What is polypharmacy? A systematic review of definitions — TEI-tagged view

Nashwa MasnoonpersName, Sepehr ShakibpersName, Lisa M. Kalisch EllettpersName, Gillian E. CaugheypersName (2017date). “What is polypharmacy? A systematic review of definitions.” BMC Geriatricstitle·venue.

Object of study — THE DEFINITIONS THEMSELVES - a systematic reviewterm·mth whose unit of analysis is not a patient or an outcome but a DEFINITION, counting how many are in use for one word and what each of them says

Research question — what polypharmacyterm means in the published literature, and whether any article distinguishes appropriate from inappropriate polypharmacyterm

Contribution — 138 definitions of polypharmacyterm and its derived terms, extracted from 110 articles and classified as numerical only, numerical-with-duration-or-setting, or descriptive - with the full range of thresholds and the share of studies using each

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33 bmcgeri BMC Geriatrics BMC Geriatr BMC PMC5635569 5635569 5635569 29017448 10.1186/s12877-017-0621-2 What is polypharmacyterm? A systematic reviewterm·mth of definitions MasnoonpersName Nashwa 1 2 ✉ ShakibpersName Sepehr 3 4 Kalisch-Ellett Lisa 1 CaugheypersName Gillian E 1 3 4 1 Quality Use of Medicines and Pharmacy Research Centre, School of Pharmacy and Medical Sciences, University of South Australia, Frome Road, Adelaide, South Australia Australia 2 Department of Pharmacy, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia Australia 3 Department of Clinical Pharmacology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia Australia 4 Discipline of Pharmacology, School of Medicine, University of Adelaide, North Terrace, Adelaide, South Australia Australia ✉ Corresponding author.

10 10 2017 17 230 230 18 10 2017 © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Abstract Background Multimorbidity and the associated use of multiple medicines (polypharmacyterm), is common in the older population. Despite this, there is no consensus definition for polypharmacyterm. A systematic reviewterm·mth was conducted to identify and summarise polypharmacyterm definitions in existing literature.

Methods The reporting of this systematic reviewterm·mth conforms to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. MEDLINE (Ovid), EMBASE and Cochrane were systematically searched, as well as grey literature, to identify articles which defined the term polypharmacyterm (without any limits on the types of definitions) and were in English, published between 1st January 2000 and 30th May 2016. Definitions were categorised as i. numerical only (using the number of medicationsterm·var to define polypharmacyterm), ii. numerical with an associated duration of therapy or healthcare setting (such as during hospital stay) or iii. Descriptive (using a brief description to define polypharmacyterm).

Results A total of 1156 articles were identified and 110 articles met the inclusion criteria. Articles not only defined polypharmacyterm but associated terms such as minor and major polypharmacyterm. As a result, a total of 138 definitions of polypharmacyterm and associated terms were obtained. There were 111 numerical only definitions (80.4% of all definitions), 15 numerical definitions which incorporated a duration of therapy or healthcare setting (10.9%) and 12 descriptive definitions (8.7%). The most commonly reported definition of polypharmacyterm was the numerical definition of five or more medicationsterm daily ( n = 51, 46.4% of articles), with definitions ranging from two or more to 11 or more medicines. Only 6.4% of articles classified the distinction between appropriate and inappropriate polypharmacyterm, using descriptive definitions to make this distinction.

Conclusions Polypharmacyterm definitions were variable. Numerical definitions of polypharmacyterm did not account for specific comorbidities present and make it difficult to assess safety and appropriateness of therapyterm in the clinical setting.

Keywords: Polypharmacyterm, Multimorbidity, Comorbidity, Inappropriate prescribing, Aged, Systematic reviewterm·mth status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2017 May 15; Accepted 2017 Oct 2; Collection date 2017.

Background Multimorbidity, commonly defined as the co-existence of two or more chronic health conditions, is common in the older population [ 1 ]. The presence of multiple chronic conditions increases the complexity of therapeutic management for both health professionals and patients, and impacts negatively on health outcomes. Multimorbidity is associated with decreased quality of life, self-rated health, mobility and functional ability as well as increases in hospitalisations, physiological distress, use of health care resources, mortality and costs [ 2 – 4 ]. Globally, the health burden of multimorbidity is expected to rise significantly as a result of the growing number of older people and increasing numbers of people living with multimorbidity [ 5 ].

The use of multiple medicines, commonly referred to as polypharmacyterm is common in the older population with multimorbidity, as one or more medicines may be used to treat each condition. Polypharmacyterm is associated with adverse outcomes including mortality, falls, adverse drug reactions, increased length of stay in hospital and readmission to hospital soon after discharge [ 6 – 8 ]. The risk of adverse effects and harm increases with increasing numbers of medications [ 9 ]. Harm can result due to a multitude of factors including drug-drug interactions and drug-disease interactions. Older patients are at even greater risk of adverse effects due to decreased renal and hepatic function, lower lean body mass, reduced hearing, vision, cognition and mobility [ 10 ].

While in many instances the use of multiple medicines or polypharmacyterm may be clinically appropriate, it is important to identify patients with inappropriate polypharmacyterm that may place patients at increased risk of adverse events and poor health outcomes. Studies have suggested a shift towards adopting the term ‘appropriate polypharmacyterm’ in order to differentiate between the prescribing of ‘many’ and ‘too many’ drugs instead of a simple numerical countterm of medications, which is of limited value in practice [ 11 , 12 ]. In order to make this distinction between appropriate and inappropriate polypharmacyterm, the term polypharmacyterm needs to be clearly defined. We therefore conducted a systematic reviewterm·mth to explore the definitions of polypharmacyterm in existing literature. We additionally aimed to explore whether articles differentiated between appropriate and inappropriate polypharmacyterm and how this distinction was made.

Methods Data sources and search strategy The reporting of this systematic reviewterm·mth conforms to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) checklist.

MEDLINE (Ovid), EMBASE and Cochrane databases were searched between 1st January 2000 and 30th May 2016.

The following search terms (Medical Subject Headings or MESH and keywords) were used in EMBASE and MEDLINE (Ovid): polypharmacyterm/ (MESH) OR multiple medication* OR multiple medicine* OR multiple drug* (key words) OR many medication* OR many medicine* OR many drug* (key words) (for all articles referring to polypharmacyterm) AND.

defin* (key word) or explan* (keyword) (for all articles defining or explaining polypharmacyterm).

For the review of the Cochrane database, the term “polypharmacyterm” was searched.

The search was limited to primary research articles which defined the term polypharmacyterm in any shape or form, conducted in humans and published in English between the years 2000 and 2016. Articles were considered if the abstracts were available in English and were published or in press. Reference lists of relevant articles and grey literature were screened to identify other relevant articles. The search strategy was developed in consultation with a librarian specialising in health databases, with a pre-determined protocol developed collaboratively with the authors for methods to search and select relevant articles.

Study selection and data extraction Articles that met the inclusion criteria and provided a definition of polypharmacyterm were included. One author (NM) conducted the initial database search and primary screening of article titles and abstracts and articles were categorised as: relevant, irrelevant or unsure. Three reviewers (NM, SS, GC) discussed the appropriateness of inclusion of each article classed as relevant or unsure. Once all relevant articles were identified, one author (NM) reviewed full texts of all identified articles and extracted the data. A pre-defined data extraction template was developed by all authors and then applied to ensure consistent data extraction from each of the identified studies. Data items extracted included the definitions of polypharmacyterm and associated terms such as minor, moderate and excessive polypharmacyterm and whether studies distinguished between appropriate and inappropriate polypharmacyterm and if so, how this distinction was made or defined. The definitions of polypharmacyterm and associated terms were categorised as: i. numerical only (using the number of medicationsterm·var to define polypharmacyterm), ii. numerical for a given duration of therapy or healthcare setting for e.g. during hospital stay or iii. Descriptive (using a brief description to define polypharmacyterm). Once the primary data extraction was complete all authors reviewed the content analysis for each of the extracted studies, with data further categorised and summarised in tables.

Results A total of 1156 articles were identified and 110 articles met the full inclusion criteria for this systematic reviewterm·mth [ 10 – 119 ]. Fig. 1 shows a flowchart of study selection according to the PRISMA checklist.

Fig. 1 Study selection flowchart according to PRISMA checklist Studies not only defined polypharmacyterm but also used associated terms to define the level of polypharmacyterm; including minor (8 studies, 7.3%), moderate (1 study, 0.9%), major (12 studies, 10.9%), hyper (2 studies, 1.8%), excessive (10 studies, 9.1%), severe (1 study, 0.9%), appropriate (1 study, 0.9%), rational polypharmacyterm and indiscriminate prescribing (1 study, 0.9%), persistent (1 study, 0.9%), chronic (1 study, 0.9%), and pseudopolypharmacyterm (1 study, 0.9%). As a result, a total of 138 definitions of polypharmacyterm and associated terms were obtained. There were 111 numerical only definitions (80.4% of all definitions), 15 numerical definitions which incorporated a duration of therapy or healthcare setting (10.9%) and 12 descriptive definitions (8.7%). Table 1 presents a breakdown of the number of definitions for each term.

Table 1 Breakdown of polypharmacyterm definitions according to the category of definition Term Numerical only Numerical in a given duration of time or setting Descriptive Total number of definitions Polypharmacyterm 81 9 9 99 Minor Polypharmacyterm 8 0 0 8 Moderate polypharmacyterm 1 0 0 1 Major polypharmacyterm 11 1 0 12 Hyperpolypharmacy 1 1 0 2 Excessive polypharmacyterm 8 2 0 10 Severe polypharmacyterm 1 0 0 1 Persistent polypharmacyterm 0 1 0 1 Chronic polypharmacyterm 0 1 0 1 Appropriate polypharmacyterm 0 0 1 1 Rational polypharmacyterm and indiscriminate prescribing 0 0 1 1 Pseudopolypharmacyterm 0 0 1 1 Total number of definitions according to category of definition 111 15 12 138 Out of the 110 identified articles, 81 (73.6%) included only a numerical definition of polypharmacyterm (i.e. did not specify duration of therapy or healthcare setting). Nine articles (8.2%) included numerical definitions of polypharmacyterm for a given duration of time or healthcare setting and nine articles (8.2%) included descriptive definitions of polypharmacyterm. Four articles included two categories of polypharmacyterm definitions: two articles (1.8%) included both numerical only definitions and numerical definitions of polypharmacyterm for a duration of time or healthcare setting and two articles (1.8%) included both numerical only and descriptive definitions of polypharmacyterm.

Numerical only definitions of polypharmacyterm in existing literature Table 2 shows the various numerical only categorisations of polypharmacyterm and associated terms and the number of studies using these definitions.

Table 2 Various numerical only definitions of polypharmacyterm and associated terms in existing literature Term Number of medicationsterm·var Number of studies References Polypharmacyterm ≥ 2 1 [ 13 ] 2 to 9 1 [ 14 ] ≥ 3 1 [ 15 ] 3 to 6 1 [ 16 ] ≥ 4 6 [ 17 – 22 ] ≥ 4 or ≥ 5 1 [ 23 ] ≥ 5 51 [ 11 , 24 – 73 ] ≥ 6 10 [ 10 , 74 – 82 ] ≥ 7 2 [ 83 , 84 ] 5 to 9 3 [ 85 – 87 ] ≥ 9 1 [ 88 ] ≥ 10 1 [ 89 ] ≥ 11 1 [ 90 ] number of drugterm classes 1 [ 91 ] Minor Polypharmacyterm 2 to 4 6 [ 92 – 97 ] 2 to 3 1 [ 98 ] 0 to 4 1 [ 99 ] Moderate polypharmacyterm 4 to 5 1 [ 98 ] Major polypharmacyterm ≥ 5 6 [ 92 – 95 , 97 , 100 ] ≥ 6 3 [ 96 , 98 , 101 ] 5 to 9 1 [ 99 ] ≥ 11 1 [ 74 ] Hyperpolypharmacy ≥ 10 1 [ 102 ] Excessive polypharmacyterm ≥ 10 7 [ 30 , 58 , 65 , 70 , 85 – 87 ] ≥ 21 1 [ 74 ] Severe polypharmacyterm ≥ 10 1 [ 99 ] There was a wide range of variability in the definitions of polypharmacyterm as well as associated terms such as minor, moderate and major polypharmacyterm. The most commonly used term was polypharmacyterm, but there was variation with regard to the actual definition of polypharmacyterm, which ranged from two or more medications to 11 or more medications [ 13 , 90 ]. The most commonly used definition for polypharmacyterm was five or more medicationsterm daily, with 46.4% ( n = 51) of studies using this definition [ 11 , 24 – 73 ]. The second most common definition for polypharmacyterm was six or more medications, with ten studies using this definition [ 10 , 74 – 82 ]. Only one study defined polypharmacyterm as the number of drugterm classes used by a patient [ 91 ].

Numerical definitions of polypharmacyterm incorporating a duration of therapy or healthcare setting Eleven studies (10.0% of all studies) used numerical definitions of polypharmacyterm which incorporated a duration of therapy in the definition and four studies (3.6%) used definitions of polypharmacyterm which incorporated a healthcare setting (Table 3 ). The definitions of polypharmacyterm involving a duration of therapy, ranged from use of two or more medications for more than 240 days (‘long term use’) to five to nine medications used for 90 days or more [ 101 , 108 ]. Polypharmacyterm definitions incorporating a healthcare setting included the use of five or more medicationsterm at hospital discharge, and the use of 10 or more medications during hospital stay [ 106 , 110 ].

Table 3 Numerical definitions of polypharmacyterm and associated terms by duration of therapy/ healthcare setting Term Number of medicationsterm·var Number of studies References Polypharmacyterm ≥ 2 for > 240 days (long term) 1 [ 101 ] ≥ 5 medications in the same month 1 [ 103 ] > 5 medications for ≥ 90 days 1 [ 104 ] ≥ 5 medications in the same quarter of a year 1 [ 105 ] ≥ 5 medicines at hospital discharge 1 [ 106 ] 5 to 9 medicines on the day of maximum number of prescriptions of the study year (on the day of the study year when the number of medicationsterm·var prescribed was highest) 1 [ 107 ] 5 to 9 medications for ≥ 90 days 1 [ 108 ] 5 to 9 medicines during hospital stay 1 [ 109 ] ≥ 10 medicines during hospital stay 1 [ 110 ] Major polypharmacyterm ≥ 10 on the day of maximum number of prescriptions of the study year (on the day of the study year when the number of medicationsterm·var prescribed was highest) 1 [ 107 ] Hyperpolypharmacy ≥ 10 medications for ≥90 days 1 [ 108 ] Excessive polypharmacyterm ≥ 10 medications in the same quarter of a year 1 [ 105 ] ≥ 10 medications during hospital stay 1 [ 109 ] Persistent polypharmacyterm ≥ 5 medications for 181 days 1 [ 52 ] Chronic polypharmacyterm ≥ 5 medications in 1 month for 6 months (consecutive or not) in a year 1 [ 111 ] Descriptive definitions of polypharmacyterm Twelve studies used descriptive definitions of polypharmacyterm (Table 4 ). Some studies used different wording but conveyed the same definition of polypharmacyterm. For example, the definitions “Co-prescribing multiple medications” [ 113 ] and “Simultaneous and long term use of different drugs by the same individual” [ 77 ] describe polypharmacyterm as the use of multiple medications concurrently. Other studies alluded to a different issue of medications being appropriate or inappropriate for a given patient [ 10 , 79 , 114 – 118 ].

Table 4 Descriptive definitions of polypharmacyterm and associated terms Term Definition Number of studies References Polypharmacyterm Patients visiting multiple pharmacies to obtain medications 1 [ 112 ] Coprescribing multiple medications 1 [ 113 ] Simultaneous and long term use of different drugs by the same individual 1 [ 77 ] Polypharmacyterm definition ranges from the use of a large number of medicationsterm·var, to the use of potentially inappropriate medications, medication underuse and medication duplication 1 [ 114 ] Potentially inappropriate medications 2 [ 10 , 79 ] Use of multiple medications concurrently and the use of additional medications to correct adverse effects 1 [ 115 ] Use of medications which are not clinically indicated 1 [ 116 ] More drugs being prescribed or taken than are clinically appropriate in the context of a patient’s comorbidities 1 [ 12 ] Appropriate polypharmacyterm Optimisation of medications for patients with complex and/or multiple conditions where medicine usage agrees with best evidence 1 [ 117 ] Rational polypharmacyterm and indiscriminate prescribing Rational polypharmacyterm recognizes legitimate prescribing and indiscriminate prescribing suggests inappropriate prescribing (the terms “legitimate prescribing” and “inappropriate prescribing” were not explained) 1 [ 118 ] Pseudopolypharmacyterm Patients being recorded as taking more medications than they are actually taking 1 [ 119 ] Appropriate and inappropriate polypharmacyterm Only seven studies (6.4% of all studies) defined appropriate or rational polypharmacyterm, or recognised the distinction between appropriate and inappropriate medications [ 10 , 79 , 114 – 118 ]. These studies either defined polypharmacyterm using a brief description only ( n = 3) [ 79 , 115 , 117 ] or used a brief description and polypharmacyterm tools such as the Beers criteria and the Medication Appropriateness Index (MAI) ( n = 4 studies) [ 10 , 114 , 116 , 118 ]. An example of a polypharmacyterm definition which recognised the use of appropriate and inappropriate medications is “polypharmacyterm ranges from the use of a large number of medicationsterm·var, to the use of potentially inappropriate medications, medication underuse and duplication” and “potentially inappropriate medications” [ 114 ]. Out of the two studies defining polypharmacyterm as “potentially inappropriate medications”, one study simply mentioned “potentially inappropriate medications” without further explanation [ 79 ] and the other study included examples of potentially inappropriate medications from existing literature such as duplication of medications, drug-drug interactions, medications used to treat side effects of other medications and medications which are unnecessary for a specific patient [ 10 ]. Only one study explicitly defined appropriate polypharmacyterm, which was defined as “the optimisation of medications for patients with complex and/or multiple conditions where medicine usage agrees with best evidence” [ 117 ].

Four studies (3.6%) used polypharmacyterm tools or criteria to identify potentially inappropriate medications [ 10 , 114 , 116 , 118 ]. The Beers criteria as an indicator of potentially inappropriate medications were used in all four (three studies used Beers criteria 2003 and one used Beers criteria 1997) [ 10 , 114 , 116 , 118 ]. One study used the Medication Appropriateness Index (MAI) and the Healthcare Effectiveness Data and Information Set (HEDIS) [ 114 ]. None of the studies explicitly identified the need to distinguish between appropriate and inappropriate polypharmacyterm based on the pharmacology of medications involved, how they interact with each other and comorbidities for a specific patient.

Of the 110 studies included in the review, only one highlighted the inconsistencies in the definitions of polypharmacyterm in the literature. The authors of this study suggested that polypharmacyterm be defined as patients visiting multiple pharmacies which may be associated with safety concerns relating to potential outcomes such as medication duplication, drug-drug interactions and adverse effects [ 112 ].

Discussion The results of this systematic reviewterm·mth show that there is large heterogeneity in the definition of polypharmacyterm; ranging from numerical countsterm only, numerical countsterm for a given duration of therapy or setting or descriptive, which included terms such as minor, moderate, major and excessive polypharmacyterm. The lack of a clear and universal definition of polypharmacyterm as well as terms such as minor, moderate major polypharmacyterm makes it challenging for healthcare professionals to assess and consider efficacy and safety issues within the clinical setting.

The most commonly reported category of definitions for polypharmacyterm and associated terms was numerical only. The most commonly used term was polypharmacyterm which was defined as five or more medicationsterm by 46.4% of studies (51 articles). There was a wide range of numerical only definitions of polypharmacyterm, ranging from two or more medications to 11 or more medications. However, the clinical basis for using a numerical countterm such as five or more medicationsterm to define polypharmacyterm and the potential of this to rationalise medication use and optimise health outcomes is not elucidated in most studies. It has been postulated that while the term polypharmacyterm has evolved over time, the basis for the definition is simply more drugs being prescribed or taken than are clinically appropriate in the context of a patient’s comorbidities [ 12 ]. It is commonly reported that as the number of prescribed drugs increases, so do the chances of adverse drug events and likelihood of harm [ 120 ]. However, the specific number of drugsterm taken is not itself indicative of appropriateness of therapyterm as all of the drugs may be clinically necessary and appropriate for the patient. Despite this, only one study argued that instead of using numerical countsterm of medications, clinicians should identify appropriateness of therapyterm, where potential benefits outweigh the potential harms [ 121 ]. There is a clear need towards adopting the term ‘appropriate polypharmacyterm’ in order to differentiate between the prescribing of ‘many’ and ‘too many’ drugs instead of a simple numerical countterm of medications, which is of limited value in practice [ 11 , 12 , 120 – 122 ].

Whilst the addition of duration of therapy or healthcare setting to a count of medicines in the definition of polypharmacyterm provided more specific definitions, it did not provide any further clarity or consistency. Five or more medicationsterm were again used in the definitions but with a period of time attached such as 90 days or more [ 104 ]. The use of duration in the definitions appeared to be included to identify those patients with longer term or chronic use of medications, potentially identifying those patients who might be at greatest risk of medication-related problems. Definitions incorporating a healthcare setting commonly used five or more medicationsterm as the count, but using a setting such as at the time of hospital discharge [ 106 ].These definitions were largely based on the dispensing data available to assess prevalence and incidence of polypharmacyterm, rather than an evidence based approach of determining appropriateness of therapyterm; the setting provided little addition to existing definitions of polypharmacyterm in a clinical sense of medication rationalisation and minimisation of harm.

A recent commentary on polypharmacyterm stated that while a large body of literature confirms the fact that patients are increasingly taking large numbers of medications, numerical definitions of polypharmacyterm do not ascertain the clinical appropriateness of therapyterm and the process of rationalising those medications [ 123 ]. The author argued that when each of the medications can be linked to practice guidelines for chronic conditions for a given patient, using a numerical cut-off to define polypharmacyterm becomes irrelevant. While the number of medicationsterm·var can be a starting point, medications should be assessed in terms of their indication, efficacy and potential for harm with each other (not in isolation) given pharmacokinetic and pharmacodynamics interactions, in order to facilitate deprescribing of inappropriate medications [ 123 , 124 ]. Medications should be assessed for risks and benefits and the final combination of medications should be based on benefits outweighing the risks [ 124 , 125 ]. Current literature is alluding to looking beyond single disease management guidelines and considering the patient’s complete scenario by considering all comorbidities and medications being prescribed for a given patient to consider the patient as a whole and focusing on improving the overall health [ 11 , 12 , 117 , 120 – 122 , 125 ].

While the use of multiple medicines may be clinically appropriate for some patients, it is important to identify those patients who may be at risk of adverse health outcomes as a result of inappropriate polypharmacyterm. Only seven studies recognised the distinction between appropriate and inappropriate polypharmacyterm. This is crucial to facilitate the deprescribing of inappropriate medications and optimal use of appropriate medications. Consideration of comorbid conditions and other medications is required to make definitions clinically relevant, to facilitate medication assessment and rationalisation in every day practice. While a small number of studies (3.6%) used polypharmacyterm tools or criteria including the Beers criteria, MAI and HEDIS to identify potentially inappropriate medications to detect potentially inappropriate medications, the limitations of the tools and criteria in the everyday clinical setting were recognised [ 10 , 114 , 116 , 118 ].The Beers criteria which was used in all four studies identified, is a commonly used prescribing assessment tool based on a list of potentially inappropriate medications to be avoided in the older population [ 126 , 127 ]. However, it has recognised limitations such as requiring regular updates to ensure clinical relevance and including a list of outdated medications which may not be used in practice at that time.

Strengths and limitations Strengths of this systematic reviewterm·mth include the novelty of summarising the range of polypharmacyterm definitions available in literature. A comprehensive search strategy of three large and reliable databases (MEDLINE, EMBASE and Cochrane) was used, meaning that it is likely that all relevant articles were identified.

A limitation of this review is the inclusion of studies in English only which can cause information bias. While EMABSE, MEDLINE (Ovid) and Cochrane databases were searched, the absence of other databases such as Scopus could have introduced selection bias. Additionally articles from the year 2000 until present have been included. There may be clinically relevant definitions for polypharmacyterm which were added to literature prior to 2000 which have not been included in this review. While authors discussed the inclusion criteria and data being extracted, there is still the potential for confusion bias.

Conclusions While the most commonly used definition of polypharmacyterm is being on five or more medicines, definitions are variable, which can cause confusion for researchers as well as clinicians in practice. Numerical definitions of polypharmacyterm do not account for specific comorbidities present and make it difficult to assess safety and appropriateness of therapyterm in the clinical setting. There is a need for an internationally agreed definition of polypharmacyterm. The results indicate the need for a shift towards the term ‘appropriate polypharmacyterm’ using a holistic approach of assessing medication use in context of comorbidities present, according to best available evidence in order to optimise health outcomes.

Acknowledgements Not applicable.

Funding NM is supported by an Australian Government Research Training Program (RTP).

Availability of data and materials Majority of data generated or analysed during this study are included in this published article. Any other datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations HEDIS Healthcare Effectiveness Data and Information Set MAI Medication Appropriateness Index PRISMA Preferred Reporting Items for Systematic reviews and Meta-Analyses Authors’ contributions NM conducted the primary screening of article titles and abstracts and categorisation of articles as: relevant, irrelevant or unsure. Articles which were categorised as ‘unsure’ were discussed with SS and GC. The final list of relevant articles was formed by consensus amongst all authors. Once all relevant articles were identified, NM reviewed full texts of all identified articles and categorised the different polypharmacyterm definitions. NM, SS, LK and GC made substantive intellectual contributions to the conception and design of the study as well as interpretation of data. NM drafted the initial manuscript and all authors were involved in critically reviewing and revising the manuscript. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work.

Ethics approval and consent to participate Not applicable.

Consent for publication Not applicable.

Competing interests The authors declare that they have no competing interests.

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information Nashwa MasnoonpersName, Email: Nashwa.MasnoonpersName@mymail.unisa.edu.au.

Sepehr ShakibpersName, Email: Sepehr.ShakibpersName@sa.gov.au.

Lisa Kalisch-Ellett, Email: Lisa.Kalisch@unisa.edu.au.

Gillian E. CaugheypersName, Email: Gillian.CaugheypersName@unisa.edu.au