship.”

Reviewer 1

Response: We thank the reviewer for the comments and suggestions on our paper. We have implemented them in our manuscript, as described in the point-by-point response below.

1. From the way the article is written, these authors appear to have assumed that pa-tients are likely to be aware of the PIMs that they are taking. I am very surprised by this assumption. My surprise is compounded when I read this statement in the arti-cle's "Comparison with existing literature" section: "This is in line with previous qualitative studies on deprescribing, showing that patients generally lack understand-ing of potential harms of medicines and showing the GP as a central and prominent figure in decision-making when it comes to deprescribing." So they evidently knew of this to begin with. Because of this, I struggle with their overall framing of the paper.

Response: Thank you for this comment. We have revised the manuscript to make it more explicit about our hypothesis (page 4). We hypothesized that people with PIM are experienc-ing more side effects, especially when using multiple PIMs simultaneously. Therefore, we thought that this could positively influence their willingness to deprescribe, as we can imag-ine that having many or worse side effects can drive the will to stop medication. So we did not necessarily assume that patients are likely to be aware of the PIMs that they are taking, but we assumed that, indirectly, (the number of) PIMs would influence patients’ willingness to have medication deprescribed due to a presumably higher number of side effects or severe side effects. We have added the following sentence to the manuscript to briefly summarize this: “We hypothesized that patients who use PIMs, irrespective of whether the medication they use are potentially inappropriate, experience more side effects than patients who do not use any PIMs, which in turn might affect their willingness to deprescribe” (page 4).

2. I also think that their hypothesis could in fact be investigated with a revised design, perhaps along the following lines. First, identify a population of older patients who are on PIMs. Second, tell them they are on a PIM. Third, propose deprescribing. Rec-ord the response. Then explain the PIM, then propose again and record the response, and compare.

Response: Thank you for your comment. We agree that the design you mentioned could be used to investigate the same hypothesis that we addressed in our manuscript. We chose to conduct a cross-sectional study since we could use data collected during the LESS-study as mentioned in our methods section. We will keep your suggestions in mind when working on future research projects to further examine the association between the use of potentially in-appropriate medications and patients’ willingness to deprescribe.

3. Specific Points to Address:

1) Method section of abstract. Statement should read "...towards the willingness to deprescribe..."

2) First sentence of the "Study population" section is incoherent.

3) Sixth line under "Medication appropriateness", parenthesis should be "poor or unreadable"

4) Same line, "...in team with...": replace "team" with "consultation" of "collabora-tion".

5) Results section, near top of page 9, "feeling less given up [on] by their physician..." -- ie insert "on"

6) First line of conclusion should be "...generally willing to deprescribe."

Response: Thank you for highlighting these typos. We corrected all of them.

Reviewer 2:

Response: We thank the reviewer for the helpful comments on our paper. We address the comments individually in our point-by-point response below.

1. Background: For the sentence "It can reduce the number of side effects, improve patients’ quality of life and promote medication adherence." - this is logical and sup-ported by the evidence for polypharmacy/PIMs' impact on these outcomes. However perhaps any studies that have shown deprescribing impacts on these could be refer-enced, or the sentence changed to "It may reduce...".

Response: Thank you for highlighting this. As suggested, we have changed the sentence to “It may reduce…” (page 4).

2. Background: The reference to assessment of PIM and deprescribing as "corner-stones" of primary healthcare could be revised. Although their importance may be well recognised, as you suggest their implementation is not optimal.

Response: Thank you for your comment. We agree with it, and thus we removed this part.

3. Methods: The Study population section refers to 64 GPs recruiting. Were these all from difference general practices/primary care centres?

Response: The 64 GPs that recruited patients for the LESS study were all practicing in dif-ferent general practices.

4. Methods: The same sentence refers to "the German part of Switzerland". Is this the most appropriate description, or would "German-speaking part" be better in-stead?

Response: We changed it into “the German-speaking part of Switzerland” (page 5).

5. Methods: The same section states "GPs were instructed to consecutively screen and select all eligible patients in a defined timeframe (e.g. 2 weeks)". Can you please clarify was this period the same for all GPs or how was the timeframe defined on an individ-ual basis e.g. was this until a certain number of patients had accured?

Response: All GPs were asked to consecutively recruit 5 study participants and to document the screening process of all eligible participants. We have adapted the text in the manuscript accordingly to reflect the information from our study protocol because the mentioning of "e.g. 2 weeks" was an example if a GP chose to define his time frame to this lenght knowing the population they take care for. The text now reads: “GPs were instructed to consecutively screen 5 eligible patients and to report the number of patients screened throughout the screen-ing process, to reduce the risk of selection bias.” (page 5).

6. Methods: In the Medication appropriateness section, there is a sentence on the ac-curacy of self-report medication. While this is generally true, there are cases from the two studies referenced (and the literature as a whole) of medications with poorer agreement, such as psycholeptics and analgesics. This has implications given these medications feature often in the Beers criteria. I feel this should be expanded on here, and in the study limitations section.

Response: Thank you for your comment. We do believe you address a very relevant topic and want to elaborate on that. It is indeed mentioned in some of the literature that specific drug categories are poorer self-reported. We are very much aware of the limitations that ac-company the use of self-reported data on medication intake. We have revised the limitation section of the manuscript accordingly (page 12 and 13).

7. Methods: It would be helpful to provide a list of the included 52 criteria in the ap-pendix. Also, the "description of the method for counting of medicines" does not ac-tually seem to be included in Appendix 1 at the moment.

Response: Thank you for your comment. We agree that it might be useful for the reader to have a list of included criteria and therefore, we added a list of the 52 included Beers criteria in Appendix 1. We removed the description of the method for counting of medicines from the appendix.

8. Results: The sentence "We did, however, find an association of females having more PIM (p=0.007) than men with increasing numbers of PIM." is somewhat un-clear and could benefit from rephrasing.

Response: We have changed the sentence to: “We did, however, find an association of fe-males using more PIMs (p=0.007) than men, as well as females using more PIMs simulta-neously (page 8).

9. Results: Again, reference to "...patients with PIM feeling less given up by their physician" is a little unclear. Perhaps something such as the following may be clearer: "...patients with PIM agreeing less that they felt their physician was giving up on them".

Response: Thank you for your comment. We decided to revise the entire sentence and re-moved the part of the sentence that was unclear.

10. Discussion: The Discussion states "Furthermore, very few of the individual ques-tions and factor scores were related with PIM use." It may be worth considering if the study was sufficiently powered to detect such differences. This could be acknowl-edged by rephrasing that very few of the individual questions and factor scores had evidence to support a relationship with PIM use.

Response: Thank you for this suggestion. We have replaced the sentence by: “very few of the individual factors had evidence to support a relationship with the use of PIMs, which stems from the fact that the study might not have been sufficiently powered to detect such differences” (page 11).

11. Discussion: The sentence beginning "Patients seem to not..." could be rephrased to say "Our findings suggest that patients seem to not...", just to clarify that this wasn't specifically investigated in this study.

Response: We have decided to remove this sentence from the discussion, so it is no longer necessary to make an adjustment.

12. Table 1: I would suggest relabelling the <9 medicines categories to 5-9 medicines to re-emphasise that all patients were on at least 5 medicines.

Response: We have adapted the manuscript text accordingly.

13. Appendix 1: In the table titled "Results of the rPATD factor scores", it's unclear exactly what the % in the PIM/no PIM columns refer to, and the medians/IQRs. Could these be elaborated on in the table title, or in the table legend?

Response: Thank you for highlighting this. We have added further explanations to the figure 1 legend. We have added the following information to the figure legend: “Involvement, bur-den, appropriateness and concerns about stopping are factor scores from the rPATD ques-tionnaire. (39) Each of the four factors consisted of 5 questions of which the possible score ranged from 1-5. We grouped the answers of each patient to either ‘yes’ (if the factor score was higher than the median) or ‘no’ (if the factor score was lower than the median). We then calculate the proportion of patients answering “yes”.” (page 9).

22 Sep 2020

PONE-D-20-16955R1

Potentially inappropriate medication and attitudes of older adults towards deprescribing

PLOS ONE

Dear Dr. Streit,

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 Nov 06 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Christine Leong, Pharm. D.

Academic Editor

PLOS ONE

[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 #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 #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: Thank you for the responses to my review. I feel they have addressed the majority of issues.

1. Thank you for the clarification that each GP was in a different practice/clinic. This should be added to the Methods section.

2. Regarding screening, the newly inserted sentence says GPs were instructed to consecutively screen 5 eligible patients. Should this be "to consecutively screen eligible patients and recruit 5 participants, reporting the number of patients screened..."?

3. The new legend that was intended for Figure 1 appears to have been inserted below the Figure 2 title in error.

4. Two revisions to the manuscript mentioned in the response letter have not actually been included in the manuscript (they have been inserted and then deleted in the tracked changes version). These related to hypothesising patients using PIMs were more likely to experience side effects in the Introduction, and that the study may not have been powered for examining individual questions in the Limitations. I feel these are both important and warrant inclusion.

5. The proposed addition relating to the hypothesis may warrant rephrasing as it is contradictory as is : "We hypothesized that

patients who use PIMs, irrespective of whether the medication they use are potentially inappropriate, experience...". Should the part beginning irrespective refer to the number of medications they use, or simply be removed?

**********

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: Yes: Frank Moriarty

[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.

25 Sep 2020

Recipient

Christine Leong, Pharm. D.

Academic Editor

PLOS ONE

Revision of manuscript ID: PONE-D-20-16955

Dear Dr Leong, dear PLOS ONE Editorial Board,

We were invited to submit a revised version of our manuscript:

“Potentially inappropriate medication use and attitudes of older adults towards deprescribing”

We accepted the opportunity to revise and resubmit a revised version of this manuscript and we would like to thank you for this opportunity.

We wrote a response to the reviewer’s comments that is attached below, answering every comment point-by-point. With that, we hope to have sufficiently answered and implemented all questions, suggestions and comments.

We dearly hope to have made the necessary adaptations for convincing you to accept our revised submission. Again, we want to express our gratitude for the opportunity to improve our manuscript with the relevant and valuable input from the reviewer.

Yours sincerely,

Prof. Sven Streit, MD, MSc, PhD

Professor in Primary Care, Head of Interprofessional Primary Care

Institute of Primary Health Care Bern (BIHAM)

University of Bern, Mittelstrasse 43

3012 Bern, Switzerland

Tel +41 31 631 58 75

Email: sven.streit@biham.unibe.ch

Point-by-point response to reviewers' comments:

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: (No Response)

Response: We would like to thank the reviewer for his positive feedback on our first revision. We have address the additional comments in the point-by-point response below.

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 appropri-ate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Response: Thank you for this comment. We are happy to read that we addressed the com-ments in the first revision adequately.

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

Reviewer #2: Yes

Response: We would like to thank the reviewer for this assessment.

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 ex-ample, 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. partici-pant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Response: Thank you.

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

Response: Thank you.

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, re-search ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for the responses to my review. I feel they have addressed the ma-jority of issues.

Response: We would like to thank the review for this assessment. The new comments are addressed in the point-by-point response below.

1. Thank you for the clarification that each GP was in a different practice/clinic. This should be added to the Methods section.

Response: Thank you. We have added this information to the methods section (p. 5, l. 2). The text now reads: “All of them were located in different GP offices.”

2. Regarding screening, the newly inserted sentence says GPs were instructed to consecu-tively screen 5 eligible patients. Should this be "to consecutively screen eligible patients and recruit 5 participants, reporting the number of patients screened..."?

Response: Thank you for highlighting this error. We have replaced the sentence as suggest-ed. The text now reads: “GPs were instructed to consecutively screen eligible patients and recruit 5 participants, reporting the number of patients screened, to reduce the risk of selec-tion bias” (p. 6, l. 6-7).

3. The new legend that was intended for Figure 1 appears to have been inserted below the Figure 2 title in error.

Response: Thank you. We have moved the figure legend.

4. Two revisions to the manuscript mentioned in the response letter have not actually been included in the manuscript (they have been inserted and then deleted in the tracked changes version). These related to hypothesising patients using PIMs were more likely to experience side effects in the Introduction, and that the study may not have been powered for examining individual questions in the Limitations. I feel these are both important and warrant inclusion.

Response: Thank you for highlighting this shortcoming. We have inserted these two revision in the manuscript text.

1) “We hypothesized that patients who use PIMs experience more side effects than patients who do not use any PIMs, which in turn might affect their willingness to deprescribe” (p. 4, l. 15-17). (this sentence was adapted based on the comment below)

2) “Furthermore, very few of the individual factors had evidence to support a relationship with the use of PIMs, which stems from the fact that the study might not have been suffi-ciently powered to detect such differences.” (p. 11, l. 11-13)

5. The proposed addition relating to the hypothesis may warrant rephrasing as it is contradic-tory as is : "We hypothesized that patients who use PIMs, irrespective of whether the medi-cation they use are potentially inappropriate, experience...". Should the part beginning irre-spective refer to the number of medications they use, or simply be removed?

Response: Thank you. We have removed the part “irrespective of whether the medication they use are potentially inappropriate” from the manuscript text.

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.

Response: I agree

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Sep 2020

Potentially inappropriate medication and attitudes of older adults towards deprescribing

PONE-D-20-16955R2

Dear Dr. Streit,

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,

Christine Leong, Pharm. D.

Academic Editor

PLOS ONE

29 Sep 2020

PONE-D-20-16955R2

Potentially inappropriate medication and attitudes of older adults towards deprescribing

Dear Dr. Streit:

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. Christine Leong

Academic Editor

PLOS ONE