Overprescribing Review Final Report

Overprescribing review Final report Evidence for the impact of interventions for, and medicines reconciliation in, problematic polypharmacy: a rapid review of systematic reviews and scoping searches

November 2019

Authors: Rita Faria1, Marrissa Martyn-St James2, Ruth Wong2 , Alison Scope2, Mark Sculpher1

1 Centre for Health Economics, University of York, UK 2 School of Health and Related Research, University of Sheffield, Sheffield, UK

Funding and disclaimer This report is independent research funded by the National Institute for Health Research Policy Research Programme (NIHR PRP) through its Policy Research Unit in Economic Evaluation of Health & Care Interventions (EEPRU, grant reference PR-PRU-1217-20401). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.

Abstract

1. This rapid review and scoping searches aimed to understand the literature on problematic polypharmacy (PP) and identify key areas of uncertainty for future research. 2. PP was defined as “prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised” (following the 2013 King’s Fund definition). 3. Researchable questions were specified by topic of interest: burden of PP, interventions to reduce PP, implementation activities to increase uptake of interventions to reduce PP and efficient handover between primary and secondary care to reduce PP. 4. The rapid systematic review included nine systematic reviews (10 references). All reviews were international, with most including UK studies. 5. The findings of the rapid review of systematic reviews are as follows: 5.1. Burden of PP. There is no consensus in the literature regarding the definition of polypharmacy. The prevalence of polypharmacy in people residing in long-term care facilities and of PP is generally high but varies widely depending on the definitions, country and setting. Polypharmacy is associated with greater risk of death, estimates of which are likely to be confounded by poorer health. 5.2. Interventions to reduce PP. The evidence suggests that the interventions can reduce PP, although reductions in polypharmacy are more uncertain. Deprescribing and other interventions to reduce PP appear to have no effect on all-cause mortality. There is no clear evidence of an effect on other relevant outcomes such as quality of life and hospitalisations. 5.3. Implementation activities to increase uptake of interventions to reduce PP. No systematic reviews were found on this topic. 5.4. Efficient handover between primary and secondary care to reduce PP. There is some evidence that medicine reconciliation activities reduce medication discrepancies at care transitions. 6. Further review update or scoping searches retrieved a total of 7,006 records, which suggests that PP is an active topic for research. 7. Given the evidence identified, some areas are suggested for future research: 7.1. Burden of PP. Research on the prevalence of polypharmacy and PP in the UK, the factors that predict PP, and on the causal effect of PP on costs and health outcomes. 7.2. Interventions to reduce PP and Efficient handover between primary and secondary care to reduce PP. Research on the comparative effectiveness of interventions to reduce PP, considering the quality of the primary studies and their generalisability to the UK; on the interventions’ resources and costs; and on their cost-effectiveness. 7.3. Implementation activities to increase uptake of interventions to reduce PP. Research on the current uptake of interventions to reduce PP, the barriers to their implementation, and the implementation activities to address them; on the comparative effectiveness of interventions to reduce PP, considering the quality of the primary studies and their generalisability to the UK; and the cost-effectiveness of investments in implementation activities.

Plain English summary

Our objectives were to understand what we know about “problematic polypharmacy”, find out the gaps in our knowledge and suggest areas to research in the future. “Problematic polypharmacy” refers to when people take too many medicines or when people do not get the full benefit from their medicines. We started by setting out our questions. The questions were about the burden of problematic polypharmacy and what can we do to address this problem. We looked for a type of study called “systematic review”. Systematic reviews summarise the research about a topic. We found nine systematic reviews. All reviews were international, with most including UK studies. Thanks to the evidence in these systematic reviews, we concluded that:  Researchers disagree on how many medicines are too many. Some studies showed that people living in long-term care facilities (e.g. care homes) take too many medicines but these studies may not apply to the UK.  Taking many medicines is related to having a greater risk of death. This might be because people who have poorer health take more medicines and, due to their poorer health, are also at greater risk of death.  Studies showed that there are actions that we can take to reduce the problem of problematic polypharmacy, such as reviewing the medication list and stop certain medicines. These actions do not seem to have an impact on the risk of death, quality of life and the risk of going into hospital.  Medicine reconciliation are activities where doctors, nurses or pharmacists check the medicines list of people when they go into hospital and/or when they leave hospital. Medicine reconciliation lowers the risk of errors in the medicines list. We ran new searches to find out if there were new studies since the systematic reviews had came out. We found a total of 7,006 records. This means that there may be studies with information about this topic, but which were not included in the systematic reviews. Given what we know now, we suggest that more research is done on problematic polypharmacy:  On how many people take too many medicines, how to find them using routine health records, and the impact of taking too many medicines on their health and the costs to the NHS.  On what can we do to reduce the problem of taking too many medicines, how well it works and how far it is good value for money for the NHS.

Executive summary

Introduction

This rapid review and scoping searches were commissioned to inform the review into overprescribing in the NHS. The overarching aims are to understand the literature on problematic polypharmacy (PP) and suggest key areas of uncertainty for future research. The specific objectives were to specify a series of potentially researchable questions, to investigate the scale and nature of the available literature to answer each question, and to assess which questions are more amenable for future research. PP was defined as “prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised” (following the 2013 King’s Fund definition).

Development of research questions

Ten researchable questions were specified by topic of interest as follows: Burden of PP: What is the (1) prevalence (and/or incidence), (2) costs to the NHS and (3) health consequences of PP in the UK? Interventions to reduce PP: What is the effectiveness of (4) interventions to reduce PP, with specific focus on (5) deprescribing guidelines, (6) routine data, (7) digital technologies? Implementation activities to increase uptake of interventions to reduce PP: What is the effectiveness of (8) implementation activities to increase the uptake of interventions that reduce PP, (9) with specific focus on activities to increase shared decision making? Efficient handover between primary and secondary care to reduce PP: (10) What is the effectiveness of medicine reconciliation interventions to reduce discrepancies in medication in people at risk of PP?

Methods

Rapid review of systematic reviews Identifying studies MEDLINE (via Ovid), Embase (via Ovid) and Cochrane Database of Systematic reviews (via Wiley) were searched in June 2019 to identify systematic reviews on the topics of interest. The search was limited to systematic reviews, in English, published in the last 10 years, and in people aged 65 years and over. This rapid review was registered with PROSPERO (CRD42019141295). Criteria for considering studies for this review Studies were included if they were peer-reviewed, full-text reports of systematic reviews, of good methodological quality, on one of the researchable questions of interest. Studies were considered to be of good methodological quality if the search strategies were comprehensive, if the data extraction was performed in duplicate, if a satisfactory technique was used to assess study quality, and if the primary studies were described in adequate detail. There were no restrictions on country, except to inform the topic on burden of PP (where reviews had to include UK studies); no restrictions in the location of care and no restrictions on outcomes. Data extraction

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Study selection. One reviewer conducted the title screen. The studies which passed the title screen were obtained as full-text and divided between two reviewers for a second screen. Quality assessment. Quality assessment of the included systematic reviews was undertaken using a modified version of AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) by a single reviewer. Data extraction. Data were extracted directly into evidence tables in Excel, including: searching methods, study selection methods, data extraction and quality assessment methods, number and types of included studies, study characteristics of included studies, assessment methods and results of included studies, overall findings, author conclusions, and limitations and uncertainties. A single systematic reviewer was responsible for data extraction. An independent reviewer checked the data extracted into the evidence tables of the final report against the original publication for accuracy. Data synthesis. A narrative synthesis was undertaken on the included systematic reviews for each topic. Scoping searches Search update of included systematic reviews. Searches were updated in MEDLINE for the systematic reviews which reported the search strategy fully and which completed the searches more than two years ago (before August 2017). Filters were applied to retrieve primary studies from the UK on burden, and to retrieve RCT on studies on the effectiveness of interventions to reduce PP. New scoping searches. New searches were conducted in MEDLINE on the prevalence and/or incidence of PP, its costs to the NHS and its health consequences. This topic was prioritised given the findings of the rapid review. It was not feasible to develop new searches for the effectiveness of implementation activities to increase the uptake of interventions to reduce PP. Searches of clinical trial registers. The Clinicaltrials.gov register and WHO International Clinical Trials Registry Platform were searched on 14th August 2019 to retrieve ongoing or completed but unpublished trials using keywords for polypharmacy.

Results

Rapid review of systematic reviews Records identified and systematic reviews included. The rapid systematic review search identified 481 unique records, of which 14 systematic reviews (15 references) met the inclusion criteria. Of these, nine systematic reviews (10 references) were considered to be of good quality and were taken forward for data extraction. Summary of systematic reviews. Three systematic reviews were included on burden of PP, six systematic reviews on the effectiveness of interventions to reduce PP and one systematic review on the efficient handover between primary and secondary care. No systematic reviews were found on implementation activities to increase uptake of interventions to reduce PP. All reviews were international, with most including UK studies. Burden of PP. Three systematic reviews were identified: Jokanovic et al (2015), Leelakanok et al (2017) and Hill-Taylor et al (2013). UK studies. Six UK studies were included: Gadsby et al (2011), Honney et al (2014), Parsons et al (2012), Richardson et al (2011), Shah et al (2013) and Whitney et al (2012).

Summary of findings. Jokanovic et al (2015) and Leelakanok et al (2017) suggest that there is no consensus in the literature on the definition of polypharmacy. Jokanovic et al (2015) found that the prevalence of polypharmacy in people residing in long-term care facilities was high although the primary studies were at risk of selection bias. Leelakanok et al (2017) found that polypharmacy is associated with greater risk of death, although this may not reflect a causal effect due to confounding and publication bias. From Hill-Taylor et al (2013), and assuming that potentially inappropriate prescribing corresponds to PP, the prevalence of PP is 21-79% depending on the country. Quality assessment. The systematic reviews were generally of good quality, with some limitations relating to lack of clarity on an a priori protocol, sources of funding of the included studies, and details on the excluded studies. There were limitations in the meta-analysis by Leelakanok et al (2017) in that estimates from different study designs, analytical approaches and quantities were pooled together. Hence, their results should be interpreted as evidence of association, albeit uncertain, and not as evidence of a causal effect. Interventions to reduce PP. Six systematic reviews were identified: Clyne et al (2015); Hill-Taylor et al (2013 and 2016); Johansson et al (2016); Kua et al (2019), Page et al (2016) and Rankin et al (2018). Kua et al (2019) was specifically on the effectiveness of deprescribing guidelines to reduce PP. No systematic reviews were found that evaluated the effectiveness of using routine data to reduce PP, or on the effectiveness of digital technologies to reduce PP. UK studies. Across the six reviews, 26 UK studies were included: Alsop et al (2001), Ballard et al (2004, 2008, 2009 and 2016), Borrill et al (2009), Choudhury et al (2007), Cunnington et al (2012), Curran et al (2003), Daly and Edwards (1983), Esselinckx et al (1977), Fair et al (1990), Fortherby et al (1994), Fossey et al (2006), Furniss et al (2000), Hearing et al (1999), Jackson et al (2005), Jarad et al (1999), Jordan et al (2015), Lenaghan et al (2007), Minett et al (2003), Patterson et al (2010), Pope et al (2010), Sambu et al (2011), Sturgess et al (2003), Zermasky et al (2006). Summary of findings. Clyne et al (2016), Page et al (2016), Hill-Taylor et al (2016), Kua et al (2019) and Rankin et al (2018) all found that the interventions reduce PP. Reductions in polypharmacy were uncertain (Johansson et al (2016), Page et al (2016)). Hill-Taylor et al (2013, 2016) concluded that specific tool (the STOPP/START criteria; version not specified but likely version 1) could be useful to identify people at risk of potentially inappropriate prescribing, although more research was required on their feasibility and effectiveness. Clyne et al (2016) and Johansson et al (2016) found that there is no clear evidence of an effect on clinically relevant outcomes. From a safety perspective, Page et al (2016) found no evidence to suggest that deprescribing increases the risk of adverse outcomes. Johansson et al (2016) and Page et al (2016) (and to some extent Kua et al (2019)) found no effect on all-cause mortality. According to Page et al (2016), Kua et al (2019) and Rankin et al (2018), evidence is mixed on the effect on disease-specific outcomes, quality of life and hospitalisations. Clyne et al (2016), Hill-Taylor et al (2013, 2016), Johansson et al (2016), Page et al (2016) and Rankin et al (2018) all found that the primary studies were at risk of bias. Hence the findings are subject to high levels of uncertainty. Quality assessment. The systematic reviews were generally of good quality. The limitations relate to lack of clarity on whether an a priori protocol had been developed (Kua et al (2019)), lack of details on excluded studies (Clyne et al (2016), Hill-Taylor et al (2013; 2016), Kua et al (2019)), and sources of funding of the included studies (Clyne et al (2016), Kua et al (2019), Rankin et al (2018)). Of note, none of the five reviews presenting a meta-analysis considered

study quality in the analysis; and two reviews (Kua et al (2019) and Rankin et al (2018) found evidence of publication bias. There were limitations in the Kua et al (2019) meta-analysis given the choice of fixed-effects (rather the random-effects) as the preferred results. For these reasons, the results from all meta-analyses should be interpreted with caution. Implementation activities to improve uptake of interventions to reduce PP. No systematic reviews were found on this topic. Efficient handover between primary and secondary care to reduce PP. One systematic review was found, Redmond et al (2018). UK studies. Redmond et al (2018) included two UK studies: Bolas et al (2004) and Cadman et al (2017). Summary of findings. The interventions implemented in the studies reduced the medication discrepancies at care transitions, although the evidence was deemed to have very low certainty. There was little or no effect on adverse drug events, preventable adverse drug events, or health care utilisation, although these findings are also uncertain due to the quality of the primary studies. Quality assessment. Redmond et al (2018) is a good quality systematic review. Whilst study quality was not considered in the meta-analysis, a funnel plot suggested the possibility of publication bias. Scoping searches Search update of included systematic reviews. The searches retrieved 106 unique records under the topic of burden of PP and 1,094 unique records under the topic of effectiveness of interventions to reduce PP. New scoping searches. The new searches retrieved 5,494 records (576 records following application of the filter for UK studies) on the burden of PP. Searches of clinical trial registers. The searches on clinical trial registers retrieved 215 studies in clinicaltrials.gov and 97 studies in the World Health Organisation International Clinical Trials Registry Platform.

Key findings

Rapid review of systematic reviews Burden of PP. There is no consensus in the literature regarding the definition of polypharmacy. The prevalence of polypharmacy in people residing in long-term care facilities and of PP varies widely depending on their definitions, country and setting but is thought to be high. Polypharmacy is associated with greater risk of death, estimates of which are likely to be confounded by poorer health. Interventions to reduce PP. The evidence suggests that the interventions can reduce PP, although reductions in polypharmacy are more uncertain. Deprescribing and other interventions to reduce PP appear to have no effect on all-cause mortality. There is no clear evidence of an effect on other relevant outcomes such as quality of life and hospitalisations. Implementation activities to increase uptake of interventions to reduce PP. No systematic reviews were found on this topic.

Efficient handover between primary and secondary care to reduce PP. There is some evidence that medicine reconciliation activities reduce medication discrepancies at care transitions. Scoping searches The scoping searches retrieved a total of 7,006 records, which suggests that PP is an active topic for research.

Strengths and limitations

The rapid review summarised the literature on three of the four broad topics of interest, and identified the areas with stronger evidence and the areas where more research is required. Extensive literature searches were conducted to understand the size and growth in the literature. References lists are provided, which can inform future systematic reviews. The limitations stem from the time and resource constraints, in that the rapid review and scoping searches were designed to obtain an overview of the literature in a pragmatic and efficient way. The systematic review searches were highly specific, which may have led to some relevant studies being missed. The study selection process, quality assessment and data extraction were conducted by a single researcher, while a third researcher checked the data extraction for outcomes. Hence, eligible systematic reviews may have been missed at the study selection stage and elements of the data extraction process may not be completely accurate. The records retrieved by the searches could not be screened to identify those related with PP.

Remaining uncertainties

Burden of PP. The evidence on the prevalence of polypharmacy referred to people residing in long- term care facilities, was highly heterogeneous and only included three UK studies. The evidence on the prevalence of PP was limited to a few studies, of which only one study was in the UK. The evidence on the association between polypharmacy and mortality risk was mostly international and estimates are unlikely to reflect a causal effect due to confounding bias. For these reasons, the prevalence of polypharmacy and PP as well as the costs and health consequences due to PP in the UK remain unclear. Interventions to reduce PP. The generalisability of the results from international studies and/or studies in controlled environments to the current clinical practice in the UK is unclear. There is uncertainty on the impact of interventions to reduce PP due to the variable quality of the primary research, heterogeneity in their methodology and limitations of the evidence synthesis. Implementation activities to increase uptake of interventions to reduce PP. Given that no evidence was found on implementation activities, the uncertainties regarding this topic remain. Efficient handover between primary and secondary care to reduce PP. The evidence is generally of poor quality and its generalisability to the current clinical practice in the UK is unclear.

Suggestions for future research

Burden of PP. Further research is warranted on the prevalence of PP in the UK, and its costs and health consequences, to understand its magnitude and its consequences. The research could consider the following areas:  To estimate the prevalence of polypharmacy and the prevalence of PP in the UK, according to a definition that represents the current expert consensus.

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 To identify the factors that predict PP in the UK with the aim of routinely identifying people at risk of PP and who should be prioritised for interventions to reduce PP.  To estimate the causal effect of PP on costs and on health outcomes; in other words, what would have been the costs and health outcomes of a group of people exposed to PP had they not been exposed to PP? Interventions to reduce PP and Efficient handover between primary and secondary care to reduce PP. Future research could inform which interventions are most likely to be effective and cost- effective in reducing PP in the UK. Given the evidence identified in this rapid review and in the scoping searches, the future research could consider the following approaches:  To identify relevant primary studies on the effectiveness of interventions to reduce PP (e.g. from the included systematic reviews and from the scoping searches).  To use the appropriate evidence synthesis methodology and content expertise to estimate the comparative effectiveness of each intervention to reduce PP, considering the quality of the primary studies and their generalisability to the UK.  To estimate the resources and costs required to implement and run the various interventions (for which the evidence synthesis estimated a reliable effect).  To estimate the cost-effectiveness of the interventions, with cost-effectiveness modelling of the long-term costs and health outcomes of current practice with or without interventions, given the prevalence of PP, the consequences of PP on costs and health outcomes and the effectiveness of interventions in reducing PP. Implementation activities to increase uptake of interventions to reduce PP. Given the lack of evidence on this topic, future research could explore the following areas:  To understand the extent to which interventions to reduce PP are used in the UK, and if uptake is suboptimal, to identify the barriers to uptake and the implementation activities that could address these.  To review the literature and conduct evidence synthesis to estimate the comparative effectiveness of the relevant implementation activities in changing uptake, considering the quality of the primary studies and their generalisability to the UK.  To conduct cost-effectiveness modelling of the value of implementation given the current uptake, the effectiveness of implementation activities, the cost-effectiveness of interventions to reduce PP and the prevalence of PP.

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Contents

Abstract ...... i Plain English summary ...... ii Executive summary ...... iii Introduction ...... iii Development of research questions ...... iii Methods ...... iii Results ...... iv Key findings ...... vi Strengths and limitations...... vii Remaining uncertainties ...... vii Suggestions for future research ...... vii Contents ...... 1 Abbreviations ...... 3 1. Introduction ...... 4 1.1. Objectives ...... 5 2. Development of the research questions ...... 5 3. Review of systematic reviews ...... 6 3.1. Methods ...... 6 3.1.1. Identifying Studies ...... 6 3.1.2. Criteria for considering studies for this review ...... 7 3.1.3. Data Extraction...... 9 3.2. Results ...... 10 3.2.1. Identifying and selecting systematic reviews ...... 10 3.2.2. Summary of included systematic reviews ...... 14 3.2.3. Quality of the included studies ...... 23 3.2.4. Summary of findings and key uncertainties ...... 26 4. Scoping searches ...... 29 4.1. Overview ...... 29 4.2. Methods ...... 29 4.2.1. Search update of included systematic reviews ...... 29 4.2.2. New scoping searches ...... 30 4.2.3. Searches of clinical trial registers ...... 30 4.3. Results ...... 31

4.3.1. Search update ...... 31 4.3.2. New scoping searches ...... 31 4.3.3. Searches of clinical trial registers ...... 31 5. Conclusions ...... 31 5.1. Key findings ...... 31 5.1.1. Rapid review ...... 31 5.1.2. Scoping searches ...... 32 5.2. Strengths and limitations ...... 32 5.3. Remaining uncertainties ...... 33 5.4. Suggestions for future research ...... 33 6. References ...... 34 7. Appendices ...... 39 7.1. Appendix 1: Medline search strategy ...... 39 7.2. Appendix 2: Citations which passed the title screen ...... 39 7.3. Appendix 3: Data extraction tables ...... 45 7.4. Search strategies...... 61 7.4.1. Update to the searches by the systematic reviews ...... 61 7.4.2. Strategy for new scoping searches ...... 79 7.4.3. Strategy for searching clinical trial registers ...... 81 7.5. Appendix 4: Titles identified in the scoping searches ...... 82 7.5.1. Titles identified in the update to the searches by the systematic reviews ...... 82 7.5.2. Titles identified in new scoping searches on Topic A: Burden of PP ...... 155 7.5.3. Titles identified in the clinical trial registers ...... 193

Abbreviations

AMSTAR-2: A MeaSurement Tool to Assess systematic Reviews ADE: adverse drug events CI: confidence interval DHSC: Department of Health and Social Care HR: hazard ratio MD: mean difference NHS: National Health Service OR: odds ratio PICO: Population, Intervention, Comparator, Outcomes PIM: Potentially inappropriate medicine PIP: potentially inappropriate prescribing PP: Problematic polypharmacy PPO: potential prescribing omission PADE: preventable adverse drug events RCT: randomised controlled trial RR: relative risk SMD: standardised mean difference UK: United Kingdom

1. Introduction

The Secretary of State for Health, Matt Hancock, commissioned a review into overprescribing in the NHS in December 2018, led by the Chief Pharmaceutical Officer Dr Keith Ridge as part of the Short Life Working Group on Overprescribing [1]. The review will consider polypharmacy, efficient handover between primary and secondary care, using routinely collected prescribing and dispensing data to improve implementation of guidelines, the role of digital technologies in reducing polypharmacy, and promoting and enabling effective shared decision making. To inform this review, the Department of Health and Social Care (DHSC) commissioned this rapid review and scoping searches. The goals are to understand the literature on overprescribing and scope the areas where the DHSC review might focus its work [2]. Overprescribing is interpreted here as problematic polypharmacy (PP), following the King’s Fund 2013 definition: “prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised” [3]. In contrast, appropriate polypharmacy is where an individual is prescribed multiple medicines according to best evidence, and their use was optimised [3]. The prevalence of polypharmacy has slightly increased over time (Figure 1) [4]. From 2012/13 to 2015/16, the proportion of people prescribed 5-7 medicines increased by 8% and, in those on 8 or more medicines, by 3%. In 2015/2016, the proportion of people on 5-7 medicines was 8.8% and on 8 or more medicines was 5.0%. Extrapolating to the population in England, this amounts to 4.8 million people on 5-7 medicines and 2.8 million people on 8 or more medicines.

Figure 1: Number of prescribed medicines taken in the last week by age in 2012-13 and 2015-16 [4] This figure was drawn using data from the Health Survey for England 2012-2013 and 2015-2016, Table 13 on the number of prescribed medicines taken in the last week, excluding smoking cessation products and contraceptives [4].

1.1. Objectives

The aim of the rapid review is to understand the literature on PP and suggest key areas of uncertainty for future research. The specific objectives are: 1. To specify a series of potentially researchable questions regarding PP; 2. To investigate the scale and nature of the available literature to answer each question; 3. To assess which questions are more amenable for future research. The rapid review considers the following topics:  Burden of PP (prevalence, incidence, costs to the NHS and health consequences);  Interventions to reduce PP, with a special focus on deprescribing guidelines, the use of routine data, digital technologies and shared decision making, but not exclusive to these;  Implementation activities to improve uptake of interventions to reduce PP;  Efficient handover between primary and secondary care to reduce PP. The study design of a rapid review of systematic reviews was chosen because it meets the objectives of the research within the available time and resources to conduct it. It is recognised that a rapid review of systematic reviews will not identify primary studies which have not yet been included in systematic reviews.

2. Development of the research questions

Each of these topics were examined to specify research questions. These research questions were developed with the goal to help improve the understanding of the burden of overprescribing and the effectiveness and cost-effectiveness of interventions to address the problem; and to distinguish between research questions which could be answered by literature reviews and questions which require primary research. The research questions are summarised in Table 1.

Table 1: Research questions per topic

Topic Research question

1. What is the prevalence (and/or incidence) of PP in the UK?

A. Burden of PP 2. What are the costs to the NHS of PP in the UK? 3. What are the health consequences of PP in the UK?

4. What is the effectiveness of interventions to reduce PP?

5. What is the effectiveness of deprescribing guidelines to reduce PP? B. Interventions to reduce PP 6. What is the effectiveness of using routine data to reduce PP?

7. What is the effectiveness of digital technologies to reduce PP?

8. What is the effectiveness of implementation activities to increase uptake of interventions that reduce PP? C. Implementation activities to increase uptake of interventions to reduce PP 9. What is the effectiveness of implementation activities to increase shared decision making to reduce PP?

D. Efficient handover between primary and 10. What is the effectiveness of medicine reconciliation interventions to secondary care to reduce PP reduce discrepancies in medication in people at risk of PP?

3. Review of systematic reviews

This report aims to evaluate over prescribing in the NHS through an abbreviated systematic review (rapid review). This rapid review was registered with PROSPERO (CRD42019141295). The rapid review focused on the following tasks:  Conduct literature searches for published systematic reviews relating to relevant questions, which are good quality, recent, applicable to the NHS and address the relevant research questions; critically appraise them and summarise their conclusions and key uncertainties.  Update the searches that informed the included systematic reviews (which provided search strategies) if the search strategies were conducted more than two years ago, report on the number of records and conduct a title screen to ascertain the number which relate to problematic polypharmacy.  For research questions where systematic reviews are not already available, and which are amenable topics for literature reviews, to conduct scoping searches to estimate the size and understand the nature of the literature.  If time allows, to examine clinical trial registries for ongoing studies which may answer the relevant questions.

3.1. Methods

3.1.1. Identifying Studies

Three electronic databases, MEDLINE (via Ovid), Embase (via Ovid) and Cochrane Database of Systematic reviews (via Wiley) were searched in June 2019 to identify systematic reviews published on the following topics: 1. Effectiveness of interventions to address polypharmacy 2. Efficient handover between primary and secondary care relating to polypharmacy

3. Effectiveness of deprescribing guidelines in reducing PP, and effectiveness of activities to implement deprescribing guidelines 4. The role of digital technologies in reducing polypharmacy 5. Promoting and enabling effective shared decision making The strategies comprised keywords for: ‘polypharmacy’, ‘inappropriate prescribing’, ‘deprescribing’, adapted from recently published reviews [5-11] and identified through keyword searching (‘polypharmacy’ and ‘systematic reviews’) using Google Scholar. A copy of the MEDLINE search strategy is presented in Appendix 1. The search was limited to English language literature published in the last 10 years (from 2009 onwards). The search was further limited to studies in people aged 65 and over by applying an elderly search filter in Ovid,[12] and systematic reviews by applying high specificity systematic review search filters in MEDLINE and Embase.[13, 14] References were managed using Endnote X9. 2.

3.1.2. Criteria for considering studies for this review

Each topic and each question was reviewed to identify the population, intervention and comparators (or exposure, as relevant), and outcomes; i.e. the PICO. These are summarised in Table 2. The criteria for considering studies for this review were developed based on the PICO for each topic and it is discussed in detail below.

Table 2: Population, Intervention, Comparators and Outcomes (PICO) per topic

Topic Population Intervention/comparators Outcomes Exposure People on PP in the UK or a UK nation. A. Burden of PP Systematic reviews are included as long as PP; appropriate polypharmacy included studies in the UK.

Any intervention vs. standard care. Specific focus on: Measures of medication appropriateness; B. Interventions to reduce PP  Deprescribing guidelines number of medicines; healthcare resource  Routine data use; costs to the NHS; health-related quality  Digital technologies of life; mortality.

Any implementation activity vs. another People on PP; any country. implementation activity or vs. no activity C. Implementation activities to improve (standard practice) uptake of interventions to reduce PP Specific focus on interventions to promote shared decision making.

Any medicines reconciliation activity vs. D. Efficient handover between primary and As above, additionally medication another medicine’s reconciliation activity or secondary care to reduce PP discrepancies and adverse drug events. vs. standard practice.

Types of studies Only systematic reviews were included, defined according to the taxonomy by Kahn et al. (2003)[15] that includes five steps: defining the review question, identifying relevant studies, assessment of study quality, evidence synthesis and interpretation of findings. Only systematic reviews that were considered to be of good methodological quality were included (see Quality assessment section below). Systematic reviews reported as conference abstracts were excluded. A systematic review was included if it answered one of the 10 research questions of interest (see Table 1) and met all of the following quality criteria: 1. Did the review authors use a comprehensive literature search strategy? This includes searching at least 2 databases, providing keywords and/or search strategies, and justifying publication restrictions. 2. Did the review authors perform data extraction/checking in duplicate? 3. Did the review authors use a satisfactory technique for assessing study quality? 4. Did the review authors describe the included studies in adequate detail?

Types of settings Countries For the research questions 1-3 relating to burden, the systematic reviews were included if they included evidence from the UK. The burden of PP is likely to depend on the demographics, socio- economic conditions and organisation of the health care system in each setting. Hence studies in other settings may not be generalisable to the UK. For those research questions relating to effectiveness, there were no restrictions on the country. The assumption is that the impact of interventions is generalisable to the UK NHS. Primary vs secondary care There were no restriction on location of care.

Types of PP Systematic reviews were preferred that defined PP in accordance with the definition provided by the King’s Fund as “prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised” [3]. Where no systematic review using this definition was available for a specific research question, other systematic reviews were eligible for inclusion as long as their focus was on PP, whichever it was defined.

Types of outcomes There were no restrictions on outcomes.

3.1.3. Data Extraction

Study selection A screening process was developed to efficiently screen the studies to include in the review, given the criteria above (see Figure 2). Due to the time constraints, one author conducted the title screen (MMSJ). The studies which passed the title screen were obtained as full-text and divided between two authors (MMSJ and RF) for a second screen based on the full-text.

Quality assessment Quality assessment of the included systematic reviews was undertaken using a modified version of AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) by a single reviewer (MMSJ) [16]. AMSTAR 2 is a critical appraisal tool for systematic reviews that include randomised or non- randomised studies of healthcare interventions. The tool comprises a 16-item questionnaire covering the stages of the systematic review process.

Data extraction Given that this study was a rapid review, a data extraction template was not developed and instead the data were extracted directly into evidence tables in Excel. Data was extracted on searching methods, study selection methods, data extraction and quality assessment methods, number and types of included studies, study characteristics of included studies, assessment methods and results of included studies, overall findings, author conclusions, and limitations and uncertainties. The short timeline for the project meant that a single systematic reviewer was responsible for data extraction (either RF or MMSJ). A second independent reviewer (AS) checked data extracted into the evidence tables of the final report against the original publication for accuracy.

Data synthesis A narrative synthesis was undertaken on each topic. A statistical synthesis of the data was not undertaken.

Figure 2: Review process

3.2. Results

3.2.1. Identifying and selecting systematic reviews

Figure 3 shows the PRISMA flow diagram for the study selection process. The electronic searches identified 651 citations. Following deduplication, there were 481 citations of which 401 were

excluded based on the title and 80 obtained as full-text (see list in Appendix 2). Of the 80 studies obtained as full-text, 21 studies (22 references) passed the abstract screen and 17 studies (18 references) were assessed as relevant in one of the four topics of interest. Of these, 14 studies (15 references) related to one of the questions of interest. Five studies were excluded after quality assessment. Nine studies (10 references) were included and carried forward for data extraction. Figure 4 summarises the topics in 21 studies (22 references) which passed the abstract screen [5, 9, 11, 17-35]. Most studies (n=13, 14 references) were on interventions to reduce PP [5, 9, 11, 17-22, 24, 29, 31, 32, 34], four studies were on the burden of PP [20, 23, 25, 35], none was on implementation activities and one study was on the efficient handover between primary and secondary care [30]. Four studies were on other topics, namely approaches to identifying inappropriate medication [18], association of polypharmacy with frailty [26], effectiveness of interventions to improve adherence to medication by older adults prescribed polypharmacy [27] and risk factors for rehospitalisation in older patients who took part in randomised controlled studies of transitional care interventions [28]. Figure 5 shows the breakdown of the studies which passed the topic screen (n=17 studies, 18 references) by question [5, 9, 11, 17-25, 29-32, 34, 35]. Most studies (n=14 studies, 15 references) were on a question of interest, generally on question 4 on the effectiveness of interventions (n=11 studies, 12 references) [5, 9, 11, 17, 19-22, 24, 29, 32, 34]. Three studies provided information on Topic A: Burden of PP: one study was on the prevalence of polypharmacy [23]; another on the relationship between polypharmacy and mortality risk; and a third study had some information on the prevalence of PP (this study was also included under Topic B: Interventions to reduce PP) [20]. One study related to Topic D, specifically on the effectiveness of medicines reconciliation activities [30]. Table 3 summarises the results of the screening based on quality. Of the 14 studies (15 references) which were on one of the questions of interest, five were excluded due to not meeting at least one of the quality criteria [5, 11, 19, 32, 34]. All of the five excluded studies were on the effectiveness of interventions to reduce PP (see Figure 5). All studies met the criteria of having a comprehensive search strategy and of describing the included studies in a comprehensive manner; three studies did not report doing data extraction in duplicate; and four studies did not do an appropriate quality assessment.

MEDLINE Embase CDSR Scholar 2009-26/06/2019 2009-26/06/2019 2009-26/06/2019 2009-26/06/2019 283 records 304 records 60 records 4 records

481 unique records

401 records excluded at title screen

80 articles retrieved 58articles excluded at abstract screen: N=11 were not a full systematic review N=16 were not a full-text peer-reviewed paper

N=26 were not on patients on polypharmacy N=2 were a previous version of an included study N=1 was a dual publication of an included study N=1 was not in English 22 articles (21 studies) passed

abstract screen

4 articles were excluded due to not being on a topic of interest

18 articles (17 studies) were on a topic of interest

3 articles were excluded due to not being on a question of interest

15 articles (14 studies) were on a question of interest

5 articles were excluded due to not meeting the quality criteria

10 articles (9 studies) were data extracted

Figure 3: PRISMA diagram

Figure 4: Topics of the systematic reviews which passed the abstract screen

Figure 5: Questions covered by the systematic reviews relating to one of the four topics of interest (before and after quality assessment screen)

Table 3: Quality assessment results of systematic reviews

Study Comprehensive Duplicate data Quality Study Conclusion search strategy extraction assessment description

Clyne et al, 2012 [5] Yes Can’t tell Can’t tell Yes Exclude

Clyne et al, 2016 [36] Yes Yes Yes Yes Include

Gutierrez Valencia et Yes Yes Can’t tell Yes Exclude al, 2016 [19]

Hill-Taylor et al, 2016 Yes Yes Yes Yes Include [20, 21]

Johansson et al, 2016 Yes Yes Yes Yes Include [22]

Jokanovic et al, 2015 Yes Yes Yes Yes Include [23]

Kua et al, 2018 [24] Yes Yes Yes Yes Include

Leelakanok et al, Yes Yes Yes Yes Include 2017 [25]

Page et al, 2016 [9] Yes Yes Yes Yes Include

Rankin et al, 2018 Yes Yes Yes Yes Include [29]

Redmond et al, 2018 Yes Yes Yes Yes Include [30]

Tani et al, 2013 [11] Yes Can't tell No Yes Exclude

Thillainadesan et al, Yes No Yes Yes Exclude 2018 [32]

Tija et al, 2013 [34] Yes Yes No Yes Exclude

3.2.2. Summary of included systematic reviews

Table 4 briefly summarises the included systematic reviews. The systematic reviews are also described below in turn, ordered by topic. Where UK studies were included and their data summarised in the systematic review, a brief summary of each study is also reported. Studies were considered to be in the UK if they were set in England and/or Wales and/or Scotland and/or Northern Ireland (but not if the systematic review indicated the study as being in Ireland). Appendix 7.3 reports the data extraction tables.

Table 4: Summary of included systematic reviews

Study Number of studies Key findings UK Total Topic A: Burden of PP (6 UK studies out of 104) Jokanovic et al, 3 44  Studies varied on the definition of polypharmacy. 2015 [23]  Prevalence of polypharmacy varied by study  Polypharmacy more likely with greater number of comorbidities, recent hospital discharge and greater number of prescribers.  Polypharmacy less likely with older age, cognitive impairment, impairment in activities of daily living and length of stay in long-term care facility. Leelakanok et 2 47  Studies varied on the definition of polypharmacy. al, 2017 [25]  Polypharmacy is associated with higher mortality risk.

Hill-Taylor et 1 13  The prevalence of PIMs varied between 21-79% and the prevalence of PPO varied between 23-74%. al, 2013 [20]  Higher prevalence of PIMs and of PPOs was associated with older age, female sex, polypharmacy and comorbidities.  The direct cost of PIP (PIM or PPO) was estimated in three studies: at €263-€318 per patient per year (Northern Ireland and Republic of Ireland). No further details were provided in the systematic review. Topic B: Interventions to reduce PP (28 UK studies out of 240) Clyne et al, 0 12  Organisational interventions reduce PIP (N=4 out of 6 RCTs). 2016 [36]  Evidence of the effectiveness of multidisciplinary teams was weak.  Clinical decision support systems reduce new PIP but not existing PIP (N=2 RCTs).  Multifaceted interventions reduce PIP (N=3 out of 4 RCTs). Hill-Taylor et 1 15  2013 review: there were some challenges in applying the STOPP/START criteria (version not specified but likely al, 2013 and version 1). 2016 [20, 21]  2013 review: 6 studies found the STOPP criteria more sensitive than Beers to detect PIP.  2016 review: interventions increased the chances that PIMs were reduced (random effects; OR 2.98; 95%CI 1.30, 6.93; N=4 RCTs; I-squared=87.6%). Johansson et al, 4 25  No effect on all-cause mortality and low levels of statistical heterogeneity (random-effects; OR 1.02; 95%CI 0.84 to 2016 [22] 1.23; N=25 studies; I-squared=8%; OR 1.05; 95%CI 0.85, 1.29; N=16 RCTs; I-squared=12%).  Very low quality evidence on the effect of interventions on hospitalisation.  Limited evidence on reduction of polypharmacy.

Study Number of studies Key findings UK Total Kua et al, 2019 8 41  Deprescribing was associated with lower mortality risk, although the studies’ results were highly heterogeneous. [24]  No evidence to suggest an effect of deprescribing on falls and hospitalisation risk.  Evidence to suggest that deprescribing reduced PIMs. Page et al, 2016 15 115  No effect on mortality (OR 0.82, 95%CI 0.61, 1.11; N=10 studies; n=3,151 people; I-squared=23%). [9]  Some evidence to suggest that deprescribing polypharmacy leads to a reduction in the number of medicines and to a reduction in the number of PIMs.  No evidence was found to suggest an increased risk of adverse outcomes, and some evidence was found on benefits. Rankin et al, 0 32  Evidence synthesis focussed on pharmaceutical care + standard care vs standard care. 2018 [29]  Statistically significant effect on medication appropriateness (random effects; MD -4.76; 95%CI -9.20, -0.33; N=5 studies; n=517; I-squared=95%); number of PIMS (random effects; SMD -0.22; 95%CI -0.38, -0.05; N=7 studies; n=1,832; I-squared=67%), proportion of patients with one or more PPOs random effects; RR 0.40, 95% CI 0.18, 0.85; N=5 studies; n=1,310; I-squared=90%).  Non-significant effect on the proportion of patients with one or more PIMs (random effects; RR 0.79; 95%CI 0.61, 1.02; N=11 studies; n=3,079; I-squared=85%); no consistent effect on medication-related problems; no evidence of impact on quality of life or hospitalisations. Topic D: Efficient handover between primary and secondary care Redmond et al, 1 25  Medicine reconciliation interventions reduced the proportion of people with at least one medication discrepancy 2018 [30] compared to standard care (random effects; RR 0.53; 95%CI 0.42, 0.67; N=20 RCTs; n=4,629; I-squared=91%).  Non-significant reductions in the number of discrepancies per person and the number of discrepancies per participant medication, with high levels of statistical heterogeneity.  Limited effect on PADEs (RR 0.37. 95% CI 0.09, 1.57; N=3 RCTs; n=1,253; I-Squared=84%), or on ADEs (RR 1.09, 95% CI 0.91 to 1.30; N=4 RCTs; I-Squared=0%).  Conflicting evidence on healthcare utilisation: RR on composite measure of emergency department, rehospitalisation 0.78; 95%CI 0.50, 1.22; N=4 RCTs; n-1,363; I-Squared=48%).

ADEs: adverse drug events; CI: confidence interval; MD: mean difference; OR: odds ratio; PADEs: preventable adverse drug events; PIM: potentially inappropriate medicine; PIP: potentially inappropriate prescribing; PP: problematic polypharmacy; PPO: potentially prescribing omission; RCT: randomised controlled trial; SMD: standardised mean difference.

Topic A: Burden of PP Jokanovic et al (2015) is a systematic review on the prevalence of, and the factors associated with, polypharmacy in people living in long-term care facilities [23]. The authors had a comprehensive search strategy and broad inclusion criteria. They included 44 primary studies, with a mean number of medicines ranging between 3.8-16.6 per resident. The primary studies generally had clearly defined inclusion criteria as well as objective criteria to assess outcomes, but were at risk of selection and confounding biases. Jokanovic et al found that the definition of polypharmacy, and hence the prevalence of polypharmacy, varied by study. The authors concluded that the prevalence of polypharmacy in residents of long-term care facilities is high. For example, 4-50% were on 12+ medicines (N=2 studies), 11-65% people were on 10+ medicines (N=11 studies) and 13-75% people were on 9+ medicines (N=13 studies). The factors positively associated with polypharmacy were number of comorbidities, recent hospital discharge and number of prescribers. The factors inversely associated with polypharmacy were older age, cognitive impairment, impairment in activities of daily living and length of stay in long-term care facility. Jokanovic et al included three UK studies:  Gadsby et al (2011) was a retrospective case notes review in 75 people with diabetes living in 11 long-term care facilities; they found that 45.3% of patients were on 4-7 medicines, 24.7% on 8-11 medicines and 4% on 13+ medicines [37]  Honney et al (2014) was a cross-sectional study of 316 people living of a long-term care facility who had an emergency hospital admission; they found that 50.5% were on 4-7 medicines and 42.1% were on 9+ medicines [38]  Whitney et al (2012) was a prospective cohort study in 240 patients aged over 60 years and resident in 10 long-term care facilities; they found that 69% were on 7+ medicines [39] Leelakanok et al (2017) is a systematic review and meta-analysis on the association between polypharmacy and mortality risk [25]. The searches and inclusion criteria were broad. Estimates were synthesised with random effect models with inverse variance weighting, including odds ratio (OR), relative risk (RR) and hazard ratio (HR) and across study designs. Leelakanok et al included and meta-analysed 47 studies, mostly with observational designs. At the quality assessment, 19 studies were considered to be of medium quality and 28 studies of high quality. Publication bias was assessed with a funnel plot and found to suggest some publication bias against smaller studies and/or studies with negative findings. Leelakanok et al found that the definition of polypharmacy varied across the studies, hence they meta- analysed the studies according to groupings by number of medicines considered to be polypharmacy as well as by the discrete number of medicines. They found that people who take more medicines are at higher mortality risk, and that the risk increases with more medicines. Leelakanok et al included two UK studies:  Richardson et al (2011) was a prospective cohort study in England and Wales comparing the outcomes of 1,586 older people on ≥5 medicines with 10,837 people on <5 medicines over 18 -years follow-up; the risk ratio for all-cause mortality controlling for age and comorbidities was 1.30 (95% confidence interval (CI) 1.19 to 1.42) [40].  Shah et al (2013) was a retrospective cohort study using routine health care records, comparing the outcomes of a community cohort of 354,306 patients on 0-2 medicines with those of an institutional cohort of 9,772 patients on 6-10 medicines; the risk ratio for all-cause

mortality, and adjusting for age, sex, comorbidities and other characteristics was 1.96 (95%CI 1.42 to 2.71) [41] Hill-Taylor et al are two systematic reviews on the prevalence of potentially inappropriate prescribing (PIP) in older adults and on the effectiveness of the application of the Screening Tool of Older Persons’ potentially inappropriate prescriptions/Screening Tool to Alert doctors to the Right Treatment (STOPP/START) criteria [20, 21]. The 2013 review provides some evidence on the prevalence and costs of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) [20]. The 2013 and 2016 reviews also provide evidence on the effectiveness of the STOPP/START criteria to detect and address these, which is discussed under Topic B below. The 2013 Hill-Taylor et al review included 13 studies, of which 12 were observational studies and one was an RCT, with a total of 344,957 participants, whose mean age of study was 75-87 years. The prevalence of PIMs varied between 21-79% and the prevalence of PPO varied between 23-74%. Higher prevalence of PIMs and of PPOs was associated with older age, female sex, polypharmacy and comorbidities. The direct costs of PIP was reported in three studies: €188 per patient with PPO per year and €318 per patient with PIM per year, both in 2007 in the Republic of Ireland; and €263 per patient with PIP per year in a study in Northern Ireland and in the Republic of Ireland (year not reported). Hill-Taylor et al does not detail what these costs include (e.g. drugs and/or complications due to PIP). Hill-Taylor et al found no studies on the cost-effectiveness of the STOPP/START criteria. The 2013 Hill-Taylor et al review included one primary study in Britain (excluding Northern Ireland):  Parsons et al (2012) conducted an observational cross-sectional study which applied the partial STOPP criteria to 119 people living with dementia in long-term care facilities, whose mean age was 87 years. The mean number of medicines was 8; 41-46% had ≥1 PIMs [42].

Topic B: Effectiveness of interventions to reduce PP Clyne et al (2016) is a systematic review on the effectiveness of interventions to reduce PIP in community-dwelling older adults [36]. The primary outcome was change in PIP using specified implicit or explicit tools. Clyne et al included 12 RCTs, with a total of 156,529 participants, with mean age between 65-81 years. None of the included RCTs was in the UK. The RCTs studied various types of interventions: organisational interventions (six RCTs), computerised clinical decision support systems (two RCTs) and multifaceted interventions (four RCTs). The studies were heterogeneous in size, outcome and intervention types, which precluded quantitative synthesis. The quality assessment suggests that the RCTs were at some risk of bias due to issues with the randomisation, allocation concealment and blinding. Overall, four of the six organizational intervention RCTs reported a decrease in PIP, particularly through medication reviews by pharmacists. Evidence of the effectiveness of multidisciplinary teams was weak. The two RCTs on clinical decision support systems found that these interventions were effective in decreasing new PIP but not existing PIP. Three of the four RCTs on multifaceted interventions were effective in reducing PIP. From the evidence summarised, the authors attested that it was unclear whether the interventions can result in clinically significant improvements in patient outcomes. Both the 2013 and the 2016 Hill-Taylor et al reviews examined the effectiveness of the STOPP/START criteria [20, 21]. The 2016 Hill-Taylor et al review included four RCTs (including the RCT found in the 2013 review), with a total of 1,935 participants. No studies were in the UK. Two

RCTs were on people who had been discharged from acute care whereas the other two RCTs were based in care homes. Across all included studies, study quality varied and only two of the four RCTs were at low risk of bias across key bias domains. Although referred to as ‘STOPP’ or ‘START’, some researchers used versions of the criteria that had been modified for their jurisdictional prescribing practices or formularies. For the 2016 review, the primary outcome was the change in the proportion of patients having at least one PIM. They found that the interventions increased the chances that PIMs were reduced, although the magnitude of the effect varied between studies (random effects; OR 2.98; 95%CI 1.30, 6.93; N=4 RCTs; I-squared=87.6%). The version of the STOPP/START criteria was not explicitly stated. Given the date of the studies, it is likely to be version 1. The 2013 review found that there were some challenges in applying the STOPP/START criteria, such as the need to consult medical history and learning curve effects. Six studies found the STOPP criteria more sensitive than Beers to detect PIP. The 2013 review concluded that the STOPP/START criteria are a promising tool to assess PIP in older adults, but more work was needed on their application to various care settings and jurisdictions. The 2016 review concluded that the STOPP/START criteria may be effective in reducing PIP, although more research is required. Johansson et al (2016) is a systematic review on the effectiveness of interventions to reduce polypharmacy on mortality, hospitalisation and number of drugs in elderly patients [22]. This review included 25 studies, of which 21 were RCTs. The included studies recruited between 79-2,454 participants, whose mean age was between 70-88 years. Most studies aimed to increase the quality of polypharmacy by eliminating inappropriate medicines, while five studies aimed to reduce the quantity of medicines. They categorised the interventions as pharmacist-led (N=13 studies), physician-led (N=3 studies), multidisciplinary-led (N=8 studies), and in one study either a pharmacist or a physician conducted medication reviews independently. Across all studies, there were potential methodological biases, particularly in relation to selection bias; the overall GRADE assessment was low to very low. Johansson et al found no effect on all-cause mortality and low levels of statistical heterogeneity (random-effects; OR 1.02; 95%CI 0.84 to 1.23; N=25 studies; I-squared=8%; OR 1.05; 95%CI 0.85, 1.29; N=16 RCTs; I-squared=12%). Some studies examined the effect of interventions to reduce polypharmacy on hospitalisation, but the evidence was deemed to be of very low quality. Although 23 studies provided data on the number of medicines at entry to the study and at follow-up, only three studies conducted a between-groups analysis. From the evidence summarised, the authors attested that there is no convincing evidence that the strategies assessed are effective in reducing polypharmacy or have an impact on clinically relevant endpoints. Johansson et al included four UK studies:  Lenaghan et al (2007) is an RCT comparing home-base medication reviews by a pharmacist with usual care in 134 community-dwelling older people over 6 months’ follow-up [43]. The primary outcome was number of non-elective admissions (RR 0.92; 95%CI 0.50, 1.70); other outcomes included change in EQ-5D index scores (MD 0.09; 95%CI 0.19, 0.02), change in EQ-5D VAS (MD 4.8; 95%CI -12.5, 2.8); and number of items prescribed (MD -0.87; 95%CI -1.66, -0.08).  Pope et al (2010) is an RCT comparing specialist geriatric input and medication review compared with usual care (review as required by a medical officer) in 225 people in continuing-care wards over 6 months’ follow-up [44]. The primary outcomes were number of drugs prescribed (statistical measures of effect not reported) and medication cost (net reduction in total medication cost = £20 per person).

 Zermasky et al (2006) was an RCT comparing clinical medication review by a pharmacist with usual care in 661 older people living in care homes over 6 months [45]. The outcomes included number of repeat drugs per patient at follow-up (MD 0.98 95%CI 0.92, 1.04), hospitalisations per patient (OR 0.75; 95%CI 0.52, 1.07), mortality (OR 0.89; 95%CI 0.56, 1.41), drug cost (MD -£0.70; 958%CI -£7.28, £5.71) and number of GP consultations (MD 1.03; 95%CI 0.93, 1.15).  Sturgess et al (2003) is an RCT comparing a structured pharmaceutical care programme with usual care in 191 community-dwelling older people over 18 months’ follow-up [46]. The outcomes included health-related quality of life measured with SF-36, number of hospitalisations, prescribed drug use, compliance to medication, number of contacts with health care professionals, and cost of healthcare per patient; only the p-value of the effect were reported but not the summary measure of effect. Kua et al (2019) is a systematic review on the effectiveness of deprescribing on polypharmacy in people living in nursing homes [24]. Kua et al included 41 RCTs with 18,408 people, mostly elderly and female. There were risks of detection bias across all studies, as the blinding of study participants and personnel was not possible due to the nature of the interventions. The primary outcome of the systematic review was mortality, for which the authors found: 14 RCTs on drug discontinuation, 11 RCTs on the impact of medication review, six RCTs on educational programs, and 10 RCTs on other interventions. Other outcomes included number of people who had falls, number of people who were hospitalised and number of people with PIM. Deprescribing was associated with lower mortality risk, although the studies’ results were highly heterogeneous. Kua et al preferred the results of the fixed effects meta-analysis, which suggested a statistically significant association between deprescribing and mortality risk (fixed effect: OR=0.90, 95%CI 0.82, 0.99; N=26 RCTs; n=12,248 people; I-squared=76.7%). This result was driven by results of studies on medication review-directed deprescribing intervention. The results of the random effects meta-analysis were not statistically significant (OR=1.02; 95%CI 0.85, 1.23; I-squared=51%). Kua et al found no evidence to suggest an effect of deprescribing on falls and hospitalisation risk. The five studies which examined the effect on PIMs found a statistically significant reduction with deprescribing, which was consistent with the meta-analysed results. The authors concluded that, compared to other deprescribing interventions, medication review-directed deprescribing was beneficial for older residents in nursing homes. Kua et al included eight UK studies:  Ballard et al (2004 and 2008) examined the discontinuation of neuroleptics by doctors and pharmacists over 3 months in 100 people and over 12 months in 165 people, respectively [47, 48].  Ballard et al (2016) examined medication review using dementia guidelines by doctors over 9 months in 277 people [49].  Fossey et al (2006) examined education training and support on alternatives to drugs for the management of agitated behaviour in dementia by pharmacists over 12 months in 359 people [50].  Furniss et al (2000) examined medication reviews by doctors and pharmacists over 3 months in 330 people [51].  Jordan et al (2015) examined adverse drug reaction profiling by nurses over 6 months in 43 people [52].

 Patterson et al (2010) examined medication review using a review model by pharmacists over 12 months in 334 people [53].  Zermanky et al (2006) examined medication review by pharmacists over 6 months in 661 people [45]. Page et al (2016) is a systematic review on the safety, effectiveness and feasibility of deprescribing interventions on mortality and other health outcomes [9]. The study included 56 RCTs (n=17,428 people), 22 comparative studies with concurrent control group (n=14,522 people) and 37 comparative studies without concurrent control group (n=2,207 people). Studies were based in hospital (N=14), residential aged care (N=29), community-dwellers (N=73) or mixed settings (N=2). Deprescribing interventions were examined by the number and type of medicines discontinued (e.g. polypharmacy, therapeutic category, class, medicine), by the person responsible for deprescribing (e.g. doctors, investigators, pharmacists, etc.) and by type (e.g. recommendations to the prescriber, educational programmes, etc.). Approximately two thirds of RCTs were at high or unclear risk of bias; results for non-randomised studies were not reported. Page et al examined mortality as the primary outcome and a wide range of health outcomes and process measures as secondary outcomes. The meta-analysis results based on the RCT evidence suggests no effect on mortality (OR 0.82, 95%CI 0.61, 1.11; N=10 studies; n=3,151 people) with low statistical heterogeneity (I-squared=23%). The results of two studies suggest that deprescribing polypharmacy leads to a reduction in the number of medicines and, from three studies, to a reduction in the number of PIMs. On health outcomes, the studies reported the consequences of deprescribing on a large variety of measures, which were generally relevant only for the target disease areas. Given the results of the meta-analysis, the authors concluded that deprescribing appears to be feasible and safe. Page et al included 15 UK studies:  Five studies were RCTs: Hearing et al on the deprescription of atenolol [54] Ballard et al (2008 and 2004; 2009) on the deprescription of antipsychotics [47, 48, 55]; Curran et al (2003) on the deprescription of benzodiazepines [56]; Borrill et al (2009) on the deprescription of inhaled fluticasone and salmeterol [57]; Choudhury et al (2007) on the deprescription of inhaled corticosteroids [58].  Three non-randomised comparative studies: Minett et al (2003) on the deprescription of donezepil [59]; Cunnington et al (2012) on the deprescription of dopamine agonists [60]; Jarad et al (1999) on the deprescription of inhaled corticosteroids [61].  Seven studies were before-and-after studies: Alsop et al (2001) and Fortherby et al (1994) are before-and-after studies on the deprescription of antihypertensives [62, 63]; Jackson et al (2005) on the deprescription of nitrates [64]; Sambu et al (2011) on the deprescription of clopidogrel [65]; Esselinckx et al (1977) on the deprescription of prednisolone [66]; Fair et al (1990) [67] and Daly and Edwards (1983) on the deprescription of digoxin [68]. Rankin et al (2018) is a systematic review on the effectiveness of interventions to improve the appropriate use of polypharmacy and reducing medication-related problems in older people [29]. They included 32 studies, namely 18 RCTs, 10 cluster RCTs and 4 non-randomised controlled studies, involving 28,672 people with mean age of 73 years and receiving a mean of 9 medicines. Rankin et al did not include any UK studies. The settings included hospital (N=16 studies), primary care (N=10 studies) and nursing homes (N=6 studies). All but one study examined complex multifaceted interventions of pharmaceutical care; this one study examined a computerised decision

support system provided to GPs. Across all studies, there was a high and/or unclear risk of bias across a number of domains; and the overall GRADE assessment was low to very low. The primary outcomes were: medication appropriateness, PIMs, PPOs and hospital admissions. Evidence synthesis was conducted for the comparison between pharmaceutical care vs. usual care. The results were mixed, generally uncertain and highly heterogeneous: medication appropriateness (random effects; MD -4.76; 95%CI -9.20, -0.33; N=5 studies; n=517; I-squared=95%); number of PIMs (random effects; SMD -0.22; 95%CI -0.38, -0.05; N=7 studies; n=1,832; I-squared=67%); proportion of patients with one or more PIMs (random effects; RR 0.79; 95%CI 0.61, 1.02; N=11 studies; n=3,079; I-squared=85%); proportion of patients with one or more PPOs (random effects; RR 0.40, 95% CI 0.18, 0.85; N=5 studies; n=1,310; I-squared=90%). The authors examined medication- related problems but found no consistent effect. Quality of life was reported in 12 studies, of which 10 found no differences; one study found an increase in quality of life in the intervention group, and one study found that both the intervention and the control group had a decline in quality of life. Two studies examined hospital admissions and found no effect. The authors concluded that it is unclear whether interventions to improve appropriate polypharmacy result in clinically significant benefits.

Topic C: Implementation activities No systematic reviews were found on the effectiveness of implementation activities to increase the uptake of interventions to reduce PP.

Topic D: Efficient handover between primary and secondary care Redmond et al (2018) is a systematic review on the effectiveness of medicines reconciliation on medication discrepancies, patient-related outcomes and healthcare utilisation during care transitions [30]. They included 25 RCTs, involving 6,995 people whose mean age was 66 years. All the studies were conducted in hospital or immediately related settings. All the medicine reconciliation interventions were organisational, with 23 RCTs on pharmacist mediated interventions and 2 RCTs on structural interventions, specifically an electronic reconciliation tool and on a change in medical records. There was a high and/or unclear risk of bias across all RCTs. The overall GRADE assessment varied from moderate to low or very low reliability. The primary outcome of the systematic review was medication discrepancies. Medicine reconciliation interventions reduced the proportion of people with at least one medication discrepancy compared to standard care (random effects; RR 0.53; 95%CI 0.42, 0.67; N=20 RCTs; n=4,629; I-squared=91%). Redmond et al found reductions in the number of discrepancies per person and the number of discrepancies per participant medication, but non-significant, with wide confidence intervals and high levels of statistical heterogeneity. Reconciliation had an uncertain effect on preventable adverse drug events (PADEs) (RR 0.37. 95% CI 0.09, 1.57; N=3 RCTs; n=1,253; I-Squared=84%), or on ADEs (RR 1.09, 95% CI 0.91 to 1.30; N=4 RCTs; I-Squared=0%). Evidence of the effect of the interventions on healthcare utilisation was uncertain (RR on composite measure of emergency department, rehospitalisation 0.78; 95%CI 0.50, 1.22; N=4 RCTs; n-1,363; I-Squared=48%). From the evidence summarised, the authors attested that interventions implemented in the studies in this review reduced the number of medication discrepancies at care transitions. However, the certainty in this result is unclear as the evidence was of very low certainty. There was also uncertainty of the effect of the interventions on the secondary clinical outcomes of ADEs, PADEs and healthcare utilisation. Redmond et al included two UK studies:

 Cadman et al (2017) is an RCT comparing a standardised operating procedure based on hospital guidelines to deliver medication reviews by trained MRP within 24 hours of admission and at point of transfer of care out of hospital against usual care in 200 people at hospital admission [69]. The outcomes included length of stay (MD -0.40; 95%CI -2.08, 1.29), unintentional discrepancies (not reported), hospital readmissions (RR 0.86; 95%CI 0.58, 1.28), mortality (RR 0.75; 95%CI 0.27, 2.08) and EQ-5D-3L index scores (not reported).  Bolas et al (2004) is an RCT comparing a medicines reconciliation intervention with standard clinical care in 243 people after an emergency or unplanned admission to a hospital in Northern Ireland [70]. The primary outcome was unclear; other outcomes included Eadon scores, medicines discrepancies, emergency readmission rates and rates of reconciliation. No results were reported.

3.2.3. Quality of the included studies

Table 5 presents the results from the AMSTAR-2 quality assessment. All the included systematic reviews defined the research question and the reported aims, and reported: the inclusion criteria for the population, intervention and comparator (for the intervention reviews), outcomes, and setting (where reviews were setting specific). Across eight of the studies, the population was defined by age and/or setting [9, 20-24, 29, 30, 36]. For one study the population was simply defined as ‘human’ [25]. For five of the included systematic reviews, a protocol was available detailing its methods [9, 20-22, 29, 30]. For the remainder of the systematic reviews, it was unclear from the publication if a protocol was available. Eight of the systematic reviews reported the study design type(s) for inclusion [9, 20- 24, 29, 30, 36]. For one systematic review, whilst there were exclusion criteria for study design types, there was no explicit inclusion criterion [25]. Only four of the systematic reviews provided details of studies excluded at the full-text stage, with reasons for exclusion [9, 22, 29, 30], and only four of the systematic reviews reported the funding source for studies included in the review [9, 20-22, 30]. Seven of the systematic reviews pooled their included study data in a meta-analysis [9, 20-22, 24, 25, 29, 30], of which five reported broadly appropriate methods for the meta-analysis [9, 20-22, 29, 30]. Kua et al., on deprescribing interventions, report results for both random- and fixed-effects models, but based their conclusions on the results from the fixed-effects meta-analysis [24]. Given the Cochran Q test p-value, small sample size and small number of studies [71], the results from the random-effects meta-analysis should have been preferred and are reported in the present rapid review. Leelakanok et al., on the association between polypharmacy and mortality risk, pooled data from different study designs, different effect estimates, estimates which were not adjusted for possible confounders [25]1. Hence the meta-analysed estimates are likely to be subject to confounding bias (also known as endogeneity). Six of the seven systematic reviews that undertook a meta-analysis did not incorporate study quality into the analysis, e.g., presenting subgroup analyses by study quality or, where different study designs were pooled together, presenting sensitivity analyses for randomised controlled trials only [9, 20-22, 24, 29, 30]. One systematic review did present meta-analysis results by high and low study quality [25].

1 In the epidemiology literature, a confounder is a characteristic or factor that affects the exposure and the outcome, and can be time-varying or time-independent. In the econometrics literature, this situation is referred to as endogeneity.

All of the nine systematic reviews considered the quality of their included studies in the interpretation of results in the discussion. Likewise, all nine systematic reviews considered heterogeneity (clinical/methodological/statistical) when interpreting results in the discussion. Only four of the systematic reviews that undertook a meta-analysis also undertook a formal assessment of publication bias, all by visual inspection of funnel plot symmetry [24, 25, 29, 30]. Results varied, with one systematic review on deprescribing interventions reporting that funnel plots did not indicate any evidence of publication bias [24], one systematic review on the association between polypharmacy and death reporting that the funnel plot indicated that there may be some publication bias with negative studies not being published [25], and two systematic reviews, one on interventions for polypharmacy and the other on medication reconciliation at transition, reporting that, from the funnel plot, there was a possibility of publication bias because some smaller studies might have produced exaggerated intervention effect estimates [29, 30]. Seven of the systematic reviews reported on funding sources for the review and author conflicts [9, 20-25, 36], of which the systematic reviews by Clyne at al., on interventions to address potentially inappropriate prescribing [36], and Hill-Taylor et al., on the prevalence of potentially inappropriate prescribing in older adults [20, 21], declared that there were author conflicts. Two of the included systematic reviews were Cochrane reviews [29, 30]. Cochrane reviews cannot be funded or conducted by commercial sponsors or commercial sources, and Cochrane prohibit conflicted authors from participating in the review team [72]. As such, these two systematic reviews were judged as ‘yes’ for this domain of AMSTAR-2.

Table 5: AMSTAR-2 assessment of the included studies

Study

reported?

textexcluded

analysis,are the analysis,has study analysis,has

- - -

studyquality used tointerpret

Is thereIs aclear research question and inclusioncriteriafor studies? Weremethods established prior the reviewinaprotocol? Werestudy designs forinclusion in thereview reported? Wasthere acomprehensive literature searchstrategy? Wasstudy selection undertaken in duplicate? Wasdata extraction undertaken in duplicate? thereIs alist offull studieswithreasons? Arethe included studies described in adequatedetai thereIs an appropriate quality assessmentofstudies? Arethe sources offunding for includesstudies reported? thereIf ameta is methodsappropriate? thereIf ameta is qualitybeen considered inthe analysis? Is resultsand discussion? thereIs explanation andfor, discussionobservedof, heterogeneity? thereIf ameta is publicationbias been assessed? Areofconflicts ofinterest, and fundingforthe review

Clyne et al, 2016[36] Yes NR Yes Yes Yes Yes No Yes Yes No N/A N/A Yes Yes N/A Yes

Hill-Taylor et al, Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No Yes Yes No Yes 2013/2016[20, 21]

Johansson et al, 2016[22] Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes

Jokanovic et al, 2015[23] Yes NR Yes Yes Yes Yes No Yes Yes No N/A N/A Yes Yes N/A Yes

Kua et al, 2018[24] Yes NR Yes Yes Yes Yes No Yes Yes No No No Yes Yes Yes Yes

Leelakanok et al, No NR No Yes No Yes No Yes Yes No No Yes Yes Yes Yes Yes 2017[25]

Page et al, 2016[9] Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes

Rankin et al, 2018[29] Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes Yes (Cochrane review)

Redmond et al, 2018[30] Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes (Cochrane review)

NA, not applicable; NR, not reported

3.2.4. Summary of findings and key uncertainties

This rapid review included nine good quality systematic reviews [9, 20-25, 29, 30, 36]. Data from these systematic reviews were synthesised according to each of the topics and research questions, and an assessment of their methodological quality was undertaken using AMSTAR-2 [16]. No quantitative synthesis was undertaken.

Topic A: Burden of PP Overview For the topic of burden of PP, three systematic reviews were included: Jokanovic et al [23], Leelakanok et al [25] and Hill-Taylor et al [20]. The three systematic reviews were international, with all UK studies: three by Jokanovic et al [23], two by Leelakanok et al [25] and one by Hill-Taylor et al [20]. Summary of findings The reviews suggest that there is no consensus in the literature on the definition of polypharmacy [23, 25]. The definitions vary by the number of medicines and whether or not to include medicines prescribed on as “when required” basis and over-the-counter medicines. The prevalence of polypharmacy in people residing in long-term care facilities was thought to be high [23], although a benchmark was not defined. The UK studies included in Jokanovic et al suggest that 69% of residents aged >= 60 years were on 7+ medicines [39]; 42% of residents who had an emergency hospital admission were on 9+ medicines [38]; and 29% of residents with diabetes were on 13+ medicines [37]. Irrespective of setting, polypharmacy is associated with greater risk of death [25]. Since people with poorer health tend to take more medicines and are at higher mortality risk, and considering that some estimates of risk were obtained from observational studies and/or unadjusted analysis, this association is unlikely to accurately represent a causal effect. The prevalence and costs of PP can be inferred from the 2013 Hill-Taylor et al review [20]. Assuming that PIMs are instances of PP, the prevalence of PP is 21-79% depending on the country, setting and study design. From the single UK study included by Hill-Taylor et al, 41-46% of people living with dementia in long-term care facilities were on PP (i.e. had at least 1 PIM) [42]. Estimates of costs were reported by the 2013 Hill-Taylor et al review, but it is unclear which resources were included and what the costs represent. Quality assessment In terms of the AMSTAR-2 quality assessment, it was unclear if the Jokanovic et al and Leelakanok et al reviews had an a priori protocol detailing the review methods; and these reviews did not report the sources of funding of the included studies [23, 25]. Jokanovic et al, Leelakanok et al and Hill- Taylor et al did not provide details of the studies excluded at the full-text stage [20, 23, 25]. Leelakanok et al pooled different study designs and effect estimates together [25]. This incorrectly assumes that the measures of association, such as ORs, RRs and HRs, from RCTs and observational studies, adjusted and unadjusted, measure the same quantities and have the same interpretation. Additionally, Leelakanok et al found some evidence of publication bias against negative studies [25]. Hence, their results should be interpreted as evidence of association, albeit uncertain, and not as evidence of a causal effect.

Key uncertainties No evidence was found on the prevalence of polypharmacy in people living in the community or during a hospital admission. Evidence was found on the prevalence of polypharmacy in people residing in long-term care facilities around the world [23], but its generalisability to the UK is uncertain. Some evidence was found on the prevalence of PP, in terms of PIMs, but was mostly from outside the UK and may not be representative [20]. The heterogeneity in the measurement of the number of medicines and definition of polypharmacy adds to the uncertainty in the evidence [23, 25]. There is some evidence on the factors and costs associated with polypharmacy and PP [20, 23, 25], although these are unlikely to accurately represent a causal effect.

Topic B: Interventions to reduce PP Overview For the topic of interventions to reduce PP, six systematic reviews were included that evaluated the effectiveness of interventions to reduce PP: Clyne et al; Hill-Taylor et al; Johansson et al; Kua et al, Page et al and Rankin et al [9, 20-22, 24, 29, 36]. Kua et al was specifically on the effectiveness of deprescribing guidelines to reduce PP [24]. All reviews were international in nature, with four including studies undertaken in the UK (1 out of 13 in the 2013 review [20], 8 out of 41 [24], 4 out of 24 [22], 15 out of 116 [9]). No systematic reviews were found that evaluated the effectiveness of using routine data to reduce PP, or the effectiveness of digital technologies to reduce PP. Summary of findings There is a large body of evidence on the effectiveness and safety of deprescribing in people on polypharmacy. For example, the review with the most recent searches (Rankin et al, in February 2018), included 32 controlled studies, of which 28 were RCTs [29]. The broadest review was Page et al, which included 116 studies, of which 56 were RCTs [9]. Five reviews found that the interventions reduce PP (in terms of PIP or PIMs) [9, 21, 24, 29, 36], although reductions in polypharmacy are more uncertain [9, 22]. One review concluded that the STOPP/START criteria could be useful to identify people at risk of PIP, although more research was required on their feasibility and effectiveness [20, 21]. In general, there is no clear evidence of an effect on clinically relevant outcomes [22, 36]. From a safety perspective, evidence from 116 primary studies suggests that deprescribing does not increase the risk of adverse outcomes [9]. Three systematic reviews reported meta-analysed results on the effect of interventions to reduce PP on all-cause mortality; given the heterogeneity and parameter uncertainty, the results suggest that there is no effect on all-cause mortality [9, 22, 24]. The evidence for benefits on disease-specific outcomes is mixed [9, 24], as well as on quality of life [9, 29] and hospitalisations [24, 29]. Quality assessment In terms of the AMSTAR-2 quality assessment, it was unclear if one review had an a priori protocol detailing the review methods [24], three reviews did not provided details of the studies excluded at the full-text stage [20, 21, 24, 36], three reviews did not provided sources of funding of the included studies [24, 29, 36], and none of the five reviews presenting a meta-analysis considered study quality in the analysis [9, 20-22, 24, 29]. Two of the five reviews presenting a meta-analysis assessed publication bias [24, 29]. Ranking et al concluded that there was a possibility of publication bias because some smaller studies might have produced exaggerated intervention effect estimates [29]. In contrast, Kua et al found that there was no evidence of publication bias [24]. Additionally, there are

limitations in the Kua et al meta-analysis given the choice of fixed-effects (rather the random-effects) as the preferred results. For these reasons, the results from all meta-analyses should be interpreted with caution. Key uncertainties The generalisability to the UK is unclear given that the majority of primary research studies were conducted in other countries [9, 20-22, 29, 36]. There is also uncertainty about whether the effect of interventions in the context of RCT is representative of the effect if those interventions were implemented in clinical practice, even if the RCTs were recent and in the UK. There is uncertainty in the estimates of effect due to the variable study quality, including evidence of selection bias, and heterogeneity in their methodology [9, 20-22, 29, 36]. This heterogeneity is reflected in the meta-analyses’ statistical heterogeneity, where the estimates of I-square were generally above 50% [20, 21, 29]. Given the limited quality, and despite the large body of evidence, the estimates of effect are subject to some uncertainty.

Topic C: Implementation activities to improve uptake of interventions to reduce PP No systematic reviews were found that evaluated the effectiveness of implementation activities to increase uptake of interventions that reduce PP or the effectiveness of implementation activities to increase shared decision making to reduce PP.

Topic D: Efficient handover between primary and secondary care to reduce PP Overview For the topic of efficient handover between primary and secondary care to reduce PP, one systematic review was included that evaluated the impact of medication reconciliation for improving transitions of care [30]. This review included two studies in the UK out of 25 studies [69, 70]. Summary of findings Whilst the interventions implemented in the studies reduced the medication discrepancies at care transitions, the evidence was deemed to have very low certainty. There was little or no effect on ADEs, PADEs, or health care utilisation, although these findings are also uncertain due to the quality of the primary studies. Quality assessment In terms of the AMSTAR-2 quality assessment, whilst the authors did not consider study quality in the meta-analysis, they did report that funnel plot indicated that there was a possibility of publication bias because some smaller studies might have produced exaggerated intervention effect estimates. Key uncertainties There is uncertainty in the generalisability to the UK setting given the large number of studies outside of the UK. The meta-analysis had a high degree of statistical heterogeneity, which suggests that there was variation in the results from the primary studies. Given Redmond et al’s finding that there was a possibility of publication bias, the magnitude of the benefits of medicines reconciliation activities may have been overestimated in the meta-analysis.

4. Scoping searches

4.1. Overview

To understand the size and nature of the current literature on PP, the searches that informed the included systematic reviews were re-rerun and the citations screened for their relevance to PP. Additionally, for research questions where systematic reviews were not already available, and which are amenable topics for literature reviews, new searches were developed and conducted.

4.2. Methods

The scoping searches had three components: search update, new scoping searches and searches of clinical trial registers.

4.2.1. Search update of included systematic reviews

The included systematic review searches were updated in MEDLINE provided that the search strategies were fully available and date of the last search was more than two years ago (before August 2017). A filter was applied to retrieve primary studies from the UK under Topic A: Burden. A filter to retrieve RCTs was applied to the searches under Topic B: Effectiveness of interventions to reduce PP. Five systematic reviews were selected to have their searches updated as per Table 6: Jokanovic et al [23] and Leelakakok et al [25] on Topic A: Burden; and Clyne et al [36], Johansson et al [22] and Page et al [9] on Topic B: Effectiveness of interventions to reduce PP. Hill-Taylor et al was excluded given that the search strategy was not clearly reported in the protocol [20, 21]. Rankin et al [29], Kua et al [24], and Redmond et al [30] were excluded given that their searches had been conducted less than two years from the present date. The search strategies are reported in Appendix 7.4.1.

Table 6: Selection of systematic reviews to update searches

Author Strategies Search dates and databases Update Topic A: Burden of PP Jokanovic et al [23] Yes Until September 2014 Yes

Leelakanok et al Yes Until June 2016 Yes [25] MEDLINE, Embase, Scopus Topic B: Interventions to reduce PP Clyne et al [36] Yes Until January 2015 Yes MEDLINE, Embase, Cochrane, Scopus Hill-Taylor et al Yes Until June 2014 No [20, 21] MEDLINE, Embase, CINAHL, CDSR, Strategy not clearly reported DARE, WoS in protocol Johansson et al [22] Yes Until July 2015 Yes MEDLINE, Embase, EBM reviews Page et al [9] Yes Until February 2015 Yes MEDLINE, Embase, CINAHL, DARE, Scopus Rankin et al [29] Yes Until February 2018 No Searches post-Aug 2017 Kua et al [24] Yes Until September 2017 No Searches post-Aug 2017 Redmond et al [30] Yes Until January 2018 No Searches post-Aug 2017

4.2.2. New scoping searches

New searches were conducted in MEDLINE on 8th August 2019 for primary research studies on Topic A: Burden of PP, specifically on the prevalence and/or incidence of PP, its costs to the NHS and its health consequences. This topic was prioritised for new searches given that only three systematic reviews had information on this topic [20, 23, 25], with few UK studies and limited information on health outcomes and costs caused by PP. The scoping strategy is reported in Appendix 7.4.2. Scoping searches for the effectiveness of implementation activities to increase the uptake of interventions to reduce PP was not undertaken for a number of reasons. Firstly, to search for these studies, the nature of the implementation activities will need to be defined. Secondly, Topic C relates to Topic B where the implementation activities may be covered in studies that evaluated both the effectiveness of the interventions and implementation or shared decision making e.g. uptake of deprescribing guidelines. Thirdly, searching for outcomes i.e. shared decision or implementation is fraught with difficulties, which may lead to eligible studies not being consistently retrieved.

4.2.3. Searches of clinical trial registers

The Clinicaltrials.gov register and WHO International Clinical Trials Registry Platform were searched on 14th August to retrieve ongoing or completed but unpublished trials. Keywords for polypharmacy were searched in both trial registers without applying any limits. The search terms used are reported in Appendix 7.4.3.

4.3. Results

4.3.1. Search update

Table 6 shows the results of the search update. Under Topic A: Burden, the searches retrieved 106 unique records; under Topic B: Effectiveness of interventions to reduce PP, the searches retrieved 1,094 unique records. The reference list is reported in Appendix 7.5.1.

Table 7: Search update results

Author MEDLINE update Filter applied With Filter Total by topic combined (unique) Topic A: Burden of PP Jokanovic et al [23] 210 UK 25 108 (106) Leelakanok et al [25] 637 UK 83 Topic B: Interventions to reduce PP Clyne et al [36] 307 RCT 85 1171 (1094) Johansson et al [22] 2069 RCT 238 Page et al [9] 2573 RCT 848

4.3.2. New scoping searches

The new scoping strategies on Topic A: Burden of PP retrieved 5,494 records and 576 records following application of the filter for UK studies. The reference list is reported in Appendix 7.5.2.

4.3.3. Searches of clinical trial registers

The searches on clinical trial registers retrieved 215 studies in clinicaltrials.gov and 97 studies in the World Health Organisation International Clinical Trials Registry Platform. The reference list is reported in Appendix 7.5.3.

5. Conclusions

5.1. Key findings

5.1.1. Rapid review

This rapid systematic review included nine good quality systematic reviews. Three on Topic A: Burden of PP [20, 23, 25]; six on Topic B: Interventions to reduce PP [9, 20-22, 24, 29, 36]; and one on Topic D: Efficient handover between primary and secondary care to reduce PP [30]. All reviews were international, with most including UK studies. Topic A: Burden of PP. There is no consensus in the literature regarding the definition of polypharmacy. The prevalence of polypharmacy in people residing in long-term care facilities varies widely depending on the polypharmacy definition, but is thought to be high [23]. The prevalence of PP, assuming it corresponds to PIM, was estimated at 21-79% [20]. Polypharmacy is associated with greater risk of death [25]. It is unclear the extent to which this association reflects a causal effect, due to bias due to confounding by poorer health.

Topic B: Interventions to reduce PP. The evidence suggests that the interventions can reduce PP [9, 21, 24, 29, 36], although reductions in polypharmacy (as number of medicines) are more uncertain [9, 22]. Deprescribing and other interventions to reduce PP appears to have no effect on all-cause mortality [9, 22, 24], but there is no clear evidence of an effect on other clinically relevant outcomes [9, 22, 24, 36], quality of life [9, 29] and hospitalisations [24, 29]. Topic C: Implementation activities to increase uptake of interventions to reduce PP. No systematic reviews were found on this topic. Topic D: Efficient handover between primary and secondary care to reduce PP. There is some evidence that medicine reconciliation activities reduce medication discrepancies at care transitions [30].

5.1.2. Scoping searches

The scoping searches in MEDLINE retrieved a total of 7,006 records, as follows:  Topic A: Burden of PP: 106 unique records from search update and 5,494 records from new searches, of which 576 records are thought to refer to UK studies.  Topic B: Interventions to reduce PP: 1,094 records from search update  On PP: 312 ongoing RCTs from the trials registers searches. PP is an active topic for research given the large number of records retrieved.

5.2. Strengths and limitations

The rapid review and scoping searches have examined the literature on PP in an efficient and pragmatic way. Rather than searching for and reviewing primary research studies, the rapid review searched for systematic reviews, selected good quality studies, data extracted and critically appraised them. This allowed the rapid review to summarise the literature on the three of the four broad topics of interest and identify the areas with stronger evidence and areas where more research is required. Additionally, the searches of the older systematic reviews were updated to show the growth in the literature. New searches were conducted to show the size of the literature on the burden of PP. Furthermore, two clinical trial registers were searched for ongoing RCTs which may address some of the remaining uncertainties. These reference lists can inform future systematic reviews. Given the time and resource constraints, this rapid review has some limitations. It was not feasible to consult with patients and members of the public over the 2 months of the research. Patients and members of the public could have collaborated in the development of the research questions, to ensure that they were relevant from their perspective, and in understanding the importance of the findings. The systematic review searches were designed to be highly specific. For example, an age filter targeting the over 65s was applied to identify reviews relating to a population who are more likely to be affected by PP. Whilst this filter may exclude reviews that may address the topics of interest across all populations irrespective of age, the resulting number of records retrieved would make the completion of the review unfeasible in the time available. Another limitation is that the study selection process, quality assessment and data extraction were conducted by a single researcher. This allowed the team to process studies in parallel, thereby making best use of the available resources. A third researcher checked the data extraction for outcomes to minimise the risk of data being extracted incorrectly. It is possible that eligible systematic reviews may have been missed at the study selection stage and elements of the data extraction process may not be completely accurate. Additionally, primary studies which were missed by the included systematic reviews were necessarily missed by

this review. The research questions were highly specific to allow for targeted searches and an informative review within the timeline. Inappropriate or potentially hazardous prescribing has some links with problematic polypharmacy. Its exclusion from the topics of interest may have resulted in relevant systematic reviews being missed. Furthermore, the rapid nature of the review and short timelines meant that the adequacy of the published search strategies could not be assessed, or the records retrieved by the searches could not be screened to identify those related with PP. Given the study design, there may be recent primary studies, which were not included in the systematic reviews, which could provide relevant evidence to inform the research questions.

5.3. Remaining uncertainties

Topic A: Burden of PP. The evidence on the burden of PP was scarce. The evidence on the prevalence of polypharmacy referred to people residing in long-term care facilities, was highly heterogeneous and only included three UK studies. The evidence on the prevalence of PP was limited to a few studies, of which only one study was in the UK. The evidence on the association between polypharmacy and mortality risk was mostly international and it is unlikely to reflect a causal effect due to confounding bias. From one systematic review, three studies were found on the costs due to PP, but none was in the UK and their methodology was unclear. For these reasons, the prevalence of polypharmacy and PP, and the costs and health consequences due to PP in the UK remain unclear. Topic B: Interventions to reduce PP. Despite the large body of evidence, the effectiveness of interventions to reduce PP is subject to uncertainty. The uncertainty is due to unclear generalisability of the results from international studies and/or studies in controlled environments to the current clinical practice in the UK. Furthermore, there is uncertainty on the impact of interventions to reduce PP. This uncertainty is caused by the variable quality of the primary research, heterogeneity in their methodology and limitations in the evidence synthesis. Topic C: Implementation activities to increase uptake of interventions to reduce PP. Given that no evidence was found on implementation activities, the uncertainties regarding this topic remain. Topic D: Efficient handover between primary and secondary care to reduce PP. Given the nature of the evidence, the remaining uncertainties are similar to those in Topic B. In brief, the evidence is generally of poor quality and its generalisability to the current clinical practice in the UK is unclear.

5.4. Suggestions for future research

Topic A: Burden of PP. Further research is warranted on the prevalence of PP in the UK, and its costs and health consequences, to understand its magnitude and its consequences. The research could consider the following areas:  To estimate the prevalence of polypharmacy and the prevalence of PP in the UK, according to a definition that represents the current expert consensus.  To identify the factors that predict PP in the UK with the aim of routinely identifying people at risk of PP and who should be prioritised for interventions to reduce PP.  To estimate the causal effect of PP on costs and on health outcomes; in other words, what would have been the costs and health outcomes of a group of people exposed to PP had they not been exposed to PP? Topic B: Interventions to reduce PP and Topic C: Efficient handover between primary and secondary care to reduce PP. Future research could inform which interventions are most likely to be

effective and cost-effective in reducing PP in the UK. Given the evidence identified in this rapid review and in the scoping searches, the future research could consider the following approaches:  To identify relevant primary studies on the effectiveness of interventions to reduce PP (e.g. from the included systematic reviews and from the scoping searches).  To use the appropriate evidence synthesis methodology and content expertise to estimate the comparative effectiveness of each intervention to reduce PP, considering the quality of the primary studies and their generalisability to the UK.  To estimate the resources and costs required to implement and run the various interventions (for which the evidence synthesis estimated a reliable effect).  To estimate the cost-effectiveness of the interventions, with cost-effectiveness modelling of the long-term costs and health outcomes of current practice with or without interventions, given the prevalence of PP, the consequences of PP on costs and health outcomes and the effectiveness of interventions in reducing PP. Topic D: Implementation activities to increase uptake of interventions to reduce PP. Given the lack of evidence on this topic, future research could explore the following areas:  To understand the extent to which interventions to reduce PP are used in the UK, and if uptake is suboptimal, to identify the barriers to uptake and the implementation activities that could address these.  To review the literature and conduct evidence synthesis to estimate the comparative effectiveness of the relevant implementation activities in changing uptake, considering the quality of the primary studies and their generalisability to the UK.  To conduct cost-effectiveness modelling of the value of implementation given the current uptake, the effectiveness of implementation activities, the cost-effectiveness of interventions to reduce PP and the prevalence of PP.

6. References

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7. Appendices

7.1. Appendix 1: Medline search strategy

# Searches Results

1 polypharmacy/ 4334 Polypharmacy concept 2 polypharma*.ti,ab. 7052 adapted from Cochrane 3 polytherap*.ti,ab. 1706 review search 4 ((multi-drug* or multidrug*) adj2 (prescrib* or prescription* 3775 strategy or therap* or treatment*)).ti,ab.

5 inappropriate prescribing/ 2689

6 potentially inappropriate medication list/ 302

7 ((inappropriat* or unnecessary or multipl*) adj2 (medicine* 17596 or medicat* or prescrib* or prescription* or drug*)).ti,ab.

8 ((over adj1 (prescrib* or prescript*)) or (over-prescrib* or 1523 overprescrib*)).ti,ab.

9 deprescriptions/ 228

10 (deprescrib* or deprescript*).ti,ab. 445

11 or/1-10 33714

12 MEDLINE.tw. 104892 High specificity SR 13 systematic review.tw. 130997 filter

14 meta analysis.pt. 102140

15 12 or 13 or 14 243663

16 11 and 15 928

17 limit 16 to elderly 343 Limits

18 limit 17 to (english language and yr="2009 -Current") 283

7.2. Appendix 2: Citations which passed the title screen

Black CD, Thompson W, Welch V, McCarthy L, Rojas-Fernandez C, Lochnan H, et al. Lack of Evidence to Guide Deprescribing of Antihyperglycemics: A Systematic Review. Diabetes Ther. 2017;8(1):23-31. 2. Cameli D, Francis M, Francois VE, Medder NR, Von Eden L, Truglio-Londrigan M. A systematic review of medication reconciliation strategies to reduce medication errors in community dwelling older adults. JBI Database of Systematic Reviews and Implementation Reports. 2012;10(Supplement 42):S159-S76.

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40. Monteiro L, Maricoto T, Solha IS, Monteiro-Soares M, Martins C. Computerised decision to reduce inappropriate medication in the elderly: a systematic review with meta-analysis protocol. BMJ Open. 2018;8(1):e018988. 41. Motter FR, Fritzen JS, Hilmer SN, Paniz EV, Paniz VMV. Potentially inappropriate medication in the elderly: a systematic review of validated explicit criteria. European Journal of Clinical Pharmacology. 2018;74(6):679-700. 42. Nakham A, Bond C, Newlands R, Myint P, Cruickshank M. Interventions to reduce anticholinergic burden in adults aged 65 and over: A systematic review. International Journal of Pharmacy Practice. 2019;27 (Supplement 2):41-2. 43. Nguyen T, Gurwitz J. Deprescribing in older adults: A systematic review. Journal of the American Geriatrics Society. 2016;64:S94. 44. Nicieza-Garcia ML, Salgueiro-Vazquez ME, Jimeno-Demuth FJ, Manso G. Inappropriate prescribing in polypharmacy elderly outpatients taking multiple medications. Are the STOPP criteria useful? Int J Clin Pharmacol Ther. 2016;54(3):172-6. 45. Opondo D, Eslami S, Visscher S, de Rooij SE, Verheij R, Korevaar JC, et al. Inappropriateness of medication prescriptions to elderly patients in the primary care setting: a systematic review. PLoS ONE. 2012;7(8):e43617. 46. Page AT, Clifford RM, Potter K, Schwartz D, Etherton-Beer CD. The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta-analysis. British Journal of Clinical Pharmacology. 2016;82(3):583-623. 47. Palmer K, Villani ER, Vetrano DL, Cherubini A, Cruz-Jentoft AJ, Curtin D, et al. Association of polypharmacy and hyperpolypharmacy with frailty states: a systematic review and meta-analysis. European Geriatric Medicine. 2019;10(1):9-36. 48. Patterson SM, Bradley MC, Kerse N, Cardwell CR, Hughes CM. Interventions to improve the appropriate use of polypharmacy for older people: A Cochrane Review. International Journal of Pharmacy Practice. 2011;19:17-8. 49. Patterson SM, Bradley MC, Kerse N, Cardwell CR, Hughes CM. Interventions to improve the appropriate use of polypharmacy for older people: A cochrane systematic review. Pharmacoepidemiology and Drug Safety. 2013;22 (6):685-6. 50. Patterson SM, Cadogan CA, Kerse N, Cardwell CR, Bradley MC, Ryan C, et al. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database of Systematic Reviews. 2014(10):CD008165. 51. Patterson SM, Hughes C, Kerse N, Cardwell CR, Bradley MC. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database of Systematic Reviews. 2012(5):CD008165. 52. Patton D, Hughes C, Cadogan C, Ryan C. Theory-based interventions that aim to improve medication adherence in older adults who are prescribed multiple medications: A systematic review. International Journal of Pharmacy Practice. 2016;24 (Supplement 3):41-2. 53. Piraino E, Heckman G, Glenny C, Stolee P. Transitional care programs: who is left behind? A systematic review. Int J Integr Care. 2012;12:e132. 54. Poudel A, Peel N, Mitchell C, Nissen L, Hubbard R. A systematic review of prescribing criteria to evaluate appropriateness of medications in frail older people. Reviews in Clinical Gerontology. 2014;24(4):304-18. 55. Pruskowski JA, Springer S, Thorpe CT, Klein-Fedyshin M, Handler S. Does deprescribing improve quality of life? A systematic review of the literature. Journal of the American Geriatrics Society. 2019;67 (Supplement 1):S226. 56. Raae-Hansen C, O'Mahony D, Kearney PM, Sahm LJ, Cullinan S, Rutjes AWS, et al. Changing behaviours: A systematic literature review of deprescribing interventions in older people. Age and Ageing. 2017;46 (Supplement 3):iii13. 57. Rankin A, Cadogan C, Cooper J, Patterson MS, Kerse N, Cardwell RC, et al. Interventions to improve the appropriate use of polypharmacy for older people: An updated Cochrane systematic review. International Journal of Pharmacy Practice. 2018;26 (Supplement 1):5-6. 58. Rankin A, Cadogan C, Ryan C, Clyne B, Smith MS, Hughes C. Development of a core outcome set for use in interventions aimed at improving appropriate polypharmacy in older people in primary care. International Journal of Pharmacy Practice. 2018;26 (Supplement 1):6-7.

59. Rankin A, Cadogan CA, In Ryan C, Clyne B, Smith SM, Hughes CM. Core Outcome Set for Trials Aimed at Improving the Appropriateness of Polypharmacy in Older People in Primary Care. Journal of the American Geriatrics Society. 2018;66(6):1206-12. 60. Rankin A, Cadogan CA, Patterson SM, Kerse N, Cardwell CR, Bradley MC, et al. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database of Systematic Reviews. 2018;9:CD008165. 61. Rankin A, Cadogan CA, Patterson SM, Kerse N, Cardwell CR, Bradley MC, et al. Interventions to improve the appropriate use of polypharmacy for older people. Cochrane Database of Systematic Reviews. 2018(9). 62. Redmond P, Grimes TC, McDonnell R, Boland F, Hughes C, Fahey T. Impact of medication reconciliation for improving transitions of care. Cochrane Database of Systematic Reviews. 2018(8). 63. Santos NSD, Marengo LL, Moraes FDS, Barberato Filho S. Interventions to reduce the prescription of inappropriate medicines in older patients. Rev Saude Publica. 2019;53:7. 64. Stewart D, Mair A, Wilson M, Kardas P, Lewek P, Alonso A, et al. Guidance to manage inappropriate polypharmacy in older people: systematic review and future developments. Expert Opinion on Drug Safety. 2017;16(2):203-13. 65. Tani H, Uchida H, Suzuki T, Fujii Y, Mimura M. Interventions to reduce antipsychotic polypharmacy: a systematic review. Schizophr Res. 2013;143(1):215-20. 66. Theresa Page A, Khalil H, Etherton-Beer C, Clifford R, Potter K. The efficacy of deprescribing interventions on health outcomes in people aged over 65 years: A systematic review protocol. JBI Database of Systematic Reviews and Implementation Reports. 2014;12(4):124-34. 67. Thillainadesan J, Gnjidic D, Green S, Hilmer SN. Impact of Deprescribing Interventions in Older Hospitalised Patients on Prescribing and Clinical Outcomes: A Systematic Review of Randomised Trials. Drugs Aging. 2018;35(4):303-19. 68. Thompson W, Lundby C, Graabaek T, Nielsen DS, Ryg J, Sondergaard J, et al. Tools for Deprescribing in Frail Older Persons and Those with Limited Life Expectancy: A Systematic Review. Journal of the American Geriatrics Society. 2019;67(1):172-80. 69. Tjia J, Velten SJ, Parsons C, Valluri S, Briesacher BA. Studies to reduce unnecessary medication use in frail older adults: a systematic review. Drugs Aging. 2013;30(5):285-307. 70. Todd A, Husband A, Andrew I, Pearson SA, Lindsey L, Holmes H. Inappropriate prescribing of preventative medication in patients with life-limiting illness: a systematic review. BMJ supportive & palliative care. 2017;7(2):113-21. 71. Ulley J, Harrop D, Ali A, Alton S, Fowler Davis S. Deprescribing interventions and their impact on medication adherence in community-dwelling older adults with polypharmacy: a systematic review. BMC Geriatrics. 2019;19(1):15. 72. Velten SJ, Parsons C, Briesacher B, Gurwitz J, Tjia J. Interventions to improve prescribing at the end-of-life: A systematic review. Journal of the American Geriatrics Society. 2011;59:S150. 73. Walsh K, O'Riordan D, Kearney P, Timmons S, Byrne S. Improving the appropriateness of prescribing in older patients: A systematic review and meta-analysis of pharmacists' interventions in secondary care settings. International Journal of Pharmacy Practice. 2015;23 (Supplement 1):23. 74. Walsh KA, Hill-Taylor B, Stewart SA, Hayden J, Byrne S, Sketris I. Effectiveness of the STOPP/START (Screening tool of older persons' potentially inappropriate prescriptions/ screening tool to alert doctors to the right treatment) criteria: Systematic review and meta-analysis of randomized controlled studies. Pharmacoepidemiology and Drug Safety. 2016;25 (Supplement 3):375. 75. Walsh KA, O'Riordan D, Kearney PM, Timmons S, Byrne S. Improving the appropriateness of prescribing in older patients: a systematic review and meta-analysis of pharmacists' interventions in secondary care. Age Ageing. 2016;45(2):201-9. 76. Whitman AM, DeGregory KA, Morris AL, Ramsdale EE. A Comprehensive Look at Polypharmacy and Medication Screening Tools for the Older Cancer Patient. Oncologist. 2016;21(6):723-30. 77. Wilsdon TD, Hendrix I, Thynne TR, Mangoni AA. Effectiveness of Interventions to Deprescribe Inappropriate Proton Pump Inhibitors in Older Adults. Drugs Aging. 2017;34(4):265-87. 78. Hill-Taylor B, Sketris I, Hayden J, Byrne S, O'Sullivan D, Christie R. Application of the STOPP/START criteria: a systematic review of the prevalence of potentially inappropriate prescribing

in older adults, and evidence of clinical, humanistic and economic impact. J Clin Pharm Ther. 2013;38(5):360-72. 79. Reeve E, Ong M, Wu A, Jansen J, Petrovic M, Gnjidic D. A systematic review of interventions to deprescribe benzodiazepines and other hypnotics among older people. European Journal of Clinical Pharmacology. 2017;73(8):927-35. 80. Thompson Coon J, Abbott R, Rogers M, Whear R, Pearson S, Lang I, et al. Interventions to reduce inappropriate prescribing of antipsychotic medications in people with dementia resident in care homes: a systematic review. Journal of the American Medical Directors Association. 2014;15(10):706-18.

7.3. Appendix 3: Data extraction tables

Table 8: Data extraction of the methods of the included systematic reviews

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis Jokanovic To investigate People resident in Exposure to Prevalence of Not defined 1 investigator Two Tool adapted from Narrative synthesis. et al [23] the prevalence long-term care polypharmacy. polypharmacy screened the investigators JBI Critical and the factors facilities. Polypharmacy abstracts; 2 extracted the Appraisal Checklist associated with clearly defined. investigators data for Descriptive/Case polypharmacy in assessed full- independently series. Two long-term care text using a investigators did the facilities independently, standardised QA independently, and data extraction and disagreements disagreements tool. resolved by a 3rd resolved by 3rd investigator. investigator

Leelakanok To summarise Adults (studies in Exposure: Outcomes: death, Not review 1 researcher Standardised 2 researchers did the Random effects models et al [25] the literature and children were polypharmacy as reported in a way that articles; not case screened titles data extraction QA independently, with inverse variance conduct a meta- excluded) multiple can be used to reports or case and abstracts. form. 2 and disagreements weighting; I- analysis of the medication use, calculate risk ratios series. Abstracts researchers did resolved by square<30% was association with explicit (OR, RR, HR). reviewed by 2 the data consulting 2 other considered as negligible between number of authors extraction researchers and by heterogeneity. polypharmacy medications that independently. independently; consensus. Used the Stratification by type of and mortality were considered in case of Newcastle-Ottawa risk ratio, number of risk. as polypharmacy disagreements, Quality Assessment medications, HC setting 2 other scale (scores 1-9). (community, hospital, researchers Studies scoring 1-3 institutional), and study were consulted were considered low quality. Number of and quality, 4-6 medium polypharmacy disagreements quality, 7-9 high classifications were resolved quality. categorised in 3 groups: by consensus. studies defining polypharmacy as a discrete variable, studies dichotomising polypharmacy using thresholds of <10 drugs (polypharmacy), studies dichotomising polypharmacy using thresholds of 10+ drugs

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis (excessive polypharmacy). Funnel plot for publication bias. Clyne et al To review and Included: Intervention: An Primary outcome: Randomised Three Three reviewers Methodological The studies identified [36] determine the community- intervention change in PIP, controlled trials reviewers independently quality was assessed were too heterogeneous effectiveness of dwelling older intended to measured using and cluster independently extracted data. using the Cochrane in terms of their interventions to adults (aged ≥65 improve PIP in specified implicit or randomised assessed Collaboration’s risk outcome measures and reduce PIP in or had an average primary care, explicit tools (e.g., controlled trials studies for of bias tool. intervention types to community- age of ≥65). including but not Beers, STOPP, MAI). only. eligibility. conduct a meta- dwelling older Excluded: Studies restricted to: analysis, so a narrative adults. in which more organizational, summary was than 20% of the professional, performed. Where subject population financial, appropriate, crude odds was described as regulatory, or ratios and absolute risk institutionalised multifaceted reductions (ARRs) were (e.g., nursing interventions. calculated. homes, residential Comparator: care homes or usual care or geriatric alternate inpatients). intervention Studies that focused on the reduction of inappropriate prescribing in one drug class only were also excluded.

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis Hill-Taylor To update the Adults aged 65 Intervention: 2013: Indicators of 2013: 2013: study 2013: Two 2013: 2013: Heterogeneity of et al [20, 2013 systematic years and older STOPP/START the clinical and Randomised selection was authors Methodological study populations, 21] review using criteria. humanistic impact of trials and non- performed independently quality was assessed interventions and study new evidence Comparator: not the use of randomized independently performed the using the Cochrane design precluded meta- from RCTs that reported STOPP/START study designs in an unblinded data extraction Collaboration’s risk analysis. Descriptive assess the criteria on the patient investigating the standardized (DOS & BHT). of bias tool and analysis was performed. effectiveness of and healthcare system impact and manner by two One author modified quality 2016: a random-effects STOPP/START (ADEs, physician application of authors (DOS checked assessment scale meta-analysis to criteria on visits, emergency the & BHT) extracted data initially designed for synthesise evidence on prescribing department visits, STOPP/START 2016: Two for agreement studies of prognostic the effectiveness of the quality and hospitalization and 2016: RCTs review authors (BHT). factors (QUIPS). STOPP criteria on clinical, quality of life) involving the independently 2016: Both 2016: Cochrane RoB reducing the PIM rate in humanistic and 2016: Studies that prospective appraised the review authors patients due to economic measured robust application of search results independently anticipated clinical outcomes in indicators of the the STOPP for eligibility abstracted data heterogeneity. A adults aged 65 clinical, humanistic and/or START (KW, BHT). from selected narrative synthesis was years and older and economic impact criteria studies (KW, performed for all other of the application of BHT). outcomes. the criteria. Outcome for the meta-analysis was odds ratio of patients having at least one PIM after intervention

Johansson To review Included: Older Interventions: Primary: mortality, All types of Two reviewers One author Risk of bias was Random effects meta- et al [22] strategies to patients: age ≥ 65 Electronic hospitalisation, controlled independently extracted the assessed according analysis and assess and years (or 80% of strategies to change in n drugs. studies screened each data and a to the Cochrane sensitivity/subgroups on reduce study population reduce Secondary: (randomised title and second author Collaboration methodological quality inappropriate aged ≥65 years) polypharmacy morbidity, QoL, controlled trials, abstract for independently Handbook. The and length of follow-up polypharmacy in with (clinical decision mental and physical cluster eligibility extracted the quality of the elderly patients polypharmacy: support, function, ADEs, randomised data and then evidence was on relevant four or more computerized medication controlled trials, checked the assessed using the clinical outcome prescribed or non- physician order error/inappropriate, non-randomised completeness Grading of measures such as prescribed drugs entry, others). focus of care, controlled trials, Recommendations, mortality and (or Comparators: No user/patient cohort studies Assessment, hospitalisation. 80% of study intervention or satisfaction, and case control Development and population taking usual care (other adherence, resource studies) Evaluation ≥4 drugs). comparable utilisation, and costs (GRADE) Excluded: intervention) methodology. 4 of Approaches 25 included studies investigating where not RCTs, but under prescription were quality (e.g. ‘start assessed using RoB. interventions’) and interventions

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis focusing on people receiving short-term polypharmacy (e.g. terminally ill or receiving cancer chemotherapy) Kua et al To review the Included: nursing Intervention: Any reported health Randomised Not reported Two Two investigators Fixed and random [24] effects of home residents Drug outcomes (including controlled trials investigators undertook quality effects (where Cochran deprescribing ≥60 years of age. discontinuation falls, inappropriate extracted the assessment Q test P value < .05) studies on Excluded: defined as either medications, all- data, and meta-analysis and clinical outcomes terminal or medication cause mortality, and reviewed each subgroups by that have been palliative care- discontinuation, hospitalisation rates) entry for intervention type, performed requiring nursing substitution, or accuracies medication type, among older home residents reduction intervention provider, residents in and study location nursing homes.

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis Page et al To review the Included: patients Interventions: Primary outcome: Any 2 researchers standardised Assessment of risk Studies meta-analysed [9] safety, aged 65+ years on Deprescribing by mortality. Secondary comparative independently data extraction of bias done with where possible. Studies effectiveness and 1+ regular a health care outcomes: reported design: RCTs, for all titles, form; extraction Cochrane Risk of pooled as feasibility of medicines. professional of adverse drug quasi- abstracts and by one Bias tool for RCTs 'polypharmacy' where deprescribing Excluded: medicines withdrawal events, randomised full-text researcher and and a modified tool 3+ medication classes interventions on patients at the end available in 2015 clinically relevant controlled studies; verified by a for non-RCTs, done were targeted for mortality and of life. Setting: (excludes physical health, studies, non- disagreements second by 2 researchers deprescribing. health outcomes. any. medicines cognitive function, randomised resolved by researcher. independently. Heterogeneity assessed withdrawn from psychological health, controlled consensus. Authors of with I-squared (I- the market). quality of life using studies, cohort original studies squared <=50%) or Comparators: any standardised tool. studies, case- contacted for P>0.1. Subgroup Usual care (i.e. control, 2+ missing or analyses when more continuation of single arm unclear than 10 studies were medication). studies, B&A information. found for the same Studies were studies; in target medication; based pooled as English. on age (under or above ‘polypharmacy’ 80 years of age), where the stated cognitive function (with aim or effect of or without dementia), the intervention and intervention method was to reduce (patient-specific medications interventions or across three or educational more medications programmes). Patient- or classes. specific interventions are those when the investigators identified target medications to deprescribe and implemented the process/asked prescribed to implement it.

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis Rankin et To review the Included: people All types of Validated measures Randomised three reviewers Three reviewers Risk of bias was In the presence of al [29] effectiveness of aged 65 years and interventions of inappropriate controlled trials, (AR, CAC and (AR, CAC and assessed according statistical heterogeneity interventions to older, who had aimed at prescribing such as cluster- JC) JC) to the Cochrane (greater than 50%, as improve the more than one improving Beers criteria, MAI, randomised independently independently Collaboration estimated by the I2 appropriate use long-term medical appropriate STOPP/START trials, non- screened titles extracted data Handbook. The statistic), applied a of polypharmacy condition and polypharmacy in criteria, or Assessing randomised and abstracts quality of the random-effects model and reducing were receiving any setting (such Care of Vulnerable trials, controlled evidence was for meta-analysis. For medication- polypharmacy as pharmaceutical Elderly (ACOVE) before-after assessed using the pooling, only groups of related problems (classified as four care) compared that assessed: primary studies (CBAs) Grading of studies of the same in older people or more with usual care outcomes - and interrupted Recommendations, design (randomised medicines. (as defined by the Medication time series Assessment, trials and non- Excluded: studies study). appropriateness, Development and randomised trials). in which the Potentially Evaluation When it was not intervention inappropriate (GRADE) possible to combine focused on people medications, methodology outcome data because with a single Potential prescribing of differences in long-term medical omissions, Hospital reporting or substantive condition or who admissions; heterogeneity, a were receiving secondary - narrative summary was short-term Medication-related reported. polypharmacy problems (e.g., AEs), adherence, quality of life

Study Objectives Patient Interventions Outcomes Types of studies Study Data Quality assessment Data synthesis and population Comparators selection extraction analysis Redmond To review the Included: patients Studies where the Primary: Medication Randomised Two review Two review Modified Cochrane Pooled estimates (RRs et al [30] effectiveness of experiencing a intervention was discrepancies. controlled trials authors authors RoB. The quality of with 95%CIs) of the interventions transition of care. broadly compliant Secondary: independently independently the evidence was evaluated outcome fulfilling the Care transitions with the process Participant-related screened titles undertook data assessed using the measures were Institute for referred to of medication and process and abstracts extraction Grading of calculated by the Healthcare changes in the reconciliation as outcomes, Healthcare Recommendations, generic inverse variance Improvement level, location or outlined by the utilisation, additional Assessment, method. Where it was definition of providers of care Institute for outcomes (including Development and not possible to medication as patients moved Healthcare AEs). Evaluation synthesise the data from reconciliation within the Improvement. (GRADE) the included studies, a aimed at all healthcare The intervention methodology narrative synthesis of patients system. Excluded: must have been the results, grouping experiencing a trials applied as patients together studies that transition of care investigating transitioned from used similar interventions to different levels or interventions and improve the locations of care provided a comparison quality of (or both). of different approaches prescribing during was undertaken care transitions, with no medication reconciliation focus.

Table 9: Data extraction of the results of the included systematic reviews (number of studies, study design, population, setting, interventions/exposure and risk of bias)

Study Number of Study design Population Setting Interventions/Exposure Risk of bias studies

Jokanovic N=153 records Not summarised. Residents in long-term Long-term care facilities Exposure was polypharmacy. Medication All studies reported clearly defined et al [23] after duplicates care facilities with mean use was ascertained from medication inclusion criteria; 42 (95%) studies removed; 44 age ranged 61.7-86.0 charts or medical records (n=24), drug used objective criteria to assess studies included years. 4 studies focussed registers or databases (n=6), outcomes; 20 (45%) studies aimed in the review on residents with lengths administrative or minimum data sets to have participants who were (total number of of stay longer than 1 or 3 (n=5), resident interviews (n=1), and representative of all residents in the study participants months; 4 studies pharmacist-conducted medication reviews particular LTCF; 37 (84%) studies not reported). focussed on residents (n=1). Polypharmacy defined as 5+ did not identify and control for with cognitive medicines (n=11), 9+ medicines (n=13), confounding factors using impairment, 2 studies on 10+ medicines (n=11). 24 studies multivariate analyses. residents presented to included the use of all medications taken hospital, in residents with regularly and as needed to assess diabetes, 1 in residents polypharmacy; 6 studies included only who had experienced a regular medication; 14 studies included fall, 1 in veterans. only prescribed medication; 10 studies excluded specific medicines from the polypharmacy assessment, 11 studies reported the period of time during which exposure was assessed. Leelakanok N=3892 studies Of the 47 studies, 26 36/47 studies were in Not discussed. Definition of polypharmacy varied: 11 According to Newcastle-Ottawa et al [25] after duplicates prospective cohort, 11 people with mean age studies measured polypharmacy as a Quality Assessment scale, no removed. 47 retrospective cohort, 5 case 65+ years; 8 in people discrete number of medications; 12 as 1-4 studies were low quality, 19 were studies data control, 4 clinical trials, 1 with mean age < 65 medicines, 15 as 5+, 9 as 6-9, 11 as 10+. medium quality and 28 were high extracted and cross-sectional study. years; 1 study did not The methods to determine the number of quality. Funnel plot indicates some meta-analysed. provide the age. medicines were not discussed in the publication bias against negative review. and/or smaller studies. Clyne et al N=749 records 12 RCTs, with 156,529 Across the 12 RCTs; the In the community 6 RCTs were on organisational Detection, attrition, and reporting [36] after duplicates participants. PIP was mean age of participants interventions (4 on pharmacist bias were low in most studies. removed. 12 measured using implicit ranged from 65 to 81. interventions and 2 on multidisciplinary Randomization, allocation studies included criteria in 4 studies and Baseline PIP prevalence team (MDT) approaches, 2 RCTs were on concealment, and blinding were less in the review. explicit criteria in 8 studies; ranged between 18- professional interventions (targeting reliably implemented or reported. the MAI was the only 100%. prescribers directly), and 4 RCTs were on Protection against contamination implicit measure. Of the 8 multifaceted interventions (combining was unclear in three cluster RCTs. studies using explicit two or more techniques). All cluster RCTs accounted for criteria, 1 used the Beers clustering. criteria 1997 iteration, 1 the 2003 iteration, 1 used the McLeod crtieria and 5 used combinations of existing criteria or study-specific criteria.

Study Number of Study design Population Setting Interventions/Exposure Risk of bias studies

Hill-Taylor 2013: N=77 2013: 13 studies: a single 2013: The mean age of 2013: The majority of 2013: 5 studies, including the RCT, 2013 : Study quality varied: 7 et al [20, records after randomised controlled trial participants ranged from participants in the included applied the full STOPP and START studies adequately controlled for 21] duplicates and 12 observational studies. 74. 9 to 86.9 years. The studies were community criteria to participant’s medication bias related to the study removed. 13 This review includes the majority of participants dwelling profiles, three studies applied the STOPP participation, outcome, application studies included application of were female (from 53% 2016: 2 RCTs following criteria, and one study of STOPP/START and confounding in the review. STOPP/START to the to 80%). The majority of discharge from the acute applied the START criteria. Seven of the measurement domains.3 were 2016: N=230 health records of participants were from care, 2 RCTs in long-term observational studies compared considered at a low risk of bias due records after approximately 344,957 the Northern Ireland and care homes STOPP/START with other explicit to methods of data and 5 at low risk duplicates adults the Republic of Ireland. criteria of bias due to approach for removed. 4 2016: 4 RCTs with 1,935 Prevalence of PIP 2016: 3 RCTs used the criteria to assess application of the STOPP/START studies included participants between 21.4-79% prescribing quality. 1 RCT conducted in tool. One study was found to have a in the review although affected by Ireland used the full STOPP and START high risk of bias with regard to the heterogeneity in sample criteria as a screening tool application of the screening tool. 5 population and study studies were considered at moderate design. or high risk of bias in the statistical 2016: Participants in all analysis and data presentation four studies were at least domains 65 years of age, although 2016: 2 RCT were at a low risk of one study restricted bias in all key domains, but concern participants to those aged existed regarding the risk of bias in 75 years and older. The the other 2 RCTs majority of participants were female (from 53% to 73%). Healthcare systems from four nations were represented (Republic of Ireland, Belgium, Spain and Israel). Baseline PIM between 32.4-66.8%. Johansson N=19,052 17 RCTs, 4 cluster RCTs , 4 The mean age of study 13 studies in general 13 studies were pharmacist-led The main limitations contributing to et al [22] records after non-randomised controlled participants ranged from practitioner surgeries, 2 interventions, 4 studies were physician- risk of bias were related to the duplicates studies ; range 79–2454 per 69.7 to 87.7 years and the studies in primary care led the interventions, and 8 studies were design (e.g. inadequate removed. 25 study percentage of male centres/general practitioner multidisciplinary team-led interventions randomization, intent-to-treat studies included participants ranged from outpatient clinic, 1 in an analysis, sample size and power in the review (17 20% to 100%. internal medical clinic, 1 in calculation) or execution of the RCTs, 4 cluster a hospital, 1 in a chronic studies. All studies were unclear on RCTs, 4 non- care geriatric facility, 1 in a blinding of participants and randomised residential hospital with personnel. controlled). continuous care wards, 5 in nursing homes, and 1 in an assisted living facility Kua et al N=1,171 records 41 RCTs enrolling 18,408 34 studies mean age Nursing homes 14 studies on drug discontinuation, 11 The main limitations contributing to [24] after duplicates residents between 80 and 90 years, studies on the impact of medication risk of bias were related to detection removed. 41 and 69.4% female. 15 review, using tools such as Beers criteria bias, as blinding of the residents studies specifically or START/STOPP. 6 studies on and intervention/health care

Study Number of Study design Population Setting Interventions/Exposure Risk of bias studies

RCTs included in included only dementia educational programs. Other interventions providers was not possible because the review residents. included: case conferences, 2; of the nature of the intervention comprehensive geriatric assessment, 2; outreach visits, 2; ADE profiling, 1; alternative therapies, 1; health technologies and informatics, 2 Page et al N=21,165 56 RCTs, with 17,428 N=34,143, mean age 73.8 14 studies in hospital, 29 in Deprescribing one medication, which 18/56 (32%) RCTs were rated low [9] records after participants. 22 comparative (SD=5.4) years, 51.8% residential aged care, 73 could be a single medicine (N=34 risk of bias in at least 4/7 duplicates studies with concurrent male. Mean age>80 years community based. 1 study studies); a medicine from a single class parameters; 68% of RCTs had removed. 132 control group, with 14,522 in 38 studies (4,833 included participants in the (N=5 studies); or a medicine of a unclear or high risk of bias. Results full-text papers participants. 37 comparative people). N=33 studies community and residential therapeutical category (N=27 studies; for non-RCTs not reported. reporting 116 studies without concurrent included people with aged care, and another was withdrawing 2 medications (N=11 studies (132 control group, with 2,207 dementia (6,090 people). based in the community and studies). Deprescribing polypharmacy (3+ references) participants. Mean follow- hospital. therapeutical classes; N=21 studies), of included in the up=15.5 (SD=17.4 months) which N=18 were patient-specific review. interventions (N=11 led by doctors, N=2 led by pharmacists, N=1 led by nurses, and N=1 led by multidisciplinary teams); N=10 were investigator-led interventions (N=8 on medication reviews with recommendations to the prescriber, N=3 on educational programmes delivered at residential aged care facilities to nurses (N=1) or to the prescribing doctors (N=2). Rankin et N=7,526 records 32 studies: 18 RCTs, 10 Mean age of 72.8 years. 16 studies in hospital 31 studies examined complex,multi- Assessments using the Cochrane al [29] after duplicates cluster RCTs, 2 non-RCTs, All study participants had settings, 3 in hospital faceted interventions of pharmaceutical ’Risk of bias’ tool, found that there removed; 32 2 two controlled before-after more than one long-term outpatient clinics, 1 at the care in a variety of settings. 1 uni-faceted was a high and/or unclear risk of studies (including studies; involving 28,672 medical condition. On hospital/homecare interface, study examined computerised decision bias across a number of domains. 12 from the older people average, participants 12 in an inpatient setting, 10 support provided to GPs in their own Based on the GRADE approach, the previous update) were receiving more than in primary care, and 6 in practices overall certainty of evidence for included in the four medicines at nursing homes each pooled outcome ranged from review (18 RCTs, baseline (average 8.9 low to very low. 10 cluster RCTs, medicines at baseline) 4 non- randomised controlled). Redmond et N=13,585 25 RCTs involving 6,995 The mean age of All of the studies were All studied interventions were classified There were no major differences in al [30] records after participants participants was 66.1 conducted in hospital or as ’organisational’ according to EPOC the risk of bias of studies included duplicates years. Most studies immediately related settings taxonomy and were either Provider in the review, with 24 studies being removed. (25 recruited participants orientated or Structural. Twenty-three judged at high risk for at least one RCTs in total, 22 prescribed multiple studies were provider orientated risk of bias domain. The GRADE included in the medications. (pharmacist mediated) and two were evidence varied from moderate to meta-analyses) structural (an electronic reconciliation tool low or very low reliability. and medical record changes).

Table 10: Data extraction on the results of the systematic reviews (outcomes)

Study Outcomes: Mortality Outcomes: adverse drug effects Outcomes: health, quality of life, resources Outcomes: Evidence on the number of medicines

Jokanovic Not an outcome Polypharmacy associated with an increased Mean number of medications ranged 3.8-16.6 et al [23] risk of hospitalisation (adjusted for per resident; median ranged 4-14. Prevalence confounders; n=1), ADRs over 1 year follow- of polypharmacy varied by definition: 80-88% up (unadjusted; n=1) and falls over a period of on 4+ medicines (n=2), 38-91% on 56 (n=11), 6 months (unadjusted; n=1); the association 46-69% on 6+ (n=3), 19-47% on 7+ (n=2), 13- with increased risk of falls was diminished in 75 on 9+ (n=13), 11-65% on 10+ (n=11), 4-50 the adjusted analysis. on 12+ (n=2). Polypharmacy was significantly associated with higher Charlson Comorbidity Index scores (n=2), circulatory diseases (n=3), endocrine and metabolic disorders (n=3), neurological motor dysfunctioning (n=3), and some specific symptoms (n=2), recent discharge from hospital (n=2), and greater number of prescribers servicing the LTCF (n=2). Inverse association with age (n=5) cognitive impairment (n=3), disability in activities of daily living (n=3) and length of stay in the LTCF (n=3). Leelakanok MA of discrete polypharmacy: 1 additional Not an outcome Not an outcome Not an outcome et al [25] medicine has a risk ratio of 1.08 [1.04;1.12], I- square=54%. Polypharmacy as 1-4 medicines, risk ratio=1.24 [1.10;1.39], I-square=78%. Polypharmacy as 5+ medicines, risk ratio=1.31 [1.17;1.47] I-square=97%. Polypharmacy as 6-9 medicines, risk ratio=1.59 [1.36;1.87], I- square=39%. Polypharmacy as 10+ medicines, risk ratio=1.96 [1.42;2.71], I-square=99%. Results consistent across health care setting in studies examining polypharmacy as discrete number of medicines or as <10 medicines, but higher association in people in institutions (although small sample size). Results consistent across different measures of risk. Clyne et al Not an outcome 1 study found no significant effect on 3 pharmacist intervention studies found no The primary outcome was medication [36] adverse drug effects from a pharmacist significant effect on psychosocial outcome of appropriateness. Four of six organizational intervention. quality of life with SF-36; 1 study found a interventions reported a reduction in PIP, significant decrease in the SF-36 domains of particularly through pharmacists conducting emotional role and social functioning, which medication reviews (3 of 4 studies on was attributed to the high withdrawal rate of pharmacists interventions). Evidence of the pharmacists in the study; 1 multifaceted effectiveness of multidisciplinary teams was intervention had no significant effect on weak. Both of the two professional (targeting psychological health (12-item Well-being prescriber’s directly) interventions were Questionnaire). Health service use was computerized clinical decision support

Study Outcomes: Mortality Outcomes: adverse drug effects Outcomes: health, quality of life, resources Outcomes: Evidence on the number of medicines

assessed in 2 studies, with 1 reporting a interventions and were effective in decreasing reduction in hospitalisations but not on A&E new PIP but not existing PIP. Three of four visits. 2 studies conducted economic multifaceted approaches were effective in evaluations: 1 study found that shared reducing PIP. pharmaceutical care and written feedback had modest savings regarding medication costs (not statistically significant), and data analysis is ongoing in the 2nd study. Hill-Taylor 2013: In one study (Gallagher 2011) all-cause 2013: The STOPP criteria identified more 2013: Research involving the application of 2013: There was limited evidence that the et al [20, 21] mortality was lower in the intervention group, medications associated with adverse drug STOPP/START on the impact on the quality application of STOPP/START criteria but differences were not statistically significant events than the 2002 version of the Beers of life was not found optimised prescribing. 3 studies examined the (5 3% of the intervention group and 7 3% of the criteria. Patients with PIP, as identified by 2016: 1 RCT (Frankenthal 2014) did not report direct costs of PIP in the Republic of Ireland: control group died, p = 0 414). STOPP, had an 85% increased risk of a difference in quality of life. Resource use: 1 €188 per patient per year in 2007 (Barry et al, 2016: 1 RCT (Gallagher 2011) was not powered adverse drug events in one study study found lower primary care visits in the ref 42); €318 per patient per year in 2007 to discover mortality differences between groups (Hamilton 2011) (OR = 1 85, 95% CI: 1 intervention group. (Cahir et al, ref 44); and €263 per patient per 51–2 26; P < 0 001). year (Byrne et al, ref 17). Predictors of PIP 2016: Not reported were reported in 9 studies older age, female sex, polypharmacy, comorbidities 2016: Improvement in potentially inappropriate medication rates after intervention, 4 RCTs, OR 2.98 (random- effects; 95%CI 1.30, 6.83; I-squared=86.7%; 3 RCT (excluding outlier Gallagher 2011), OR 1.98 (random-effects; 95%CI 1.16, 3.40; I- squared=64.3%). Johansson The strategies to reduce polypharmacy had no None of the included studies analysed the Overall, the effects of interventions on the 23 studies provided data on the number of et al [22] effect on all-cause mortality ( all studies: odds effect on new morbidity, ADR, adverse predefined secondary outcomes were minimal. prescribed drugs, and 2 studies included ratio 1.02; 95% confidence interval 0.84, 1.23; events after discontinuation of drugs, or Hospitalisations: 11/25 studies reported prescribed and over the counter drugs. The RCTs only: OR 1.05, 95%CI 0.85, 1.29). I- process of care hospitalisation as an outcome measure; 2 weighted mean number of drugs at baseline squared values for statistical heterogeneity were studies found a significant effect of the was 7.4 drugs per patient in both groups; at 8% for all studies and 12% for just RCTs. intervention on hospitalisation; 1 study found a follow-up, the weighted mean number of drugs reduction in the unplanned readmission and was reduced by 0.2 in the intervention group the other found a reduction in the length of but increased by 0.2 in the control groups; it stay; 5 studies assessed all-cause hospital was not possible to calculate confidence admissions and found no significant interval. 3 studies found significant reduction differences. in a between group analysis. Kua et al Across 26 RCTs (12,248 residents) 14 studies examined drug discontinuation 10 studies (n=6905 people) examined the Five studies (2092 people) reported PIMS after [24] deprescribing reduced mortality rates (fixed by doctors, 2 studies by pharmacists and 1 number of people who fell after the the intervention period, according to various effect: odds ratio 0.90, 95% CI 0.82, 0.99). study by nurses; 86% studies targeted intervention, with most reporting no difference criteria. All studies found a significant However, in the subgroup analysis by psychotropic drugs; generally, the careful with the exception of 1 study. Pooling of 8 reduction in PIMs; the meta-analysed OR for intervention type, only medication review- discontinuation of antipsychotics and analysable studies (n=3343 people) suggest the odds of people having PIMS was 0.41 directed deprescribing interventions (fixed diuretics had negligible adverse effects on that deprescribing interventions did not (95%CI 0.19 to 0.89) from 3 analysable studies effect: 8 RCTs, 6115 residents) was statistically psychiatric and cardiovascular outcomes, significantly reduce the number of people who (1711 people). significant (OR 0.74, 95% CI 0.65, 0.84). When respectively. had falls, with a significant result in the a random-effects model was applied, statistically subgroup analysis by medication review-

Study Outcomes: Mortality Outcomes: adverse drug effects Outcomes: health, quality of life, resources Outcomes: Evidence on the number of medicines

significant differences were not evident (all directed (OR=0.76, 95%CI 0.62 to 0.93). 8 interventions, OR 1.02 95%CI 0.85, 1.23; studies (7863 residents) examined medication review, OR 0.83 95%CI 0.64, 1.07). hospitalisation rates after the intervention, and I-squared values for statistical heterogeneity most found no difference; meta-analysis of 4 were 51% for all interventions and 48% for analisable studies (n=1002) found a non- medication review. Subgroup analysis performed significant reduction in the number of by the authors found that studies conducted in hospitalised residents (OR=0.72, 95%CI 0.31 Australia found greater beneficial effects to 1.66). (OR=0.66, 95%CI 0.5 to 0.77) as well as deprescribing by multiple drug classes (OR=0.89, 95%CI 0.81 to 0.98). Page et al Polypharmacy as deprescribing target: 10 RCTs Single studies on polypharmacy, Large number of outcomes, largely disease- Deprescribing polypharmacy reduced the total [9] (3151 patients): OR=0.82 [0.61; 1.11]; I- glucosamine, carbamazepine, specific. Quality of life assessed with a variety number of medicines (MD=-0.99 [-0.93; -0.14] squared=23%; educational programmes have a antidepressants, benzodiazepine, of measures, including (but not restricted to) in 2 studies; and the number of PIMs (MD=- OR=1.21 [0.86; 1.69] whereas investigator led prednisolone, ICS); 3 studies on EQ-5D utility and SF-36. The authors noted 0.49 [-0.70; 0.28] in 3 studies. Inconsistent has OR=0.62 [0.43; 0.88]; subgroup analysis by antipsychotics. Heterogeneous results. The that in respect to deprescribing of effect depending on the type of class/medicine. age had similar results, aged 80+ OR=0.88 [0.58; authors note that neither deprescribing to polypharmacy, there was no change in the 1.34] (as per forest plot ), aged 65-79 years reduce polypharmacy nor deprescribing incidence of adverse drug events, in cognitive OR=0.64 [0.40; 1.04]; similar results by targeting single medicines were not function or the risk of falls; there was a presence of dementia (0.89 [0.63;1.27] with vs associated with a significant risk in statistically significant reduction in the number 0.64 [0.36; 1.13] without). Non-randomised adverse drug withdrawal events. of falls (MD=-0.11 [-0.21; -0.02; 844 studies on mortality OR=0.32 [0.17; 0.60] N=2]. participants; 3 studies). The authors noted that Studies on deprescribing single/classes deprescribing to reduce polypharmacy was not medicines did not find a stats significant associated with significant changes in quality difference on mortality odds. beta-blockers (N=1 of life, although there was evidence of a RCT; OR=1.14 [0.35; 3.72], diuretics (N=2 reduction in the decline in quality of life RCT, OR=3.21 [0.96; 10.70], statins (N=1 RCT, (MD=0.03 [0.01; 0.06], 189 patients, 1 study). OR=0.87 [0.58; 1.31]), bisphophonates (N=2 In respect to deprescribing of single medicines, RCT, OR==1.02 [0.46; 2.26], carbamazepine there were some changes in relevant outcomes, (N=1 RCT, OR=0.28 [0.01; 7.33]), specifically increase in blood pressure when antidepressants (N=2 RCT, OR=1.13 [0.47; antihypertensive drugs were prescribed (e.g. 2.69]), antipsychotics (N=5 RCT, OR=0.59 increase in 9.73 mm Hg in systolic blood [0.33; 1.07]), benzodiazepines (N=1 RCT, pressure with deprescribing of diuretics). OR=0.10 [0.01; 1.93]), anticholinesterease inhibitors (N=2 RCT, OR=4.63 [0.93; 23.12]), ICS (N=1 RCT, OR=0.14 [0.01; 2.67]). Rankin et al Not an outcome Medication-related problems were reported In 1 study participants in the intervention It is uncertain whether pharmaceutical care: [29] in eight studies (N = 10,087) using group experienced an increased quality of life improves medication appropriateness (as different terms (e.g. adverse drug (QoL), in 1 study there was a decline in QoL measured by an implicit tool), mean difference reactions, drug-drug interactions). No in both the intervention and control group, and (MD) -4.76, 95% CI -9.20 to -0.33; reduces the consistent intervention effect on in 10 studies no changes in QoL were detected. number of potentially inappropriate medication-related problems was noted Pharmaceutical care may make little or no medications (PIMs), standardised mean across studies. difference in hospital admissions (2 studies). difference (SMD) -0.22, 95% CI -0.38 to -0.05; reduces the proportion of patients with one or more PIMs, risk ratio (RR) 0.79, 95%CI 0.61 to 1.02; reduces the proportion of patients with

Study Outcomes: Mortality Outcomes: adverse drug effects Outcomes: health, quality of life, resources Outcomes: Evidence on the number of medicines

one or more PPOs (RR 0.40, 95% CI 0.18 to 0.85. Pharmaceutical care may slightly reduce the number of potential prescribing omissions (PPOs) (SMD -0.81, 95% CI -0.98 to -0.64 (2 studies). Redmond et One study reported no difference in mortality One study reported potential ADEs; Reconciliation also had little or no effect on 20 studies comparing medication reconciliation al [30] (RR 0.75, 95% CI 0.27 to 2.08) defined as being due to discrepancies. preventable adverse drug events (PADEs) (RR interventions to standard care of participants Three studies described an outcome of 0.37. 95% CI 0.09 to 1.57; 3 studies; I- with at least one medication discrepancy PADEs or ameliorable ADEs calculated Squared=84%), or on ADEs (RR 1.09, 95% CI showed a risk ratio (RR) of 0.53 (95% CI 0.42 using the Bates methodology to 0.91 to 1.30; 4 studies; I-Squared=0%). to 0.67; I-Squared=91%). Reconciliation’s retrospectively identify medication-related Evidence of the effect of the interventions on effect on the number of reported discrepancies ADEs with no certainty of whether healthcare utilisation was conflicting, and had per participant was also uncertain (mean reconciliation reduced PADEs or non- an uncertain effect on a composite measure of difference (MD) -1.18, 95% CI -2.58 to 0.23; 4 adherenceFour studies reported hospital utilisation (emergency department, studies; I-Squared=96%), as well as its effect reconciliation may make little or no rehospitalisation RR 0.78, 95% CI 0.50 to on the number of medication discrepancies per difference to ADEs (RR 1.09, 95% CI 0.91 1.22; 4 studies; I-Squared=48%). participant medication (RR 0.13, 95% CI 0.01 to 1.30; I-squared=o%) to 1.29; 2 studies; I-Squared=98%).

Table 11: Data extraction on the conclusions of the included systematic reviews

Study Conclusions of the systematic review Limitations as reported by the authors Areas for future research suggested by the authors

Jokanovic The prevalence of polypharmacy in residents in LTCF is high, Not all relevant studies may have been picked up by the Future studies should use consistent definitions of et al [23] but varies widely between LTCF and depending on the searches due to restrictions due to language (English) and date polypharmacy, have a longitudinal design and collect definition of polypharmacy. The factors positively associated (year 2000+). Clinical appropriateness was not assessed in this information on factors that may influence the exposure to with polypharmacy are comorbidity, recent hospital discharge, review. No meta-analysis performed, which was due to the polypharmacy and health outcomes. number of prescribers; inversely associated are older age, heterogeneity in the included studies. cognitive impairment, ADL disability, length of stay in LTCF. Leelakanok Polypharmacy is associated with higher mortality risk, and Risk of exposure misclassification in the included studies, Not discussed. et al [25] relationship is dose-dependent (higher mortality risk for more given that some studies did not provide detailed information on medicines). the medicines and/or collected information from self-report or surveys. Risk of confounding bias in that the association between polypharmacy and mortality may not be causal. Focus on mortality, when drugs may be prescribed to improve QoL with known increased risk of mortality (e.g. opioids in palliative care). Heterogeneity in the definition of polypharmacy. Exclusion of studies due to lack of data to calculate a risk ratio for the association. Clyne et al Interventions including organisational (pharmacist Meta-analysis could not be undertaken due to heterogeneity; Although the interventions appear to have been beneficial in [36] interventions), professional (computerized clinical decision few studies conducted process evaluations or presented terms of reducing PIP, the clinical effect this may have on support systems), and multifaceted approaches appear adequate detail to allow for an analysis; studies did not describe outcomes such as ADEs and QoL is unknown. Future research beneficial in terms of reducing PIP, but the range of effect usual care in adequate detail; potential biases limited studies, should consider involving individuals to explore their sizes reported was modest, and it is unclear whether such particularly in relation to selection bias; and only half of the preferences in relation to PIP and interventions to decrease it interventions can result in clinically significant improvements studies had adequate sample size and explore whether the differences in decreasing the in patient outcomes initiation of PIP, as opposed to the discontinuation of existing PIP, results from differences in the interventions or differences in applying explicit or implicit criteria. Hill-Taylor 2013: The STOPP/START criteria appear to be more sensitive 2013: Although referred to as ‘STOPP’ or ‘START’, some 2013: To date, the clinical, humanistic and economic impacts et al [20, 21] than the 2002 version of the Beers criteria. Limited evidence researchers used versions of the criteria that had been modified of the application of the STOPP/START criteria have not been was found related to the clinical and economic impact of the for their jurisdictional prescribing practices or formularies and well explored STOPP/START criteria in some instances were shortened. Not all researchers had 2016: Additional research investigating STOPP/START is 2016: STOPP/START may be effective in improving access to complete medication profiles including over-the- needed, especially in frail elderly and community-living prescribing quality, clinical, humanistic and economic counter medications. No study indicated an attempt to patients receiving primary care. outcomes. document or evaluate adherence. Researchers who had used pharmacy claims data were only able to confirm that patients had made a claim for medications, not that they have actually taken them 2016: Three of the studies had populations that were restricted to a single facility and interventions performed in the included studies varied in implementation, populations, outcomes and duration Johansson et There is no convincing evidence that the strategies assessed The quality of the evidence assessed using GRADE on There is a need to develop more effective strategies to reduce al [22] are effective in reducing polypharmacy or have an impact on strategies to reduce polypharmacy was rated as low to very inappropriate polypharmacy and to test them in large, clinically relevant endpoints low, and any estimate of effect is very uncertain. There was pragmatic randomised controlled trials on effectiveness and insufficient evidence on the effect of strategies to reduce feasibility. When addressing polypharmacy, research groups

Study Conclusions of the systematic review Limitations as reported by the authors Areas for future research suggested by the authors

polypharmacy on patient relevant outcomes such as mortality should clearly define their methodology regarding the and hospitalisation. assessment of medication appropriateness, and they should also focus on clinically relevant outcomes such as mortality or hospital admissions. Kua et al Compared to other deprescribing interventions, medication There was limited evidence to show that deprescribing was Further studies are needed to fully ascertain the health benefits [24] review directed deprescribing had significant benefits on older effective in reducing all-cause mortality, number of fallers, as of medication reviewed directed deprescribing practice. residents in nursing homes. well as hospitalization rates. However, when the deprescribing activity involved a medication review by health care professionals in a structured and active way, it significantly reduced both all-cause mortality and number of fallers, compared to other types of deprescribing interventions Page et al [9] Deprescribing appears to be feasible and safe. There is no Language bias; inclusion of non-randomised studies and small Large RCTs on patient-specific deprescribing interventions to evidence of an increased risk of adverse outcomes and some RCTs with low quality; inclusion of studies that aimed to confirm the findings of the review. Research to understand evidence of greater likelihood of positive health outcomes. assess the feasibility of deprescribing intervention; which medications should be prescribed in whom and at what Overall, RCTs found no effect of deprescribing interventions heterogeneity in follow-up, settings, and patients' point in time. had on mortality risk, although patient-specific interventions characteristics. in particular had a significant reduction on mortality risk. Health outcomes varied by target medication for withdrawal, and include a reduction in the number of falls and increase in blood pressure. Deprescribing is feasible. Concluded that deprescribing should be routinely considered for older people. Rankin et al It is unclear whether interventions to improve appropriate The meta-analysis based on the number of PPOs per participant Further research should attend to rigour in study design. More [29] polypharmacy, such as reviews of patients’ prescriptions, comprised just two studies. This limits the value of any pooled research is needed to test whether existing tools for resulted in clinically significant improvement; however, they effect estimate. Based on observed heterogeneity in the pooled comprehensive medication may be slightly beneficial in terms of reducing potential effect estimates, the findings of meta-analyses [medication review can improve appropriate polypharmacy prescribing omissions (PPOs); but this effect estimate is based appropriateness (as measured by an implicit tool), the number on only two studies, which had serious limitations in terms of of PIMs and proportion of patients with one or more PIMs or risk bias. PPOs) should be treated cautiously, as the interventions did not seem to work consistently across all studies. Furthermore, the certainty of evidence presented in this review, as described by the GRADE approach, remains low or very low. Redmond et The impact of medication reconciliation interventions, in Meta-analysis of the primary outcomes showed a high degree Further work is required to develop a consensus on identifying, al [30] particular pharmacist-mediated interventions, on medication of statistical heterogeneity and low certainty of evidence, defining, measuring and reporting discrepancies. Future discrepancies is uncertain due to the certainty of the evidence making it difficult to have any certainty of the effect of the studies should utilise clear definitions of discrepancies as well being very low. There was also no certainty of the effect of the interventions. as objective measurement techniques and appropriate choice of interventions on the secondary clinical outcomes of ADEs, time points attendant to the transition point at which the PADEs and healthcare utilisation intervention is applied.

7.4. Search strategies

7.4.1. Update to the searches by the systematic reviews

Jokanovic et al Jokanovic N, Tan EC, Dooley MJ, Kirkpatrick CM, Bell JS. Prevalence and factors associated with polypharmacy in long-term care facilities: a systematic review. J Am Med Dir Assoc. 2015;16(6):535.e1-12.

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to July 31, 2019 2nd August 2019

# Searches Results 1 exp Polypharmacy/ 4552 2 polypharmacy.ti,ab. 6312 3 multiple medicine*.mp. 77 4 multiple medication*.mp. 1555 5 or/1-4 9941 6 exp Nursing Homes/ 37834 7 nursing home*.ti,ab. 28451 8 exp Homes for the Aged/ 13360 9 exp Assisted Living Facilities/ 1291 10 exp Long-Term Care/ 25152 11 residential* care.mp. 3229 12 aged care facilit*.mp. 968 13 ltcf.mp. 467 14 exp Skilled Nursing Facilities/ 4173 15 or/6-14 75586 16 exp Aged/ 2971455 17 elder*.mp. 255201 18 exp Geriatrics/ 29322 19 geriatric*.mp. 98195 20 ((old* or aged) adj (person* or adult* or people or patient*)).ti,ab. 181355 21 or/16-20 3131641 22 5 and 15 and 21 504 23 (201409* or 20141* or 2015* or 2016* or 2017* or 2018* or 2019*).dt,ed. 6613748 24 22 and 23 210 25 exp Great Britain/ 354583 26 (national health service* or nhs*).ti,ab,in. 175794 27 (english not ((published or publication* or translat* or written or 92110 language* or speak* or literature or citation*) adj5 english)).ti,ab. 28 (gb or "g.b." or britain*).ti,ab,jw,in. 48926 29 (british* not "british columbia").ti,ab,jw,in. 535620 30 (uk or "u.k." or united kingdom*).ti,ab,jw,in. 1339157 31 (england* not "new england").ti,ab,jw,in. 121903

32 ("northern ireland*" or "northern irish*" or scotland* or scottish* or 93718 welsh*).ti,ab,jw,in. 33 ((wales or south wales) not "new south wales").ti,ab,jw,in. 52567 34 or/25-33 2205566 35 (exp africa/ or exp americas/ or exp antarctic regions/ or exp arctic regions/ 2730964 or exp asia/ or exp oceania/) not (exp great britain/ or europe/) 36 34 not 35 2098952 37 24 and 36 25

Leelakanok et al Leelakanok N, Holcombe AL, Lund BC, Gu X, Schweizer ML. Association between polypharmacy and death: A systematic review and meta-analysis. J Am Pharm Assoc (2003). 2017;57(6):729-38.e10.

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to July 31, 2019 2nd August 2019

# Searches Results 1 polypharmacy/ 4386 2 polypharmacy.ti,ab. 6312 3 polypragmas*.ti,ab. 91 4 hyperpharmacotherapy.ti,ab. 3 5 multiple drug use*.ti,ab. 278 6 multiple drug therap*.ti,ab. 491 7 multiple drug prescri*.ti,ab. 14 8 multiple drug regimen*.ti,ab. 194 9 multi-drug use*.ti,ab. 37 10 multi-drug therap*.ti,ab. 359 11 multi-drug regimen*.ti,ab. 177 12 multidrug use*.ti,ab. 38 13 multidrug therap*.ti,ab. 1240 14 multidrug prescri*.ti,ab. 5 15 multidrug regimen*.ti,ab. 604 16 concomitant drug use*.ti,ab. 129 17 concomitant drug therap*.ti,ab. 160 18 concomitant drug regimen*.ti,ab. 6 19 concurrent drug use*.ti,ab. 69 20 concurrent drug therap*.ti,ab. 73 21 multiple medication use*.ti,ab. 63 22 multiple medication regimen*.ti,ab. 17 23 concomitant medication use*.ti,ab. 181 24 concomitant medication therap*.ti,ab. 4 25 concomitant medication regimen*.ti,ab. 3 26 concurrent medication use*.ti,ab. 37 27 concurrent medication therap*.ti,ab. 4

28 concurrent medication regimen*.ti,ab. 4 29 or/1-28 12572 30 death/ 17065 31 death.ti,ab. 652492 32 mortality/ 41848 33 mortality.fs. 545128 34 mortality.ti,ab. 699821 35 fatal.ti,ab. 115562 36 lethal.ti,ab. 103588 37 dying.ti,ab. 32932 38 survival/ 4621 39 survival analysis/ 128486 40 survival rate/ 163627 41 surviv*.ti,ab. 1065931 42 or/30-41 2397949 43 29 and 42 1836 44 (201606* or 201607* or 201608* or 201609* or 20161* or 2017* or 2018* 4743864 or 2019*).dt,ed. 45 43 and 44 637 46 exp Great Britain/ 354583 47 (national health service* or nhs*).ti,ab,in. 175794 48 (english not ((published or publication* or translat* or written or language* 92110 or speak* or literature or citation*) adj5 english)).ti,ab. 49 (gb or "g.b." or britain*).ti,ab,jw,in. 48926 50 (british* not "british columbia").ti,ab,jw,in. 535620 51 (uk or "u.k." or united kingdom*).ti,ab,jw,in. 1339157 52 (england* not "new england").ti,ab,jw,in. 121903 53 ("northern ireland*" or "northern irish*" or scotland* or scottish* or 93718 welsh*).ti,ab,jw,in. 54 ((wales or south wales) not "new south wales").ti,ab,jw,in. 52567 55 or/46-54 2205566 56 (exp africa/ or exp americas/ or exp antarctic regions/ or exp arctic regions/ 2730964 or exp asia/ or exp oceania/) not (exp great britain/ or europe/) 57 55 not 56 2098952 58 45 and 57 83

Clyne et al Clyne B, Fitzgerald C, Quinlan A, Hardy C, Galvin R, Fahey T, et al. Interventions to Address Potentially Inappropriate Prescribing in Community-Dwelling Older Adults: A Systematic Review of Randomized Controlled Trials. J Am Geriatr Soc. 2016;64(6):1210-22.

PubMed (US, NIH) 2nd August 2019

# Searches Results

#1 Search (inappropriate presc* OR appropriate presc* OR inappropriate 4493 pharma* OR suboptimal presc*) #2 Search ((Intervention Studies) OR Controlled Clinical Trials as Topic) OR 1092571 Controlled Clinical Trial[Publication Type] #3 Search ((Primary Health Care[MeSH Terms]) OR Physicians, Primary 238390 Care[MeSH Terms]) OR ambulatory care #4 Search (aged OR elderly OR community-dwelling elderly OR community- 5166931 dwelling older people) #5 Search ((((inappropriate presc* OR appropriate presc* OR inappropriate 219 pharma* OR suboptimal presc*))) AND (((Intervention Studies) OR Controlled Clinical Trials as Topic) OR Controlled Clinical Trial[Publication Type])) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people)) #6 Search ((((((inappropriate presc* OR appropriate presc* OR inappropriate 561 pharma* OR suboptimal presc*))) AND (((Intervention Studies) OR Controlled Clinical Trials as Topic) OR Controlled Clinical Trial[Publication Type])) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people)))) OR (((((inappropriate presc* OR appropriate presc* OR inappropriate pharma* OR suboptimal presc*))) AND (((Primary Health Care[MeSH Terms]) OR Physicians, Primary Care[MeSH Terms]) OR ambulatory care)) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people))) #7 Search ((((((inappropriate presc* OR appropriate presc* OR inappropriate 307 pharma* OR suboptimal presc*))) AND (((Intervention Studies) OR Controlled Clinical Trials as Topic) OR Controlled Clinical Trial[Publication Type])) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people)))) OR (((((inappropriate presc* OR appropriate presc* OR inappropriate pharma* OR suboptimal presc*))) AND (((Primary Health Care[MeSH Terms]) OR Physicians, Primary Care[MeSH Terms]) OR ambulatory care)) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people))) Filters: Publication date from 2015/01/01 #8 Search randomized controlled trial[Publication Type] OR 206978 randomized[Title/Abstract] OR placebo[Title/Abstract] Filters: Publication date from 2015/01/01 #9 Search (((((((((inappropriate presc* OR appropriate presc* OR inappropriate 85 pharma* OR suboptimal presc*))) AND (((Intervention Studies) OR Controlled Clinical Trials as Topic) OR Controlled Clinical Trial[Publication Type])) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people)))) OR (((((inappropriate presc* OR appropriate presc* OR inappropriate pharma* OR suboptimal presc*))) AND (((Primary Health Care[MeSH Terms]) OR Physicians, Primary Care[MeSH Terms]) OR ambulatory care)) AND ((aged OR elderly OR community-dwelling elderly OR community-dwelling older people)))) AND ( "2015/01/01"[PDat] : "3000/12/31"[PDat] ))) AND ((randomized controlled trial[Publication Type] OR randomized[Title/Abstract] OR placebo[Title/Abstract]) AND ( "2015/01/01"[PDat] : "3000/12/31"[PDat] )) Filters: Publication date from 2015/01/01

Johansson et al Johansson T, Abuzahra ME, Keller S, Mann E, Faller B, Sommerauer C, et al. Impact of strategies to reduce polypharmacy on clinically relevant endpoints: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016;82(2):532-48.

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to July 31, 2019 2nd August 2019

# Searches Results 1 aged.mp. or exp Aged/ 5117103 2 geriatrics.mp. or exp Geriatrics/ 33873 3 Frail Elderly.mp. or exp Frail Elderly/ 11975 4 very elderly.mp. 2180 5 elder*.mp. 255201 6 geriatric*.mp. 98195 7 old*.mp. 1375220 8 veteran.mp. or exp Veterans/ 18080 9 polypharmacy.mp. or exp Polypharmacy/ 8923 10 multidrug*.mp. 60210 11 multi-drug*.mp. 10066 12 overprescription.mp. 201 13 over-prescription.mp. 228 14 (over adj1 (prescrib* or prescript*)).ab,kf,ti. 1017 15 (over-prescrib$ or overprescrib$).ab,kf,ti. 805 16 (elder$ or geriatric$).ab,ti. 272834 17 ((old$ or aged) adj (person$ or adult$ or people or patient$ or inpatient$ or 181716 outpatient$)).ab,ti. 18 ((multi-drug$ or multidrug$) adj2 (prescrib$ or prescription$ or regimen? or 4767 therap$ or treatment?)).ab,kf,ti. 19 veteran*.mp. 39908 20 multiple medication$.mp. 1555 21 excessive medication$.mp. 35 22 multiple drug$.mp. 7653 23 polypharmacotherapy.mp. 99 24 polypharma$.ab,kf,ti. 7566 25 or/1-24 6050937 26 Hospital Information Systems.mp. or exp Hospital Information Systems/ 26450 27 Decision Support Systems, Clinical.mp. or exp Decision Support Systems, 7326 Clinical/ 28 Clinical Pharmacy Information Systems.mp. or exp Clinical Pharmacy 1197 Information Systems/ 29 Medical Order Entry Systems.mp. or exp Medical Order Entry Systems/ 2174 30 Drug Therapy, Computer-Assisted.mp. or exp Drug Therapy, Computer- 1655 Assisted/ 31 ((computer-assisted or computer assisted or computer-aided) adj2 (decision 89 making or drug therap$)).ab,ti. 32 (computerized adj2 decision support).ab,ti. 704 33 Computerized physician order entry.ab,ti. 724 34 ((medica$ or clinical) adj2 decision support system?).ab,ti. 1893 35 (medica$ adj2 (alert adj1 system?)).ab,ti. 18 36 medica$ order entry system?.ab,ti. 19 37 (E-prescription$ or e-medication or e-prescribing or electronic prescription? 1643 or electronic medication or electronic prescribing).ab,ti. 38 (CPOE or CDS or CDSS).ab,ti. 14343

39 Electronic Prescribing.mp. or exp Electronic Prescribing/ 1341 40 Adverse Drug Reaction Reporting Systems.mp. or exp Adverse Drug 7253 Reaction Reporting Systems/ 41 decision support system.mp. or exp Decision Support Systems, 3969 Management/ 42 computer assisted drug therapy.mp. or exp Drug Therapy, Computer- 1659 Assisted/ 43 ((computer$ or electronic$) adj5 (guideline$ or protocol$ or alert& or 6253 reminder$ or audit$ or feedback$)).mp. 44 ((computer$ or electronic$) adj5 decision$).mp. 6373 45 electronic prescription.mp. or exp Electronic Prescribing/ 1138 46 electronic order entry.ab,ti. 55 47 computerized prescriber order entry.ab,ti. 110 48 computerized provider order entry.ab,ti. 409 49 computerized order entry.ab,ti. 159 50 Computerized physician$ order entry system$.ab,ti. 182 51 Computerized physician$ order entry.ab,ti. 729 52 CPOE-system$.ab,ti. 448 53 electronic prescription$.ab,ti. 415 54 electronic prescription$ system$.ab,ti. 42 55 computer$ order entry.ab,ti. 215 56 Computerised clinical decision support.mp. 42 57 exp Medication Errors/pc [Prevention & Control] 6980 58 or/26-57 73438 59 mortality.mp. or exp Mortality/ 1185722 60 morbidity.mp. or exp Morbidity/ 831103 61 exp Hospitalization/ or hospitalization.mp. 297746 62 quality of life.mp. or exp "Quality of Life"/ 316667 63 Adverse drug event.mp. 915 64 "Adverse drug event*".af. 3655 65 Adverse drug reaction.mp. 11012 66 "Adverse drug reaction*".af. 20161 67 medication errors.mp. or exp Medication Errors/ 17751 68 medication errors/pc 6103 69 (medication error? or adverse drug event? or medication-related problem? or 25089 adverse drug reaction? or drug safety).ab,ti. 70 drug therapy/ae 1 71 prescription drugs/ae 1006 72 drug agonism.mp. or exp Drug Agonism/ 365 73 drug antagonism.mp. or exp Drug Antagonism/ 5222 74 exp Drug Inverse Agonism/ or drug inverse agonism.mp. 429 75 drug interactions.mp. or exp Drug Interactions/ 168342 76 (indication error$ or medication error? or medication-related problem? or 5517 drug administration error?).ab,ti. 77 ((adverse or negative) adj2 (health outcome? or drug reaction? or drug 23829 event? or drug effect?)).ab,ti. 78 ADR.ab,ti. 8227

79 ADE.ab,ti. 2302 80 Utilization of resources.mp. 531 81 Number of medications.mp. 2331 82 Hospital admission.mp. 22644 83 Drug related admissions.mp. 47 84 Drug-related readmissions.mp. 17 85 Drug-related problems.mp. 1333 86 Drug errors.mp. 284 87 Safety-Based Drug Withdrawals.mp. or exp Safety-Based Drug 372 Withdrawals/ 88 Hospitality.mp. 724 89 or/59-88 2408742 90 25 and 58 and 89 6486 91 (201507* or 201508* or 201509* or 20151* or 2016* or 2017* or 2018* or 5771587 2019*).dt,ed. 92 90 and 91 2069 93 randomized controlled trial.pt. 486502 94 randomized.mp. 797588 95 placebo.mp. 206365 96 93 or 94 or 95 858759 97 92 and 96 238

Page et al Page AT, Clifford RM, Potter K, Schwartz D, Etherton-Beer CD. The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016;82(3):583-623.

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to August 05, 2019 6th August 2019

# Searches Results 1 exp Aged/ 2972221 2 exp Geriatrics/ 29323 3 elder$.ti,ab. 243771 4 geriatric$.ti,ab. 44337 5 veteran$.ti,ab. 33404 6 old$.ti,ab. 1372608 7 aged.ti,ab. 532940 8 or/1-7 4361312 9 (medication$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 12980 withheld or discontinu$ or reduc$)).ti,ab. 10 (medicin$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1351 or discontinu$ or reduc$)).ti,ab. 11 (prescription$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1620 withheld or discontinu$ or reduc$)).ti,ab.

12 (prescrib$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 2184 or discontinu$ or reduc$)).ti,ab. 13 (polypharmac$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 315 withheld or discontinu$ or reduc$)).ti,ab. 14 (aperient adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 0 or discontinu$ or reduc$)).ti,ab. 15 (fiber adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 2176 discontinu$ or reduc$)).ti,ab. 16 (laxative$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 125 or discontinu$ or reduc$)).ti,ab. 17 (lactulose adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 89 or discontinu$ or reduc$)).ti,ab. 18 (glycerol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 696 or discontinu$ or reduc$)).ti,ab. 19 (sorbitol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 416 or discontinu$ or reduc$)).ti,ab. 20 (macrogol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1 or discontinu$ or reduc$)).ti,ab. 21 (docusate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1 or discontinu$ or reduc$)).ti,ab. 22 (Bisacodyl adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 9 withheld or discontinu$ or reduc$)).ti,ab. 23 (Senna adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 4 discontinu$ or reduc$)).ti,ab. 24 (picosulfate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 2 withheld or discontinu$ or reduc$)).ti,ab. 25 (paraffin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 35 or discontinu$ or reduc$)).ti,ab. 26 (poloxamer adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 37 withheld or discontinu$ or reduc$)).ti,ab. 27 (hormone replacement therapy adj3 (deprescrib$ or withdraw$ or ceas$ or 270 cessation or withheld or discontinu$ or reduc$)).ti,ab. 28 (?estrogen adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 2971 or discontinu$ or reduc$)).ti,ab. 29 (?estradiol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1621 or discontinu$ or reduc$)).ti,ab. 30 (?estriol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 42 or discontinu$ or reduc$)).ti,ab. 31 (tibolone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 68 or discontinu$ or reduc$)).ti,ab. 32 (direct thrombin inhibitor adj3 (deprescrib$ or withdraw$ or ceas$ or 26 cessation or withheld or discontinu$ or reduc$)).ti,ab. 33 (bivalirudin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 118 withheld or discontinu$ or reduc$)).ti,ab. 34 (dabigatran adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 179 withheld or discontinu$ or reduc$)).ti,ab. 35 (warfarin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1233 or discontinu$ or reduc$)).ti,ab. 36 (anticoagula$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 2428 withheld or discontinu$ or reduc$)).ti,ab.

37 (factor XA inhibitor$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation 38 or withheld or discontinu$ or reduc$)).ti,ab. 38 (apixaban adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 164 or discontinu$ or reduc$)).ti,ab. 39 (fondaparinux adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 78 withheld or discontinu$ or reduc$)).ti,ab. 40 (rivaroxaban adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 232 withheld or discontinu$ or reduc$)).ti,ab. 41 (pyridoxine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 119 withheld or discontinu$ or reduc$)).ti,ab. 42 (thiamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 188 or discontinu$ or reduc$)).ti,ab. 43 (calcitriol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 223 or discontinu$ or reduc$)).ti,ab. 44 (c?olecalciferol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 50 withheld or discontinu$ or reduc$)).ti,ab. 45 (ergocalciferol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 5 withheld or discontinu$ or reduc$)).ti,ab. 46 (micronutrient adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 154 withheld or discontinu$ or reduc$)).ti,ab. 47 (vitamin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 4862 or discontinu$ or reduc$)).ti,ab. 48 (mineral adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 2522 or discontinu$ or reduc$)).ti,ab. 49 (iron adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 7086 discontinu$ or reduc$)).ti,ab. 50 (ferrous adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 541 discontinu$ or reduc$)).ti,ab. 51 (calcium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 7528 or discontinu$ or reduc$)).ti,ab. 52 (potassium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 2396 withheld or discontinu$ or reduc$)).ti,ab. 53 (magnesium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1200 withheld or discontinu$ or reduc$)).ti,ab. 54 (ascorb$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 3100 or discontinu$ or reduc$)).ti,ab. 55 (folic adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 552 discontinu$ or reduc$)).ti,ab. 56 (folate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 1737 discontinu$ or reduc$)).ti,ab. 57 (hydroxocobalamin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 21 withheld or discontinu$ or reduc$)).ti,ab. 58 (cyanocobalamin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 18 withheld or discontinu$ or reduc$)).ti,ab. 59 (proton pump inhibitor adj3 (deprescrib$ or withdraw$ or ceas$ or 136 cessation or withheld or discontinu$ or reduc$)).ti,ab. 60 (acid suppression adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 39 withheld or discontinu$ or reduc$)).ti,ab. 61 (PPI adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 775 discontinu$ or reduc$)).ti,ab.

62 (pantoprazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 56 withheld or discontinu$ or reduc$)).ti,ab. 63 (omeprazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 285 withheld or discontinu$ or reduc$)).ti,ab. 64 (esomeprazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 41 withheld or discontinu$ or reduc$)).ti,ab. 65 (lansoprazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 61 withheld or discontinu$ or reduc$)).ti,ab. 66 (rabeprazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 31 withheld or discontinu$ or reduc$)).ti,ab. 67 (antacid adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 80 or discontinu$ or reduc$)).ti,ab. 68 (cimetidine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 443 withheld or discontinu$ or reduc$)).ti,ab. 69 (famotidine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 86 withheld or discontinu$ or reduc$)).ti,ab. 70 (nizatidine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 18 withheld or discontinu$ or reduc$)).ti,ab. 71 (ranitidine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 211 or discontinu$ or reduc$)).ti,ab. 72 (fenofibrate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 366 withheld or discontinu$ or reduc$)).ti,ab. 73 (gemfibrozil adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 170 withheld or discontinu$ or reduc$)).ti,ab. 74 (fibrate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 38 discontinu$ or reduc$)).ti,ab. 75 (ezetimibe adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 293 or discontinu$ or reduc$)).ti,ab. 76 (corticosteroid adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1625 withheld or discontinu$ or reduc$)).ti,ab. 77 (glucocorticoid adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1111 withheld or discontinu$ or reduc$)).ti,ab. 78 (steroid adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 4135 discontinu$ or reduc$)).ti,ab. 79 (dihyropyridines adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 0 withheld or discontinu$ or reduc$)).ti,ab. 80 (amlodipine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 383 withheld or discontinu$ or reduc$)).ti,ab. 81 (diltiazem adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 468 or discontinu$ or reduc$)).ti,ab. 82 (felodipine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 139 withheld or discontinu$ or reduc$)).ti,ab. 83 (lercanidipine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 22 withheld or discontinu$ or reduc$)).ti,ab. 84 (nifedipine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1067 withheld or discontinu$ or reduc$)).ti,ab. 85 (nimodipine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 222 withheld or discontinu$ or reduc$)).ti,ab. 86 (verapamil adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 920 withheld or discontinu$ or reduc$)).ti,ab.

87 (nitrate$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 9826 or discontinu$ or reduc$)).ti,ab. 88 (trinitrate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 70 or discontinu$ or reduc$)).ti,ab. 89 (isosorbide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 74 withheld or discontinu$ or reduc$)).ti,ab. 90 (mononitrate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 23 withheld or discontinu$ or reduc$)).ti,ab. 91 (ivabradine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 247 withheld or discontinu$ or reduc$)).ti,ab. 92 (nicorandil adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 171 withheld or discontinu$ or reduc$)).ti,ab. 93 (perhexiline adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 20 withheld or discontinu$ or reduc$)).ti,ab. 94 (antipsychotic adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 831 withheld or discontinu$ or reduc$)).ti,ab. 95 (amisulpride adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 28 withheld or discontinu$ or reduc$)).ti,ab. 96 (aripiprazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 179 withheld or discontinu$ or reduc$)).ti,ab. 97 (asenapine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 17 withheld or discontinu$ or reduc$)).ti,ab. 98 (chlorpromazine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 197 withheld or discontinu$ or reduc$)).ti,ab. 99 (clozapine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 644 or discontinu$ or reduc$)).ti,ab. 100 (droperidol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 76 withheld or discontinu$ or reduc$)).ti,ab. 101 (flupenthixol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 29 withheld or discontinu$ or reduc$)).ti,ab. 102 (fluphenazine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 47 withheld or discontinu$ or reduc$)).ti,ab. 103 (haloperidol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 927 withheld or discontinu$ or reduc$)).ti,ab. 104 (olanzapine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 326 withheld or discontinu$ or reduc$)).ti,ab. 105 (paliperidone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 20 withheld or discontinu$ or reduc$)).ti,ab. 106 (pericyazine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1 withheld or discontinu$ or reduc$)).ti,ab. 107 (quetiapine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 164 withheld or discontinu$ or reduc$)).ti,ab. 108 (risperidone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 332 withheld or discontinu$ or reduc$)).ti,ab. 109 (trifluoperazine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 79 withheld or discontinu$ or reduc$)).ti,ab. 110 (ziprasidone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 54 withheld or discontinu$ or reduc$)).ti,ab. 111 (zuclopenthixol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 4 withheld or discontinu$ or reduc$)).ti,ab.

112 (lithium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1241 or discontinu$ or reduc$)).ti,ab. 113 (buspirone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 139 withheld or discontinu$ or reduc$)).ti,ab. 114 (diphenhydramine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 89 withheld or discontinu$ or reduc$)).ti,ab. 115 (doxylamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1 withheld or discontinu$ or reduc$)).ti,ab. 116 (melatonin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1900 withheld or discontinu$ or reduc$)).ti,ab. 117 (zolpidem adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 130 or discontinu$ or reduc$)).ti,ab. 118 (zopiclone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 41 or discontinu$ or reduc$)).ti,ab. 119 (benzodiazepine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1032 withheld or discontinu$ or reduc$)).ti,ab. 120 (alprazolam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 175 withheld or discontinu$ or reduc$)).ti,ab. 121 (bromazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 10 withheld or discontinu$ or reduc$)).ti,ab. 122 (midazolam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 386 withheld or discontinu$ or reduc$)).ti,ab. 123 (clobazam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 29 or discontinu$ or reduc$)).ti,ab. 124 (nitrazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 30 withheld or discontinu$ or reduc$)).ti,ab. 125 (oxazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 41 withheld or discontinu$ or reduc$)).ti,ab. 126 (temazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 32 withheld or discontinu$ or reduc$)).ti,ab. 127 (triazolam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 72 or discontinu$ or reduc$)).ti,ab. 128 (clonazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 134 withheld or discontinu$ or reduc$)).ti,ab. 129 (diazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 785 or discontinu$ or reduc$)).ti,ab. 130 (flunitrazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 77 withheld or discontinu$ or reduc$)).ti,ab. 131 (lorazepam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 177 withheld or discontinu$ or reduc$)).ti,ab. 132 (hypnotic adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 212 or discontinu$ or reduc$)).ti,ab. 133 (sedative adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 336 or discontinu$ or reduc$)).ti,ab. 134 (melatonin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1900 withheld or discontinu$ or reduc$)).ti,ab. 135 (anticholinergic adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 224 withheld or discontinu$ or reduc$)).ti,ab. 136 (darifenacin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 11 withheld or discontinu$ or reduc$)).ti,ab.

137 (oxybutynin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 62 withheld or discontinu$ or reduc$)).ti,ab. 138 (tolterodine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 57 withheld or discontinu$ or reduc$)).ti,ab. 139 (benzhexol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 4 withheld or discontinu$ or reduc$)).ti,ab. 140 (glycopyrronium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 10 withheld or discontinu$ or reduc$)).ti,ab. 141 (hyoscine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 39 or discontinu$ or reduc$)).ti,ab. 142 (bromide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 761 or discontinu$ or reduc$)).ti,ab. 143 (biperiden adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 27 or discontinu$ or reduc$)).ti,ab. 144 (orphenadrine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 6 withheld or discontinu$ or reduc$)).ti,ab. 145 (solifenacin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 33 withheld or discontinu$ or reduc$)).ti,ab. 146 (dopamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 3718 withheld or discontinu$ or reduc$)).ti,ab. 147 (bromocriptine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 394 withheld or discontinu$ or reduc$)).ti,ab. 148 (cabergoline adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 93 withheld or discontinu$ or reduc$)).ti,ab. 149 (pergolide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 60 or discontinu$ or reduc$)).ti,ab. 150 (apomorphine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 441 withheld or discontinu$ or reduc$)).ti,ab. 151 (pramipexole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 83 withheld or discontinu$ or reduc$)).ti,ab. 152 (rotigotine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 29 or discontinu$ or reduc$)).ti,ab. 153 (rasagiline adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 20 or discontinu$ or reduc$)).ti,ab. 154 (selegiline adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 60 or discontinu$ or reduc$)).ti,ab. 155 (amantadine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 166 withheld or discontinu$ or reduc$)).ti,ab. 156 (entacapone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 34 withheld or discontinu$ or reduc$)).ti,ab. 157 (levodopa adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 684 or discontinu$ or reduc$)).ti,ab. 158 (dopamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 3718 withheld or discontinu$ or reduc$)).ti,ab. 159 (anticholinesterase adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 25 withheld or discontinu$ or reduc$)).ti,ab. 160 (donepezil adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 157 or discontinu$ or reduc$)).ti,ab. 161 (memantine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 193 withheld or discontinu$ or reduc$)).ti,ab.

162 (galantamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 52 withheld or discontinu$ or reduc$)).ti,ab. 163 (rivastigmine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 54 withheld or discontinu$ or reduc$)).ti,ab. 164 (bisphosphonate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 265 withheld or discontinu$ or reduc$)).ti,ab. 165 (raloxifene adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 275 withheld or discontinu$ or reduc$)).ti,ab. 166 (alendronate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 304 withheld or discontinu$ or reduc$)).ti,ab. 167 (clodronate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 136 withheld or discontinu$ or reduc$)).ti,ab. 168 (ibandron$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 88 withheld or discontinu$ or reduc$)).ti,ab. 169 (pamidronate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 116 withheld or discontinu$ or reduc$)).ti,ab. 170 (risedronate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 135 withheld or discontinu$ or reduc$)).ti,ab. 171 (tiludronate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 5 withheld or discontinu$ or reduc$)).ti,ab. 172 (coledron$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 0 withheld or discontinu$ or reduc$)).ti,ab. 173 (strontium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 108 or discontinu$ or reduc$)).ti,ab. 174 (aspirin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 2547 discontinu$ or reduc$)).ti,ab. 175 (antiplatelet adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1084 withheld or discontinu$ or reduc$)).ti,ab. 176 (clopidogrel adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 930 withheld or discontinu$ or reduc$)).ti,ab. 177 (thienopyridines adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 21 withheld or discontinu$ or reduc$)).ti,ab. 178 (prasugrel adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 115 or discontinu$ or reduc$)).ti,ab. 179 (ticlopidine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 147 withheld or discontinu$ or reduc$)).ti,ab. 180 (dipyridamole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 220 withheld or discontinu$ or reduc$)).ti,ab. 181 (celecoxib adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 396 or discontinu$ or reduc$)).ti,ab. 182 (diclofenac adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 351 withheld or discontinu$ or reduc$)).ti,ab. 183 (etoricoxib adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 39 withheld or discontinu$ or reduc$)).ti,ab. 184 (ibuprofen adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 409 or discontinu$ or reduc$)).ti,ab. 185 (indomethacin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1592 withheld or discontinu$ or reduc$)).ti,ab. 186 (ketoprofen adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 102 withheld or discontinu$ or reduc$)).ti,ab.

187 (ketorolac adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 152 or discontinu$ or reduc$)).ti,ab. 188 (meloxicam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 109 withheld or discontinu$ or reduc$)).ti,ab. 189 (naproxen adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 152 or discontinu$ or reduc$)).ti,ab. 190 (piroxicam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 101 withheld or discontinu$ or reduc$)).ti,ab. 191 (NSAID adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 432 or discontinu$ or reduc$)).ti,ab. 192 (non-steroidal anti-inflammatory adj3 (deprescrib$ or withdraw$ or ceas$ 175 or cessation or withheld or discontinu$ or reduc$)).ti,ab. 193 (colchicine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 393 withheld or discontinu$ or reduc$)).ti,ab. 194 (allopurinol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 365 withheld or discontinu$ or reduc$)).ti,ab. 195 (quinine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 186 or discontinu$ or reduc$)).ti,ab. 196 (levothyroxine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 204 withheld or discontinu$ or reduc$)).ti,ab. 197 (thyroxine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 581 or discontinu$ or reduc$)).ti,ab. 198 (levothyroxine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 204 withheld or discontinu$ or reduc$)).ti,ab. 199 (carbimazole adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 32 withheld or discontinu$ or reduc$)).ti,ab. 200 (propylthiouracil adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 72 withheld or discontinu$ or reduc$)).ti,ab. 201 (iodine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 708 discontinu$ or reduc$)).ti,ab. 202 (paracetamol adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 288 withheld or discontinu$ or reduc$)).ti,ab. 203 (acetaminophen adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 373 withheld or discontinu$ or reduc$)).ti,ab. 204 (antiglycaemi$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1 withheld or discontinu$ or reduc$)).ti,ab. 205 (biguanide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 31 withheld or discontinu$ or reduc$)).ti,ab. 206 (metformin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1580 withheld or discontinu$ or reduc$)).ti,ab. 207 (sulphonylurea adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 24 withheld or discontinu$ or reduc$)).ti,ab. 208 (gliclazide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 60 or discontinu$ or reduc$)).ti,ab. 209 (glibenclamide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 274 withheld or discontinu$ or reduc$)).ti,ab. 210 (glimepiride adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 67 withheld or discontinu$ or reduc$)).ti,ab. 211 (glipizide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 42 or discontinu$ or reduc$)).ti,ab.

212 (pioglitazone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 510 withheld or discontinu$ or reduc$)).ti,ab. 213 (rosiglitazone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 391 withheld or discontinu$ or reduc$)).ti,ab. 214 (insulin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 14701 discontinu$ or reduc$)).ti,ab. 215 (acarbose adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 193 or discontinu$ or reduc$)).ti,ab. 216 (alogliptin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 20 or discontinu$ or reduc$)).ti,ab. 217 (linagliptin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 58 withheld or discontinu$ or reduc$)).ti,ab. 218 (Saxagliptin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 36 withheld or discontinu$ or reduc$)).ti,ab. 219 (Sitagliptin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 176 withheld or discontinu$ or reduc$)).ti,ab. 220 (Vildagliptin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 90 withheld or discontinu$ or reduc$)).ti,ab. 221 (antiepilep$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 692 withheld or discontinu$ or reduc$)).ti,ab. 222 (anticonvulsant adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 316 withheld or discontinu$ or reduc$)).ti,ab. 223 (valproate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 342 or discontinu$ or reduc$)).ti,ab. 224 (carbamazepine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 439 withheld or discontinu$ or reduc$)).ti,ab. 225 (barbiturate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 176 withheld or discontinu$ or reduc$)).ti,ab. 226 (lithium adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 1241 or discontinu$ or reduc$)).ti,ab. 227 (lamotrigine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 183 withheld or discontinu$ or reduc$)).ti,ab. 228 (gabapentin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 386 withheld or discontinu$ or reduc$)).ti,ab. 229 (phenytoin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 416 withheld or discontinu$ or reduc$)).ti,ab. 230 (pregabalin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 287 withheld or discontinu$ or reduc$)).ti,ab. 231 (ethosuximide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 44 withheld or discontinu$ or reduc$)).ti,ab. 232 (levetiracetam adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 133 withheld or discontinu$ or reduc$)).ti,ab. 233 (topiramate adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 317 withheld or discontinu$ or reduc$)).ti,ab. 234 (vigabatrin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 93 withheld or discontinu$ or reduc$)).ti,ab. 235 (tiagabine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 50 or discontinu$ or reduc$)).ti,ab. 236 (antihistamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 73 withheld or discontinu$ or reduc$)).ti,ab.

237 (cyclizine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 2 or discontinu$ or reduc$)).ti,ab. 238 (cyproheptadine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 67 withheld or discontinu$ or reduc$)).ti,ab. 239 (dexchlorpheniramine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation 3 or withheld or discontinu$ or reduc$)).ti,ab. 240 (diphenhydramine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 89 withheld or discontinu$ or reduc$)).ti,ab. 241 (doxylamine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1 withheld or discontinu$ or reduc$)).ti,ab. 242 (pheniramine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 4 withheld or discontinu$ or reduc$)).ti,ab. 243 (promethazine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 45 withheld or discontinu$ or reduc$)).ti,ab. 244 (trimeprazine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 1 withheld or discontinu$ or reduc$)).ti,ab. 245 (cetirizine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 80 or discontinu$ or reduc$)).ti,ab. 246 (desloratadine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 28 withheld or discontinu$ or reduc$)).ti,ab. 247 (fexofenadine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 32 withheld or discontinu$ or reduc$)).ti,ab. 248 (levocetirizine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 23 withheld or discontinu$ or reduc$)).ti,ab. 249 (loratadine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 45 withheld or discontinu$ or reduc$)).ti,ab. 250 (diuretic adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 403 or discontinu$ or reduc$)).ti,ab. 251 (thiazide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 108 or discontinu$ or reduc$)).ti,ab. 252 (frusemide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 64 withheld or discontinu$ or reduc$)).ti,ab. 253 (indapamide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 90 withheld or discontinu$ or reduc$)).ti,ab. 254 (hydrochlorothiazide adj3 (deprescrib$ or withdraw$ or ceas$ or cessation 179 or withheld or discontinu$ or reduc$)).ti,ab. 255 (spironolactone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 307 withheld or discontinu$ or reduc$)).ti,ab. 256 (digoxin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld 495 or discontinu$ or reduc$)).ti,ab. 257 (amiodarone adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 607 withheld or discontinu$ or reduc$)).ti,ab. 258 (antiarrythmi$ adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 0 withheld or discontinu$ or reduc$)).ti,ab. 259 (antidepressant adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 792 withheld or discontinu$ or reduc$)).ti,ab. 260 (SSRI adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 220 discontinu$ or reduc$)).ti,ab. 261 (selective serotonin reuptake inhibitor adj3 (deprescrib$ or withdraw$ or 76 ceas$ or cessation or withheld or discontinu$ or reduc$)).ti,ab.

262 (mirtazapine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 89 withheld or discontinu$ or reduc$)).ti,ab. 263 (TCA adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 281 discontinu$ or reduc$)).ti,ab. 264 (tricyclic antidepressant adj3 (deprescrib$ or withdraw$ or ceas$ or 37 cessation or withheld or discontinu$ or reduc$)).ti,ab. 265 (mianserin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 75 withheld or discontinu$ or reduc$)).ti,ab. 266 (SNRI adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 16 discontinu$ or reduc$)).ti,ab. 267 ((serotonin and noradrenaline reuptake inhibitor) adj3 (deprescrib$ or 24 withdraw$ or ceas$ or cessation or withheld or discontinu$ or reduc$)).ti,ab. 268 (venlafaxine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 157 withheld or discontinu$ or reduc$)).ti,ab. 269 (duloxetine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 146 withheld or discontinu$ or reduc$)).ti,ab. 270 (desvenlafaxine adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 21 withheld or discontinu$ or reduc$)).ti,ab. 271 (beta-blocker adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 423 withheld or discontinu$ or reduc$)).ti,ab. 272 (beta blocker adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 423 withheld or discontinu$ or reduc$)).ti,ab. 273 (betablocker adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 11 withheld or discontinu$ or reduc$)).ti,ab. 274 (alpha-blocker adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 54 withheld or discontinu$ or reduc$)).ti,ab. 275 (alpha blocker adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or 54 withheld or discontinu$ or reduc$)).ti,ab. 276 (angiotensin II receptor antagonist adj3 (deprescrib$ or withdraw$ or ceas$ 25 or cessation or withheld or discontinu$ or reduc$)).ti,ab. 277 (sartan adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 3 discontinu$ or reduc$)).ti,ab. 278 (Angiotensin-Converting Enzyme Inhibitors adj3 (deprescrib$ or 251 withdraw$ or ceas$ or cessation or withheld or discontinu$ or reduc$)).ti,ab. 279 (ACEI adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 236 discontinu$ or reduc$)).ti,ab. 280 (statin adj3 (deprescrib$ or withdraw$ or ceas$ or cessation or withheld or 2012 discontinu$ or reduc$)).ti,ab. 281 (HmG CoA Reductase Inhibitor adj3 (deprescrib$ or withdraw$ or ceas$ or 1612 cessation or withheld or discontinu$ or reduc$)).ti,ab. 282 exp Pharmaceutical Preparations/ 811158 283 or/9-281 142222 284 deprescrib$.ti,ab. 447 285 withdraw$.ti,ab. 120567 286 ceas$.ti,ab. 23288 287 cessation.ti,ab. 70006 288 withheld.ti,ab. 4615 289 discontinu$.ti,ab. 120190

290 reduc$.ti,ab. 3147764 291 or/284-290 3398705 292 282 and 291 145256 293 mortality.ti,ab. 700526 294 exp Death/ 143646 295 falls.ti,ab. 43121 296 exp Accidental Falls/ 22518 297 cognition.ti,ab. 61251 298 exp Mental Processes/ 992123 299 behavior.ti,ab. 594121 300 exp Behavior/ and Behavior Mechanisms/ 0 301 quality of life.ti,ab. 253249 302 exp Quality of Life/ 179173 303 exp Rebound insomnia/ 12356 304 exp Drug-Related Side Effects/ and Adverse Reactions/ 0 305 rebound.ti,ab. 13122 306 or/293-305 2688393 307 8 and (283 or 292) and 306 8371 308 (201502* or 201503* or 201504* or 201505* or 201506* or 201507* or 6235588 201508* or 201509* or 20151* or 2016* or 2017* or 2018* or 2019*).dt,ed. 309 307 and 308 2573 310 randomized controlled trial.pt. 486665 311 randomized.mp. 798241 312 placebo.mp. 206509 313 or/310-312 859457 314 309 and 313 848

7.4.2. Strategy for new scoping searches

Topic A: Burden of PP 1. What is the prevalence (and/or incidence) of PP in the UK? 2. What are the costs to the NHS of PP in the UK? 3. What are the health consequences of PP in the UK?

Terms for polypharmacy were adapted from the Cochrane review search (statements #1-#11) was combined with terms for incidence and prevalence (statements #12-#14). For question 2, a best sensitivity and specificity costs filter (#45-#47) was combined with polypharmacy concept terms. For question 3, statements #16-#43 comprising terms for quality of life search filter (Arber et al., 2017) was combined with the polypharmacy concept terms. The search was limited to English language and from 2009 onwards. The search was limited to the UK (#51-#61) using a greographical search filter (Ayiku et al., 2017).

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) 1946 to July 31, 2019 8th August 2019

# Searches Results 1 polypharmacy/ 4392 2 polypharma*.ti,ab. 7162 3 polytherap*.ti,ab. 1714 4 ((multi-drug* or multidrug*) adj2 (prescrib* or prescription* or therap* or 3809 treatment*)).ti,ab. 5 inappropriate prescribing/ 2736 6 potentially inappropriate medication list/ 306 7 ((inappropriat* or unnecessary or multipl*) adj2 (medicine* or medicat* or 17775 prescrib* or prescription* or drug*)).ti,ab. 8 ((over adj1 (prescrib* or prescript*)) or (over-prescrib* or 1549 overprescrib*)).ti,ab. 9 deprescriptions/ 237 10 (deprescrib* or deprescript*).ti,ab. 478 11 or/1-10 34107 12 Incidence/ 246508 13 Prevalence/ 272713 14 (incidence or distribution or prevalence or occurrence*).ti,ab. 2210478 15 or/12-14 2360845 16 Quality-Adjusted Life Years/ 11230 17 Value of Life/ 5653 18 (qaly* or qald* or qale* or qtime*).ti,ab,kf. 9829 19 (quality adjusted or adjusted life year*).ti,ab,kf. 15310 20 disability adjusted life.ti,ab,kf. 2987 21 daly*1.ti,ab,kf. 2669 22 ((index adj3 wellbeing) or (quality adj3 wellbeing) or qwb).ti,ab,kf. 661 23 (multiattribute* or multi attribute*).ti,ab,kf. 839 24 (utility adj3 (score*1 or scoring or valu* or measur* or evaluat* or scale*1 or 31129 instrument*1 or weight or weights or weighting or information or data or unit or units or health* or life or estimat* or elicit* or disease* or mean or cost* or expenditure*1 or gain or gains or loss or losses or lost or analysis or index* or indices or overall or reported or calculat* or range* or increment* or state or states or status)).ti,ab,kf. 25 utility.ab. /freq=2 16025 26 utilities.ti,ab,kf. 6639 27 disutili*.ti,ab,kf. 434 28 (HSUV or HSUVs).ti,ab,kf. 60 29 health*1 year*1 equivalent*1.ti,ab,kf. 40 30 (hye or hyes).ti,ab,kf. 67 31 (hui or hui1 or hui2 or hui3).ti,ab,kf. 1405 32 (illness state*1 or health state*1).ti,ab,kf. 6057 33 (euro qual or euro qual5d or euro qol5d or eq-5d or eq5-d or eq5d or euroqual 9761 or euroqol or euroqual5d or euroqol5d).ti,ab,kf. 34 (eq-sdq or eqsdq).ti,ab,kf. 1 35 (short form* or shortform*).ti,ab,kf. 30827 36 (sf36* or sf 36* or sf thirtysix or sf thirty six).ti,ab,kf. 20896 37 (sf6 or sf 6 or sf6d or sf 6d or sf six or sfsix or sf8 or sf 8 or sf eight or 3080 sfeight).ti,ab,kf.

38 (sf12 or sf 12 or sf twelve or sftwelve).ti,ab,kf. 4341 39 (sf16 or sf 16 or sf sixteen or sfsixteen).ti,ab,kf. 28 40 (sf20 or sf 20 or sf twenty or sftwenty).ti,ab,kf. 331 41 (15D or 15-D or 15 dimension).ti,ab,kf. 5002 42 (standard gamble* or sg).ti,ab,kf. 9904 43 (time trade off*1 or time tradeoff*1 or tto or timetradeoff*1).ti,ab,kf. 1805 44 or/16-43 134312 45 cost:.mp. 657626 46 cost benefit analys:.mp. 79453 47 health care costs.mp. 46620 48 45 or 46 or 47 657626 49 15 or 44 or 48 3037731 50 11 and 49 9067 51 exp Great Britain/ 354719 52 (national health service* or nhs*).ti,ab,in. 175717 53 (english not ((published or publication* or translat* or written or language* or 92129 speak* or literature or citation*) adj5 english)).ti,ab. 54 (gb or "g.b." or britain*).ti,ab,jw,in. 48925 55 (british* not "british columbia").ti,ab,jw,in. 535531 56 (uk or "u.k." or united kingdom*).ti,ab,jw,in. 1338975 57 (england* not "new england").ti,ab,jw,in. 121919 58 ("northern ireland*" or "northern irish*" or scotland* or scottish* or 93707 welsh*).ti,ab,jw,in. 59 ((wales or south wales) not "new south wales").ti,ab,jw,in. 52551 60 or/51-59 2205322 61 (exp africa/ or exp americas/ or exp antarctic regions/ or exp arctic regions/ or 2733024 exp asia/ or exp oceania/) not (exp great britain/ or europe/) 62 60 not 61 2098592 63 50 and 62 856 64 limit 63 to (english language and yr="2009 -Current") 576 65 limit 50 to (english language and yr="2009 -Current") 5494 66 65 not 64 4918

7.4.3. Strategy for searching clinical trial registers

ClinicalTrials.gov (US NIH) 14th August 2019

# Searches Results 1 polypharmacy 201 2 polytherapy 22 3 deprescribing 34 4 1 or 2 or 3 257

WHOI International Clinical Trials Registry Platform

14th August 2019

# Searches Results 1 polypharma* 155 2 polytherap* 10 3 deprescrib* 46 4 1 or 2 or 3 211

7.5. Appendix 4: Titles identified in the scoping searches

7.5.1. Titles identified in the update to the searches by the systematic reviews

Jokanovic et al N=25 1. Alldred D. RPS Pharmacy Research UK Lecture Optimising medicines for older care home residents: now and the future. Int J Pharm Pract. 2015;23 Suppl 2:2-3. 2. Andreassen LM, Kjome RL, Solvik UO, Houghton J, Desborough JA. The potential for deprescribing in care home residents with Type 2 diabetes. International Journal of Clinical Pharmacy. 2016;38(4):977-84. 3. Baqir W, Barrett S, Desai N, Copeland R, Hughes J. A clinico-ethical framework for multidisciplinary review of medication in nursing homes. BMJ qual. 2014;3(1). 4. Benetos A, Novella JL, Guerci B, Blickle JF, Boivin JM, Cuny P, et al. Pragmatic diabetes management in nursing homes: individual care plan. J Am Med Dir Assoc. 2013;14(11):791-800. 5. Cool C, Cestac P, Laborde C, Lebaudy C, Rouch L, Lepage B, et al. Potentially inappropriate drug prescribing and associated factors in nursing homes. J Am Med Dir Assoc. 2014;15(11):850.e1- 9. 6. de Souto Barreto P, Lapeyre-Mestre M, Cestac P, Vellas B, Rolland Y. Effects of a geriatric intervention aiming to improve quality care in nursing homes on benzodiazepine use and discontinuation. Br J Clin Pharmacol. 2016;81(4):759-67. 7. Ellis G, Marshall T, Ritchie C. Comprehensive geriatric assessment in the emergency department. Clin Interv Aging. 2014;9:2033-43. 8. Ellwood A, Airlie J, Cicero R, Cundill B, Ellard DR, Farrin A, et al. Recruiting care homes to a randomised controlled trial. Trials. 2018;19(1):535. 9. Girard P, Sourdet S, Cantet C, de Souto Barreto P, Rolland Y. Acetaminophen Safety: Risk of Mortality and Cardiovascular Events in Nursing Home Residents, a Prospective Study. J Am Geriatr Soc. 2019;67(6):1240-7. 10. Harrison SL, Cations M, Jessop T, Hilmer SN, Sawan M, Brodaty H. Approaches to Deprescribing Psychotropic Medications for Changed Behaviours in Long-Term Care Residents Living with Dementia. Drugs Aging. 2019;36(2):125-36.

11. Hooper L, Bunn D, Jimoh FO, Fairweather-Tait SJ. Water-loss dehydration and aging. Mech Ageing Dev. 2014;136-137:50-8. 12. Ivanova I, Wauters M, Stichele RV, Christiaens T, De Wolf J, Dilles T, et al. Medication use in a cohort of newly admitted nursing home residents (Ageing@NH) in relation to evolving physical and mental health. Arch Gerontol Geriatr. 2018;75:202-8. 13. Kada O, Janig H, Likar R, Cernic K, Pinter G. Reducing Avoidable Hospital Transfers From Nursing Homes in Austria: Project Outline and Baseline Results. Gerontol. 2017;3:2333721417696671. 14. Kroger E, Wilchesky M, Marcotte M, Voyer P, Morin M, Champoux N, et al. Medication Use Among Nursing Home Residents With Severe Dementia: Identifying Categories of Appropriateness and Elements of a Successful Intervention. J Am Med Dir Assoc. 2015;16(7):629.e1-17. 15. Malek Makan A, van Hout H, Onder G, Finne-Soveri H, van der Roest H, van Marum R. Prevalence of Preventive Cardiovascular Medication Use In Nursing Home Residents. Room for Deprescribing? The SHELTER Study. J Am Med Dir Assoc. 2017;18(12):1037-42. 16. Millar AN, Hughes CM, Passmore AP, Ryan C. Intermediate care: the role of medicines management. Drugs Aging. 2014;31(1):21-31. 17. Nakham A, Myint PK, Bond CM, Newlands R, Loke YK, Cruickshank M. Interventions to Reduce Anticholinergic Burden in Adults Aged 65 and Older: A Systematic Review. J Am Med Dir Assoc. 2019;24:24. 18. Niznik JD, Zhao X, He M, Aspinall SL, Hanlon JT, Nace D, et al. Factors Associated With Deprescribing Acetylcholinesterase Inhibitors in Older Nursing Home Residents With Severe Dementia. J Am Geriatr Soc. 2019;04:04. 19. Onder G, Vetrano DL, Villani ER, Carfi A, Lo Monaco MR, Cipriani MC, et al. Deprescribing in Nursing Home Residents on Polypharmacy: Incidence and Associated Factors. J Am Med Dir Assoc. 2019;07:07. 20. Stubbs B, Eggermont L, Soundy A, Probst M, Vandenbulcke M, Vancampfort D. What are the factors associated with physical activity (PA) participation in community dwelling adults with dementia? A systematic review of PA correlates. Arch Gerontol Geriatr. 2014;59(2):195-203. 21. Sumukadas D, McMurdo ME, Mangoni AA, Guthrie B. Temporal trends in anticholinergic medication prescription in older people: repeated cross-sectional analysis of population prescribing data. Age Ageing. 2014;43(4):515-21. 22. Thiruchelvam K, Hasan SS, Wong PS, Kairuz T. Residential Aged Care Medication Review to Improve the Quality of Medication Use: A Systematic Review. J Am Med Dir Assoc. 2017;18(1):87.e1-.e14. 23. Tommelein E, Mehuys E, Petrovic M, Somers A, Van Damme C, Pattyn E, et al. Potentially inappropriate prescribing in nursing home residents detected with the community pharmacist specific GheOP(3)S-tool. International Journal of Clinical Pharmacy. 2016;38(5):1063-8. 24. Wang KN, Bell JS, Chen EYH, Gilmartin-Thomas JFM, Ilomaki J. Medications and Prescribing Patterns as Factors Associated with Hospitalizations from Long-Term Care Facilities: A Systematic Review. Drugs Aging. 2018;35(5):423-57. 25. Yarnall AJ, Sayer AA, Clegg A, Rockwood K, Parker S, Hindle JV. New horizons in multimorbidity in older adults. Age Ageing. 2017;46(6):882-8.

Leelakanok et al N=81 unique records out of 83

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7.5.2. Titles identified in new scoping searches on Topic A: Burden of PP

Burden of PP N= 576 1. Abbing-Karahagopian V, Huerta C, Souverein PC, de Abajo F, Leufkens HG, Slattery J, et al. Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications. Eur J Clin Pharmacol. 2014;70(7):849-57. 2. Abdelhafiz AH, Marshall R, Kavanagh J, El-Nahas M. Management of hypertension in older people. Expert Rev Endocrinol Metab. 2018;13(4):181-91. 3. Abdelhafiz AH, Sinclair AJ. Hypoglycaemia in residential care homes. Br J Gen Pract. 2009;59(558):49-50. 4. Abdel-Qader DH, Harper L, Cantrill JA, Tully MP. Pharmacists' interventions in prescribing errors at hospital discharge: an observational study in the context of an electronic prescribing system in a UK teaching hospital. Drug Saf. 2010;33(11):1027-44. 5. Abhishek A. Managing Gout Flares in the Elderly: Practical Considerations. Drugs Aging. 2017;34(12):873-80. 6. Abohelaika S, Kamali F, Avery P, Robinson B, Kesteven P, Wynne H. Anticoagulation control and cost of monitoring of older patients on chronic warfarin therapy in three settings in North East England. Age Ageing. 2014;43(5):708-11. 7. Ade S, Trebucq A, Harries AD, Affolabi D, Ade G, Agodokpessi G, et al. MDR-TB treatment needs in patients previously treated for TB in Cotonou, Benin. Public health action. 2013;3(2):160-5. 8. Agbabiaka TB, Spencer NH, Khanom S, Goodman C. Prevalence of drug-herb and drug- supplement interactions in older adults: a cross-sectional survey. Br J Gen Pract. 2018;68(675):e711- e7. 9. Ahmad A, Weston PJ, Ahmad M, Sharma D, Purewal T. A cost-benefit analysis of twice- daily consultant ward rounds and clinical input on investigation and pharmacy costs in a major teaching hospital in the UK. BMJ Open. 2015;5(4):e007367.

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10. Aibani N, Nesbitt H, Marino N, Jurek J, O'Neill C, Martin C, et al. Electroneutral polymersomes for combined cancer chemotherapy. Acta Biomater. 2018;80:327-40. 11. Akbarov A, Kontopantelis E, Sperrin M, Stocks SJ, Williams R, Rodgers S, et al. Primary Care Medication Safety Surveillance with Integrated Primary and Secondary Care Electronic Health Records: A Cross-Sectional Study. Drug Saf. 2015;38(7):671-82. 12. Akunne OO, Adedapo ADA. Antihypertensive prescription among black patients without compelling indications: prescription, effectiveness, quality and cost of medication. BMC Health Serv Res. 2019;19(1):373. 13. Al AlShaikh S, Quinn T, Dunn W, Walters M, Dawson J. Predictive factors of non-adherence to secondary preventative medication after stroke or transient ischaemic attack: A systematic review and meta-analyses. Eur Stroke J. 2016;1(2):65-75. 14. Al Hamid A, Aslanpour Z, Aljadhey H, Ghaleb M. Hospitalisation Resulting from Medicine- Related Problems in Adult Patients with Cardiovascular Diseases and Diabetes in the United Kingdom and Saudi Arabia. Int J Environ Res Public Health. 2016;13(5):09. 15. Al Hamid A, Ghaleb M, Aljadhey H, Aslanpour Z. A systematic review of hospitalization resulting from medicine-related problems in adult patients. Br J Clin Pharmacol. 2014;78(2):202-17. 16. Al Raiisi F, Stewart D, Fernandez-Llimos F, Salgado TM, Mohamed MF, Cunningham S. Clinical pharmacy practice in the care of Chronic Kidney Disease patients: a systematic review. International Journal of Clinical Pharmacy. 2019;41(3):630-66. 17. Alagiakrishnan K, Banach M, Mah D, Ahmed A, Aronow WS. Role of Geriatric Syndromes in the Management of Atrial Fibrillation in Older Adults: A Narrative Review. J Am Med Dir Assoc. 2019;20(2):123-30. 18. Alanazi MA, Tully MP, Lewis PJ. A systematic review of the prevalence and incidence of prescribing errors with high-risk medicines in hospitals. J Clin Pharm Ther. 2016;41(3):239-45. 19. Alfa-Wali M, Mohammed I, Yusuph H. Under the counter, underground or unethical medicines? An African perspective. Trop Doct. 2014;44(1):21-4. 20. Al-Jumaili AA, Doucette WR. Comprehensive Literature Review of Factors Influencing Medication Safety in Nursing Homes: Using a Systems Model. J Am Med Dir Assoc. 2017;18(6):470-88. 21. Alldred DP, Kennedy MC, Hughes C, Chen TF, Miller P. Interventions to optimise prescribing for older people in care homes. Cochrane Database Syst Rev. 2016;2:CD009095. 22. Alldred DP, Raynor DK, Hughes C, Barber N, Chen TF, Spoor P. Interventions to optimise prescribing for older people in care homes. Cochrane Database Syst Rev. 2013(2):CD009095. 23. Allen LN, Pullar J, Wickramasinghe KK, Williams J, Roberts N, Mikkelsen B, et al. Evaluation of research on interventions aligned to WHO 'Best Buys' for NCDs in low-income and lower-middle-income countries: a systematic review from 1990 to 2015. BMJ glob. 2018;3(1):e000535. 24. Alrwisan A, Ross J, Williams D. Medication incidents reported to an online incident reporting system. Eur J Clin Pharmacol. 2011;67(5):527-32. 25. Alves A, Green S, James DH. Deprescribing of Medicines in Care Homes-A Five-Year Evaluation of Primary Care Pharmacist Practices. Pharmacy (Basel). 2019;7(3):03.

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71. Biernikiewicz M, Taieb V, Toumi M. Characteristics of doctor-shoppers: a systematic literature review. J Mark Access Health Policy. 2019;7(1):1595953. 72. Blair PS, Turnbull S, Ingram J, Redmond N, Lucas PJ, Cabral C, et al. Feasibility cluster randomised controlled trial of a within-consultation intervention to reduce antibiotic prescribing for children presenting to primary care with acute respiratory tract infection and cough. BMJ Open. 2017;7(5):e014506. 73. Blasi F, Concia E, Del Prato B, Giusti M, Mazzei T, Polistena B, et al. The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach. J Chemother. 2017;29(5):274-86. 74. Ble A, Masoli JA, Barry HE, Winder RE, Tavakoly B, Henley WE, et al. Any versus long- term prescribing of high risk medications in older people using 2012 Beers Criteria: results from three cross-sectional samples of primary care records for 2003/4, 2007/8 and 2011/12. BMC geriatr. 2015;15:146. 75. Blenkinsopp A, Bond C, Raynor DK. Medication reviews. Br J Clin Pharmacol. 2012;74(4):573-80. 76. Boateng J. Drug Delivery Innovations to Address Global Health Challenges for Pediatric and Geriatric Populations (Through Improvements in Patient Compliance). J Pharm Sci. 2017;106(11):3188-98. 77. Boeker EB, Ram K, Klopotowska JE, de Boer M, Creus MT, de Andres AL, et al. An individual patient data meta-analysis on factors associated with adverse drug events in surgical and non-surgical inpatients. Br J Clin Pharmacol. 2015;79(4):548-57. 78. Bosnic-Anticevich S, Chrystyn H, Costello RW, Dolovich MB, Fletcher MJ, Lavorini F, et al. The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes. Int J Chron Obstruct Pulmon Dis. 2017;12:59-71. 79. Bowring DL, Totsika V, Hastings RP, Toogood S, McMahon M. Prevalence of psychotropic medication use and association with challenging behaviour in adults with an intellectual disability. A total population study. J Intellect Disabil Res. 2017;61(6):604-17. 80. Bradley MC, Fahey T, Cahir C, Bennett K, O'Reilly D, Parsons C, et al. Potentially inappropriate prescribing and cost outcomes for older people: a cross-sectional study using the Northern Ireland Enhanced Prescribing Database. Eur J Clin Pharmacol. 2012;68(10):1425-33. 81. Bradley MC, Motterlini N, Padmanabhan S, Cahir C, Williams T, Fahey T, et al. Potentially inappropriate prescribing among older people in the United Kingdom. BMC geriatr. 2014;14:72. 82. Brainin M, Feigin V, Martins S, Matz K, Roy J, Sandercock P, et al. Cut stroke in half: Polypill for primary prevention in stroke. Int j. 2018;13(6):633-47. 83. Bresnahan R, Panebianco M, Marson AG. Brivaracetam add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev. 2019;3:CD011501. 84. Brett A, Bielicki J, Newland JG, Rodrigues F, Schaad UB, Sharland M. Neonatal and pediatric antimicrobial stewardship programs in Europe-defining the research agenda. Pediatr Infect Dis J. 2013;32(12):e456-65. 85. Britton OJ, Abi-Gerges N, Page G, Ghetti A, Miller PE, Rodriguez B. Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Ex vivo

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558. Winters M, Bakker EWP, Moen MH, Barten CC, Teeuwen R, Weir A. Medial tibial stress syndrome can be diagnosed reliably using history and physical examination. BJSM online. 2018;52(19):1267-72. 559. Wirth D, Dass R, Hettle R. Cost-effectiveness of adding novel or group 5 interventions to a background regimen for the treatment of multidrug-resistant tuberculosis in Germany. BMC Health Serv Res. 2017;17(1):182. 560. Wisniowska B, Tylutki Z, Wyszogrodzka G, Polak S. Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials. BMC Pharmacol Toxicol. 2016;17:12. 561. Wolfson L, Walker A, Hettle R, Lu X, Kambili C, Murungi A, et al. Cost Effectiveness of Bedaquiline for the Treatment of Multidrug-Resistant Tuberculosis. Value in Health. 2014;17(7):A595. 562. Wolfson LJ, Walker A, Hettle R, Lu X, Kambili C, Murungi A, et al. Cost-effectiveness of adding bedaquiline to drug regimens for the treatment of multidrug-resistant tuberculosis in the UK. PLoS ONE. 2015;10(3):e0120763. 563. Wong S, Santullo P, Hirani SP, Kumar N, Chowdhury JR, Garcia-Forcada A, et al. Use of antibiotics and the prevalence of antibiotic-associated diarrhoea in patients with spinal cord injuries: an international, multi-centre study. J Hosp Infect. 2017;97(2):146-52. 564. Wong S, Santullo P, O'Driscoll J, Jamous A, Hirani SP, Saif M. Use of antibiotic and prevalence of antibiotic-associated diarrhoea in-patients with spinal cord injuries: a UK national spinal injury centre experience. Spinal Cord. 2017;55(6):583-7. 565. Woo PYM, Wong HT, Pu JKS, Wong WK, Wong LYW, Lee MWY, et al. Moving the goalposts: A comparison of different definitions for primary external ventricular drain infection and its risk factors: A multi-center study of 2575 patients. J Clin Neurosci. 2017;45:67-72. 566. Wood F, Salam A, Singh K, Day S, Jan S, Prabhakaran D, et al. Process evaluation of the impact and acceptability of a polypill for prevention of cardiovascular disease. BMJ Open. 2015;5(9):e008018. 567. Woodcock A, Bakerly ND, New JP, Gibson JM, Wu W, Vestbo J, et al. The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in asthma. BMC polm. 2015;15:160. 568. Woodman RJ, Wood KM, Kunnel A, Dedigama M, Pegoli MA, Soiza RL, et al. Patterns of Drug Use and Serum Sodium Concentrations in Older Hospitalized Patients: A Latent Class Analysis Approach. Drugs - real world outcomes. 2016;3(4):383-91. 569. Xu Y, Neuen DR, Glozier N, Nikpour A, Somerville E, Bleasel A, et al. Disability patterns over the first year after a diagnosis of epilepsy. Clin Neurol Neurosurg. 2019;179:60-5. 570. Yemm R, Jones C, Mitoko T. Displaying medication costs on dispensing labels as a strategy to reduce wastage: views of the Welsh general public. Integr. 2017;6:173-80. 571. Yeo KR, Jamei M, Rostami-Hodjegan A. Predicting drug-drug interactions: application of physiologically based pharmacokinetic models under a systems biology approach. Expert Rev Clin Pharmacol. 2013;6(2):143-57. 572. Young SL, Taylor M, Lawrie SM. "First do no harm." A systematic review of the prevalence and management of antipsychotic adverse effects. J Psychopharmacol. 2015;29(4):353-62.

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7.5.3. Titles identified in the clinical trial registers

Trials registers: Clinicaltrials.gov N=215

1. Aarhus Uo, Society DC. Suitability of an Organization With an Onco-geriatric Team to a Whole Region (Region Midt) of Denmark. https://ClinicalTrials.gov/show/NCT02072733; 2015. 2. Addiction Cf, Health M, Calgary Uo, Institute LHR, Institute DMHU. Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia. https://ClinicalTrials.gov/show/NCT03672201; 2018. 3. Aires UoB. Evaluation of a Drug Interactions Software to Limit Polypharmacy. https://ClinicalTrials.gov/show/NCT03901820; 2019. 4. Aires UoB, S.A. D. Drug Interactions in Outpatients. https://ClinicalTrials.gov/show/NCT03943524; 2019. 5. Alegre HdCdP. Pharmaceutical Care in the Reduction of Readmission Rates in Diabetes Melitus. https://ClinicalTrials.gov/show/NCT03786978; 2015. 6. Alegre HdCdP. The Effect of Water Intake on the State of Hydration and Renal Function in Elderly Patients. https://ClinicalTrials.gov/show/NCT03002415; 2017. 7. Alegre HdCdP, Sul FUoRGd. Evaluation of Evening Versus Morning Levothyroxine Intake in Elderly. https://ClinicalTrials.gov/show/NCT03614988; 2018. 8. Alfred T. Polypharmacy in the Heart Failure Patient: Are All Prescribed Drug Classes Required? Statin Withdrawal Study. https://ClinicalTrials.gov/show/NCT01554592; 2012. 9. Alfred T. Aspirin Withdrawal in Non-ischaemic Cardiomyopathy Study. https://ClinicalTrials.gov/show/NCT01534026; 2012. 10. All India Institute of Medical Sciences B. Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Seizure. https://ClinicalTrials.gov/show/NCT03590197; 2018. 11. Andrew M, University D, Network CF, Network HH, Authority NSH. Deprescribing in Primary Health Care. https://ClinicalTrials.gov/show/NCT03903484; 2019. 12. Anziani INdReCp. Epidemiological Observatory on the Health Conditions of Inpatients Aged 65 or Older at the INRCA Research Hospitals. https://ClinicalTrials.gov/show/NCT01397682; 2011.

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13. Apotek RH, Copenhagen University Hospital H. Interdisciplinary Medication Review Interventions in an Integrated Outpatient Department. https://ClinicalTrials.gov/show/NCT03912103; 2019. 14. Apotek RL, Health Mo, Prevention. Improving Compliance Among Elderly Polypharmacy Users Through Community Pharmacy Based Pharmaceutical Care Program. https://ClinicalTrials.gov/show/NCT00916214; 2009. 15. AstraZeneca. Non-interventional Study: Real-life Use of Atypical Antipsychotics in Acute Inpatient Management of Schizophrenia. https://ClinicalTrials.gov/show/NCT01491412; 2011. 16. BARMER, Westphalia/Lippe AoSHIP, University G, Cologne Uo, Bochum RUo, University B. Application for an Electronic Medication Management Support System. https://ClinicalTrials.gov/show/NCT03430336; 2018. 17. Basel Uo, Foundation SNS, Hospital FP, Sciences UoA, Switzerland AoS, University Hospital Inselspital B, et al. Nurse-led Care Models in Swiss Nursing Homes: Improving Interprofessional Care for Better Resident Outcomes (INTERCARE). https://ClinicalTrials.gov/show/NCT03590470; 2018. 18. Bern Uo, University U, Basel Uo, Zurich Uo, Foundation SNS. Optimizing PharmacoTherapy In the Multimorbid Elderly in Primary CAre: the OPTICA Trial. https://ClinicalTrials.gov/show/NCT03724539; 2019. 19. Besancon CHUd. Subjective Factors of Polymedication in the Elderly: a Qualitative Study of the Perceptions of Patients, Relatives and Referent Physicians.(DOSAGE). https://ClinicalTrials.gov/show/NCT03309228; 2016. 20. Biomedical SIf, Research C, Genomind L. Medication Optimization Using Pharmacogenetic Testing and the G-DIG to Reduce Polypharmacy in a Mental Health Population. https://ClinicalTrials.gov/show/NCT03468309; 2018. 21. Bollheimer PDmC, University RA. The Pharmacist in the Acute Geriatric Inpatient Treatment Team. https://ClinicalTrials.gov/show/NCT03412903; 2018. 22. Bologna Uo. Cytochrome P450's Pharmacogenomics in Chronic Pain Patients. https://ClinicalTrials.gov/show/NCT03411759; 2018. 23. Brigham, Hospital Ws. Add on Lacosamide Versus High Dose Monotherapy. https://ClinicalTrials.gov/show/NCT01345058; 2011. 24. Brigham, Hospital Ws, Research AfH, Quality, Health T. Electronic Medication Adherence Reporting and Feedback During Care Transitions. https://ClinicalTrials.gov/show/NCT03475030; 2016. 25. Brussel UZ. Accelerated Deep TMS in the Elderly Depressed: A Brain Imaging Approach. https://ClinicalTrials.gov/show/NCT03978182; 2019. 26. Bugnon PO, University of Geneva S. Opportunities and Limits to Deprescribing in Nursing Homes:Quality Circle Deprescribing Module. https://ClinicalTrials.gov/show/NCT03688542; 2017. 27. California UoS. Behavioral Insights to Encourage Judicious Prescribing of Opioids. https://ClinicalTrials.gov/show/NCT02790476; 2017. 28. Center AM. Prevalence of Metabolic Syndrome in Patients With Schizophrenia in Korea. https://ClinicalTrials.gov/show/NCT01477918; 2011.

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29. Center AM, Center PH, Hospital C. Multifactorial Intervention on Frailty in Vulnerable Older Adults. https://ClinicalTrials.gov/show/NCT02554994; 2015. 30. Center MUH. Understanding Benzodiazepine and Non-benzodiazepine Sedative Use. https://ClinicalTrials.gov/show/NCT02833272; 2016. 31. Center MUH, Research CIoH, University Health Network T, Hospital TO, Centre FM, Alberta Uo, et al. Reducing Post-discharge Adverse Drug Events Amongst the Elderly: a Multi-centre Electronic Deprescribing Intervention. https://ClinicalTrials.gov/show/NCT03272607; 2017. 32. Center MUH, University Health Network T, Hospital TO. Reducing Post-discharge Potentially Inappropriate Medications Among Older Adults. https://ClinicalTrials.gov/show/NCT02918058; 2016. 33. Center MUM. Effect of Spinal Cord Stimulation (SCS) in Painful Diabetic Polyneuropathy. https://ClinicalTrials.gov/show/NCT01162993; 2010. 34. Center RM. Acetazolamide for Treating NPH in Shunt-candidates Patients. https://ClinicalTrials.gov/show/NCT03779594; 2018. 35. Center RUM. Preventative Delirium Protocol in Elderly Patients. https://ClinicalTrials.gov/show/NCT03541408; 2016. 36. Center RUM. Delirium Prevention Protocol in Elderly Patients. https://ClinicalTrials.gov/show/NCT03591120; 2016. 37. Center VUM. Capturing Readmission Internationally to Prevent Readmission by Safer@Home Group. https://ClinicalTrials.gov/show/NCT02621723; 2016. 38. Center VUM, Aging NIo. A Randomized Controlled Trial to Deprescribe for Older Patients With Polypharmacy. https://ClinicalTrials.gov/show/NCT02979353; 2017. 39. Chicago UoIa. A Study Evaluating the Use of Potential Predictors of Readmission in Hospitalized Medicine Patients. https://ClinicalTrials.gov/show/NCT03791541; 2019. 40. Chile PUCd, University of Technology S. Pharmacist-led Medication Review With Follow- up on Primary Care Cardiovascular Older Adult Patients. https://ClinicalTrials.gov/show/NCT03502109; 2018. 41. Chile Uo. Impact of Clinical Pharmacist on Adverse Drug Events in Older Adults. https://ClinicalTrials.gov/show/NCT03156348; 2015. 42. Clinic C. A Patient Education Video Program for Post-Operative Recovery After Upper Extremity Surgery. https://ClinicalTrials.gov/show/NCT03366805; 2017. 43. Clinic M. Using Pharmacogenetics to Identify Patients With Polypharmacy at Risk of Medication Adverse Effects. https://ClinicalTrials.gov/show/NCT03748355; 2018. 44. Columbia UoB. Medication Minimization for Long-term Care Residents. https://ClinicalTrials.gov/show/NCT01932632; 2013. 45. Coordinación de Investigación en Salud M, Social IMdS. An Intervention for Elderly in Emergency Services. https://ClinicalTrials.gov/show/NCT01706133; 2013. 46. Cordoba HURSd, Comunitaria SAdMFy, Comunitaria SEdMFy. Efficacy of a Intervention to Reduce Medication Errors and Improve Adherence. https://ClinicalTrials.gov/show/NCT01291966; 2010.

195

47. Cork UC. Prevention of Adverse Drug Events (ADEs) in Hospitalised Older Patients. https://ClinicalTrials.gov/show/NCT01467050; 2011. 48. Cork UC. Adverse Drug Event Prevention Using Structured Pharmacist Review. https://ClinicalTrials.gov/show/NCT01467128; 2011. 49. Cork UC. Discontinuation of Long-term Medications in Older People Entering Nursing Home Care. https://ClinicalTrials.gov/show/NCT03501108; 2018. 50. Corporation G. Drug & Gene Interaction Risk Analysis With & Without Genetic Testing Among Patients Undergoing MTM. https://ClinicalTrials.gov/show/NCT02428660; 2015. 51. Corporation G, Utah Uo. YouScript IMPACT Registry. https://ClinicalTrials.gov/show/NCT02191358; 2014. 52. Council ÖC. Comprehensive Geriatric Assessment - Can it Improve Quality of Life. https://ClinicalTrials.gov/show/NCT01925105; 2013. 53. Dearing M, Network CF, Authority NSH. Pharmacist Led Intervention to Improve Medication Use in Older In-patients Living With Frailty: the Drug Burden Index. https://ClinicalTrials.gov/show/NCT03698487; 2019. 54. Denmark UoS, Copenhagen Uo, Aarhus Uo, Quality TDIf, Healthcare Ai. The Effectiveness of a Nationwide Mandatory Accreditation in General Practice in Denmark. https://ClinicalTrials.gov/show/NCT02762240; 2014. 55. Diseases GCfN, Greifswald UM. Intervention Study to Improve Life and Care for People With Dementia and Their Caregivers in Primary Care. https://ClinicalTrials.gov/show/NCT01401582; 2012. 56. Diseases IDSSC, Education S, Hospital R. Patient Factors Associated With Prescription of Antibiotics for Inappropriate Indication in Patients With AECOPD. https://ClinicalTrials.gov/show/NCT03077152; 2017. 57. District ESH, Finland UoE, Agency FM. The Interprofessional Medication Assessment for Older Patients. https://ClinicalTrials.gov/show/NCT02398812; 2015. 58. Epilepsy M-A, Sleep Center L, Inc. E. Perampanel for Treatment of Adults With Refractory Focal Epilepsy : a Pilot Study. https://ClinicalTrials.gov/show/NCT02727101; 2015. 59. Foundation IBR. A Study of IBRF Disorders of Consciousness Advanced Care/MultiModal Care Protocol in Severe Disorders of Consciousness. https://ClinicalTrials.gov/show/NCT02696512; 2016. 60. Foundation OMR, GlaxoSmithKline. Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy. https://ClinicalTrials.gov/show/NCT02270970; 2014. 61. Getafe HU. Clinical Intervention in Frail Older People (FRAILCLINIC). https://ClinicalTrials.gov/show/NCT02643069; 2014. 62. GlaxoSmithKline. Bupropion and Specific Cardiovascular Malformations. https://ClinicalTrials.gov/show/NCT01165255; 2010. 63. GlaxoSmithKline. Clinical and Economic Burden of Uncontrolled Epilepsy: Analyses From a Medicaid Database and a Private Health Plan Database. https://ClinicalTrials.gov/show/NCT01390909; 2010.

196

64. GlaxoSmithKline. Risk of Urinary Retention With Retigabine. https://ClinicalTrials.gov/show/NCT01462656; 2011. 65. GlaxoSmithKline. A Comparison Study Between the Fixed Dose Triple Combination of Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) With Budesonide/Formoterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD). https://ClinicalTrials.gov/show/NCT02345161; 2015. 66. GlaxoSmithKline. Comparative Study of Fluticasone Furoate(FF)/Umeclidinium Bromide (UMEC)/ Vilanterol (VI) Closed Therapy Versus FF/VI Plus UMEC Open Therapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD). https://ClinicalTrials.gov/show/NCT02729051; 2016. 67. Groningen Uo. DBI - Tool for Medication Reviews in Older People. https://ClinicalTrials.gov/show/NCT02317666; 2014. 68. Groningen Uo. Longitudinal Analysis of Drug Burden Index. https://ClinicalTrials.gov/show/NCT03024541; 2016. 69. Groningen Uo, Padjadjaran U. A Targeted and Tailored Pharmacist Intervention to Improve Adherence to Antihypertensive Drugs Among Diabetes Patients. https://ClinicalTrials.gov/show/NCT04023734; 2019. 70. Groningen Uo, Research ZTNOfH, Development. Discontinuing Inappropriate Medication in Nursing Home Residents. https://ClinicalTrials.gov/show/NCT01876095; 2014. 71. Health N, Sciences G. Assessing Differential Adherence to Medications and Quality of Life Among People Living With HIV and Comorbidities. https://ClinicalTrials.gov/show/NCT03387397; 2017. 72. Health O, University S. Acute Care for Elders (ACE) Program at OHSU Hospital. https://ClinicalTrials.gov/show/NCT02119078; 2014. 73. Heinrich-Heine University D. Comparison of Antipsychotic Combination Treatment of Olanzapine and Amisulpride to Monotherapy. https://ClinicalTrials.gov/show/NCT01609153; 2012. 74. Hersberger K, Basel Uo, University Hospital B, Switzerland, Polyclinique Médicale Universitaire P, Lausanne, Swiss Pharmacy Association p. Polymedication Check - a Randomised Controlled Trial. https://ClinicalTrials.gov/show/NCT01739816; 2012. 75. Hiddemann PDW, Roche H-L, GmbH MR, KG C, Munich L-M-Uo. First Line Therapy of Advanced Stage Follicular Lymphoma in Patients Not Eligible for Standard Immunochemotherapy. https://ClinicalTrials.gov/show/NCT03492775; 2017. 76. Hospice of Henderson County I, HealthCare TR. Characteristics and Clinical Implications of a Clinical Decision Support System. https://ClinicalTrials.gov/show/NCT03295097; 2018. 77. Hospital AU. Physical Health of Residents in Psychiatric Institutions. https://ClinicalTrials.gov/show/NCT00969384; 2009. 78. Hospital AU, Aarhus Uo. Geriatrician-performed Comprehensive Geriatric Care in an Outpatient Community Rehabilitation Unit. https://ClinicalTrials.gov/show/NCT01506219; 2012. 79. Hospital AU, Society DC, Aarhus Uo. Oncogeriatric Intervention and Follow-up at Home. https://ClinicalTrials.gov/show/NCT02837679; 2016.

197

80. Hospital B. Polypharmacy Outpatient Clinic. https://ClinicalTrials.gov/show/NCT03911934; 2017. 81. Hospital BV. Deprescribing of Symptomatic Medications in Rehabilitative or Subacute Care Patients. https://ClinicalTrials.gov/show/NCT03354845; 2016. 82. Hospital BV. Efficacy and Feasibility of De-prescribing Rounds in a Singapore Rehabilitative Hospital- a Pilot Randomized Controlled Trial. https://ClinicalTrials.gov/show/NCT03713112; 2018. 83. Hospital CGM. Short-term Effects of an Inpatient Geriatric Consultation Team on Geriatric Syndrome Patients. https://ClinicalTrials.gov/show/NCT03840759; 2017. 84. Hospital GTiP. Adverse Drug Reactions With Fatal Outcome. https://ClinicalTrials.gov/show/NCT02838212; 2016. 85. Hospital HU, Centre CR, Foundation L, Hovedstaden R. Biological Aging, Medication, Malnutrition and Inflammation Among Acutely Ill and Healthy Elderly. https://ClinicalTrials.gov/show/NCT03052192; 2016. 86. Hospital HU, Centre CR, Hovedstaden R, Udviklings- og forskningspuljen DRoS, Denmark RC, Lægemiddelorganisation R. Optimisation of Nutrition and Medication for Acutely Admitted Older Medical Patients. https://ClinicalTrials.gov/show/NCT03741283; 2018. 87. Hospital JG. Older Emergency Department Users and Short-term Adverse Events at the Index Visit. https://ClinicalTrials.gov/show/NCT04018898; 2019. 88. Hospital JG. Risk for Short-term Adverse Events in Older Users in the Emergency Department. https://ClinicalTrials.gov/show/NCT04038983; 2019. 89. Hospital JG, Center MUH. Frailty Heart Failure Study. https://ClinicalTrials.gov/show/NCT03887351; 2019. 90. Hospital KEA. Medication Regimen Complexity and Glycemic Control in Patients With Diabetes. https://ClinicalTrials.gov/show/NCT03324971; 2017. 91. Hospital KK-SP, Department of Health EY, R.O.C. Olanzapine vs. Low-dose Olanzapine Plus Trifluoperazine. https://ClinicalTrials.gov/show/NCT02704962; 2012. 92. Hospital MG. Pilot Study of a Pharmacy Intervention for Older Adults With Cancer. https://ClinicalTrials.gov/show/NCT02871115; 2017. 93. Hospital MG, Network NCC. Perioperative Geriatrics Intervention for Older Cancer Patients Undergoing Surgical Resection. https://ClinicalTrials.gov/show/NCT02810652; 2016. 94. Hospital N. Polypharmacy in Clozapine-resistant Schizophrenia. https://ClinicalTrials.gov/show/NCT00918021; 2009. 95. Hospital NTU. The Effectiveness of Low Carbohydrate Diet in Reducing Polypharmacy for Patients With Type 2 Diabetes Mellitus. https://ClinicalTrials.gov/show/NCT03176056; 2016. 96. Hospital OU, Denmark RoS, Denmark HoSW, Database GPR. Individually Tailored Treatment of Type 2 Diabetes. https://ClinicalTrials.gov/show/NCT02015130; 2013. 97. Hospital OU, Norway TRCo, Oslo Uo. Cooperation for Improved Pharmacotherapy in Home- dwelling Elderly People Receiving Polypharmacy - The COOP Study. https://ClinicalTrials.gov/show/NCT02379455; 2015.

198

98. Hospital RU. General Practitioner's Place in the Treatment of Fracture Osteoporosis in the Elderly. https://ClinicalTrials.gov/show/NCT03402958; 2018. 99. Hospital RU. In-hospital Falls and Hemorrhagic Complications : a Descriptive Analysis in Rennes University Hospital. https://ClinicalTrials.gov/show/NCT03687541; 2018. 100. Hospital SNU. Effects of Perampanel on Cognition and Electroencephalography in Patients With Epilepsy. https://ClinicalTrials.gov/show/NCT02900755; 2016. 101. Hospital TTS, University M, National Healthcare Group S. Nursing Home Team-Care Deprescribing Study. https://ClinicalTrials.gov/show/NCT02863341; 2016. 102. Hospital WsC, University Qs. Feasibility Randomized Control Trial of Mindfulness-Based Stress Reduction (MBSR) With Older Adults Living With Cognitive Impairment in Primary Care. https://ClinicalTrials.gov/show/NCT03867474; 2019. 103. Inca HCd. Inappropriate Prescription in Elderly and Polypharmacy Patients in Primary Care (PHARM-PC) Trial. https://ClinicalTrials.gov/show/NCT02224833; 2015. 104. Ingelheim B. Pharmacokinetics of Fixed Dose Combination (FDC) Tablets of Linagliptin Metformin. https://ClinicalTrials.gov/show/NCT01540487; 2012. 105. Ingelheim B, Lilly E, Company. Bioavailability of Empagliflozin/Metformin Fixed Dose Combinations (FDCs) in Healthy Chinese Volunteers. https://ClinicalTrials.gov/show/NCT02102932; 2014. 106. Institute OHR. Structured Polypharmacy Management Before Elective Non-cardiac Surgery in Frail and Elderly People. https://ClinicalTrials.gov/show/NCT03445767; 2018. 107. Institutet K, Stockholm County Council S. Educational Intervention to Reduce Drug-related Hospitalizations in Elderly Primary Health Care Patients. https://ClinicalTrials.gov/show/NCT01732302; 2012. 108. Interior UoB. Electronic Deprescribing Tool for the Prevention of PIP. https://ClinicalTrials.gov/show/NCT03192514; 2017. 109. Interior UoB. Deprescribing: a Portrait and Out-comes of the Reduction of Polypharmacy in Portugal. https://ClinicalTrials.gov/show/NCT03283735; 2019. 110. Kong CUoH. Post-market Study of AMAP Receptor Antagonists for Epilepsy Patients in Hong Kong. https://ClinicalTrials.gov/show/NCT03457961; 2016. 111. Laval CdQ-U, University M, Montréal Ud, Sherbrooke Ud, Québec FdlReSd. An Intervention to Reduce Inappropriate Medications in Long-term Care Residents With Severe Dementia. https://ClinicalTrials.gov/show/NCT03539276; 2014. 112. Lenval F. Pharmacogenetics Anomaly Research in Children and Adolescents With Pharmacological Resistance to Psychotropic Drugs. https://ClinicalTrials.gov/show/NCT03114098; 2016. 113. Leon UAdN. Treatment of Salivary Gland Hypofunction With Neuro- Electrostimulation. https://ClinicalTrials.gov/show/NCT01174329; 2010. 114. Leuven UZ. Rationalisation of Polypharmacy in the Elderly by the RASP Instrument. https://ClinicalTrials.gov/show/NCT01513265; 2011. 115. Leuven UZ. Feasibility of Pharmaceutical Interventions in Elderly Heart Failure Patients. https://ClinicalTrials.gov/show/NCT02149940; 2013.

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Trials registers: WHOCTRP N=97

1. NL7728. Results of the use of a trigger list to detect drug-related problems at the emergency room in older polypharmacy patients. 2019. 2. NCT03943524. Drug Interactions in Outpatients. 2019. 3. KCT0004053. Postoperative analgesic effect of nefopam monotherapy and nefopam-fentanyl polytherapy in patients underwent laparoscopic cholecystectomy. 2019. 4. ISRCTN90146150. Improving medicines use in people who take multiple medicines. 2019. 5. ISRCTN14366792. Patient activation for drug reviewing by telemedicine. 2019. 6. DRKS00016995. Does the Identification of Seniors At Risk (ISAR) score effectively select geriatric patients on emergency admission? 2019. 7. DRKS00016993. More With Less - Retrospective analysis of potentially inadequate drugs (PIM) for elderly adults at geriatric wards and association with geriatric syndromes. 2019. 8. DRKS00016728. Pilot study of an electronic tool for the assessment of patient preferences in older adults with polypharmacy. 2019. 9. DRKS00016364. Evaluation of a patient oriented deprescribing strategy to achieve reduction of oversupply of proton pump inhibitors (PPI). 2019. 10. DRKS00015696. Holistic Care Program for Elderly Patients to Integrate Spiritual Needs, Social Activity and Self-Care into Disease Management in Primary Care. 2019. 11. DRKS00014047. Mambo – Multimorbid People in Outpatient Care: Patient-Focused and demand based Healthcare Management. 2019. 12. ChiCTR1900020808. Questionnaire survey for the unsuitability polypharmacy and medication management in elderly patients with chronic diseases. 2019. 13. ACTRN12619000727145. GP-led deprescribing in community living older Australians: A pragmatic, mixed methods, exploratory controlled trial. 2019. 14. ACTRN12619000453189. AusTAPER Dem: Team Approach to Polypharmacy Evaluation and Reduction for General Practice patients with dementia: the Australian TAPER Dem study. 2019. 15. ACTRN12619000296134. Reducing the risk of post-operative delirium in elderly hip fracture surgical patients by implementing a multidisciplinary approach to analgesia, education, and medications. 2019. 16. ACTRN12619000282189. DCMedsRec; Reducing hospital readmission by enhanced My Health Record use in Community Pharmacy. An ADHA Digital Test Beds project. 2019. 17. NTR7210. Het gebruik van verschillende soorten langdurige medicatie bij ouderen in de huisartsenpraktijk. 2018. 18. NCT03689049. SPIDER: A Research & QI Collaboration Supporting Practices in Improving Care for Complex Elderly Patients. 2018. 19. JPRN-UMIN000035265. Efficacy of medication optimization protocol for older inpatients: a randomized controlled trial. 2018.

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20. JPRN-UMIN000033814. The Intervention study for Medication assist provided by pharmacist for the elderly with polypharmacy (1). 2018. 21. ISRCTN73831533. Pilot testing of a new service designed to improve the use of multiple medications by older people who are living at home in the community setting. 2018. 22. DRKS00013588. HIOPP-3-iTBX: Appropriate and safe medication for nursing home residents using an interdisciplinary toolbox (AMTS-Toolbox). 2018. 23. CTRI/2018/02/012228. Comparison of effect of chronic antiepileptic therapy on trace elements (zinc, copper, selenium and others) level in persons with epilepsy in a tertiary care hospital in India. 2018. 24. ChiCTR1800017339. Questionnaire survey on the unsuitability polypharmacy and medication management in elderly patients with chronic diseases. 2018. 25. ChiCTR1800016993. Polypharmacy in hospitalized elderly patients with chronic diseases: a multi-center cross-sectional study. 2018. 26. ACTRN12618002002268. Integrating Pharmacists within Aboriginal Community Controlled Health Services to improve Chronic Disease Management Project. 2018. 27. ACTRN12618001443280. Health and economic impacts associated with prescribing by expanded scope physiotherapists for patients with spinal pain? 2018. 28. ACTRN12618001168246. The Medicines Management Mapping Project: Using risk stratification and care coordination to bridge the care continuum gap. 2018. 29. ACTRN12618001130257. Simpler medication regimens for older people receiving care at home. 2018. 30. ACTRN12618000979257. The Australian Team Approach to Polypharmacy Evaluation and Reduction (AusTAPER) study for older hospital inpatients. 2018. 31. ACTRN12618000978268. AusTAPER Pilot: Team Approach to Polypharmacy Evaluation and Reduction A pilot study for older patients in General Practice. 2018. 32. ACTRN12618000731291. Evaluation of a multi-modal educational package for GP registrars in reviewing older patients’ medication regimens and deprescribing inappropriate medications. 2018. 33. ACTRN12618000729224. Deprescribing in older community patients. 2018. 34. ACTRN12618000580279. A trial of a specialist pharmacist review of medications for people moving to residential care for the first time. 2018. 35. ACTRN12618000284268. Use of the electronic Rapid Fitness Assessment in older adults with cancer at an Australian Regional Cancer Centre. 2018. 36. NTR6644. Improving Medication Prescription in the Context of Advanced Care Planning for Patients Receiving Nursing Home Care. 2017. 37. NCT03052192. Biological Aging, Medication, Malnutrition and Inflammation Among Acutely Ill and Healthy Elderly. 2017. 38. JPRN-UMIN000030126. Current status of polypharmacy in patients with chronic kidney disease. 2017. 39. JPRN-UMIN000025495. Intervention to improve the appropriate use of polypharmacy for older patients with hip fracture: an observational study. 2017.

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40. ISRCTN52788952. Urban Health Centres Europe, a preventive integrated health and social care approach for active and healthy ageing among community-dwelling older citizens, adapted to five European settings. 2017. 41. ISRCTN11764561. Characterization of the incretin response and microbiota following bariatric surgery, and its role for weight loss – a search for polytherapeutic strategies to combat obesity and ultimately rival surgery. 2017. 42. ISRCTN11751440. Hospital pharmacists successfully work with the acute care team to stop home medications deemed no longer necessary. 2017. 43. DRKS00012837. Pilot-testing of a simple Prioritization-table for managing polypharmacy in Primary Care Patients. 2017. 44. DRKS00012246. SiMbA- Optimizing nursing home residents`safety by checking prescribed medication. 2017. 45. DRKS00011831. A multimodal intervention program for older people with frailty – a randomized controlled pilot trial. 2017. 46. DRKS00011799. Resources and Barriers to Functionality and Subjective Well-Being in Geriatric Patients. 2017. 47. ACTRN12617001535369. Are dehydration and diuretic use more commonly associated with falls in frail, elderly patients compared with the robust elderly? 2017. 48. ACTRN12617001301358. The effects of calculating and communicating to General Practitioners a Drug Burden Index (DBI) in elderly patients discharged from the Emergency Department- a pilot study. 2017. 49. ACTRN12617001060336. SImplification of Medications Prescribed to Long tErm care Residents (SIMPLER). 2017. 50. ACTRN12617000895381. Efficacy of implementation of the Goal-directed Medication review Electronic Decision Support System (G-MEDSS) into Home Medicines Review (HMR) to deprescribe medications in older adults. 2017. 51. ACTRN12617000765325. Minimising the Functional Burden of Medications in Older Inpatients: Implementation of the Drug Burden Index. 2017. 52. ACTRN12617000214336. Effects of statins on cognition in older adults with dementia. 2017. 53. ACTRN12617000159358. Proactive palliative care nurse specialist review compared to usual care, in residential care residents who are identified as being high risk of clinically significant health and functional decline. 2017. 54. ACTRN12617000114347. A prospective cohort study evaluating the incidence of and outcomes associated with dose reductions of diabetic medications in a population of older inpatients discharged to a nursing home. 2017. 55. NTR6012. OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly. 2016. 56. NTR5887. Children with arthritis: monotherapy or polytherapy? 2016. 57. NTR5879. Morbidity in elderly travelers during a short-term stay abroad, a prospective cohort study. 2016.

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58. NTR5750. PROPOSE : PReoperative Optimization of Pharmacotherapy in frail Older patients with use of STRIP assistant. 2016. 59. NTR5713. Drug use Reconsidered in the Elderly using goal Attainment scales during Medication Review - The DREAMeR-study. 2016. 60. JPRN-UMIN000025066. The association between ABO blood group and polypharmacy: does blood group O have an affinity for medications? A retrospective and prospective cross-sectional study. 2016. 61. JPRN-UMIN000024680. Therapeutic approach in elderly patients with polypharmacy by medical team: Prospective observational study. 2016. 62. JPRN-UMIN000023782. Randomized controled trial to examine the efficacy and safety of demedicative intervention for polypharmacy in the Japanese elderly patients. 2016. 63. ISRCTN18176245. Developing a way of improving the prescribing of many drugs for older people who live in their own home and are cared for by general practitioners. 2016. 64. ISRCTN17966504. Testing of a new community pharmacy service to help older patients who live in their own homes and who are prescribed several medicines. 2016. 65. ISRCTN14976998. Study on frail patients undergoing elective and emergency cholecystectomy. 2016. 66. ISRCTN12752680. Supporting medicines management in older adults with multiple medical conditions. 2016. 67. DRKS00010242. Interview study of health literacy regarding polypharmacy and medication safety of patients aged 65 years and older: challenges and potential solutions. 2016. 68. ACTRN12616001336471. A prospective cohort study of the effect of deprescribing on mortality and readmission in a population of elderly inpatients discharged to a nursing home. 2016. 69. ACTRN12616000721404. Deprescribing anticholinergic and sedative medicines: A feasibility study in residential aged care facilities. 2016. 70. NTR5165. SCREAM. 2015. 71. NCT02428660. Drug & Gene Interaction Risk Analysis With & Without Genetic Testing Among Patients Undergoing MTM. 2015. 72. EUCTR2014-003260-20-NL. CHAMP Trial: comparing monotherapy and polytherapy treatment strategies in newly diagnosed juvenile idiopathic arthritis. 2015. 73. NTR4531. Minder kan meer zijn; terugdringen en rationaliseren van polyfarmacie bij schizofrenie. 2014. 74. NTR4500. Medication review in Parkinson. 2014. 75. NTR4389. The effectivity and feasibility of integrating nondispensing pharmacists into primary healthcare centres. 2014. 76. ISRCTN42003273. Polypharmacy reduction in patients treated for chronic diseases. 2014. 77. ISRCTN16560559. The Prevention of Polypharmacy in Primary Care Patients Trial (4P- RCT). 2014.

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78. DRKS00005734. Use of START/STOP criteria in a web-based medication review application in community-dwelling elderly. 2014. 79. ACTRN12614000309684. Halting Antipsychotic use in Long-Term care. 2014. 80. ISRCTN41595373. WestGem study: WESTphalian study on a medication therapy management and home care based intervention under Gender specific aspects in Elderly Multimorbid patients. 2013. 81. ISRCTN38449870. Reduction of inappropriate medication and adverse drug events in older patients. 2013. 82. ISRCTN34664024. Implementing recommendations for Polypharmacotherapy of multimorbid Patients (PomP). 2013. 83. CTRI/2013/05/003701. COMPARISON OF BODY WEIGHT, FAT AND TOTAL WATER CONTENT IN PERSONS WITH EPILEPSY ON LONG TERM TREATMENT WITH CONVENTIONAL AND NEWER ANTIEPILEPTIC DRUGS. 2013. 84. ACTRN12613001204730. Opti-Med: A randomised controlled trial of deprescribing to optimise health outcomes for frail older people. 2013. 85. ACTRN12613000218796. Improving care through imbedding general practitioners within residential aged care facilities. 2013. 86. ISRCTN65924234. Pilot implementation of a delirium prevention system of care. 2012. 87. ACTRN12612000798864. A randomised trial of patient centred intervention to reduce re- presentations of older people at risk after discharge from the emergency department. 2012. 88. JPRN-UMIN000006550. Efficacy of Aripiprazole in patients with chronic schizophrenia. 2011. 89. ISRCTN51444951. A study of an Electronic Medicine Management Assistant (EMMA®) system. 2011. 90. ACTRN12611000370909. Deprescribing in frail older people: a randomised controlled trial. 2011. 91. NTR2288. Central Utrecht Elderly Care Project 'Om U': “Somebody who knows what’s going on and can see things from my side.”. 2010. 92. NTR2154. PIL: Polypharmacie intervention Limburg, too much or too little? 2010. 93. ISRCTN21800480. Acute medical unit comprehensive geriatric assessment intervention study. 2010. 94. DRKS00000531. Polypharmacy as a result of multiple chronic conditions of older people: rational therapy with the new FORTA classification? 2010. 95. ACTRN12610000865011. Systematic Termination of Pharmaceutical Agents Trial (STOPAT): a pilot randomised trial of stopping drug therapy. 2010. 96. ACTRN12610000100099. A randomised controlled trial of three forms of psychosocial early intervention for borderline personality disorder in youth. 2010. 97. ISRCTN31954692. The reduction of disability in community-dwelling frail elderly. 2009.

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