Failure to Reach a Consensus in Polypharmacy Definition: An Obstacle to Measuring Risks and Impacts—Results of a Literature Review

Figures & data

Figure 1 Flow chart for review of systematic reviews of polypharmacy definition.

Table 1 Quality Assessment Using the AMSTAR Tool

	Bakaki et al 2018^Citation9	Masnoon et al 2017^Citation3	Monégat et al 2014^Citation8	Bushardt et al 2008^Citation5	Fulton et al 2003^Citation7	Veehof et al 2000^Citation6
1. Did the research questions and inclusion criteria for the review include the components of PICO?	NA
2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review	Yes	Yes	Partial Yes	Partial Yes	Yes	Yes
3. Did the review authors explain their selection of the study designs for inclusion in the review?	Yes	Yes	Yes	No	No	No
4. Did the review authors use a comprehensive literature search strategy?	Partial Yes	Partial Yes	Partial Yes	No	Partial Yes	Partial Yes
5. Did the review authors perform study selection in duplicate?	Yes	Yes	Yes	NP	NP	NP
6. Did the review authors perform data extraction in duplicate?	Yes	Yes	NP	NP	NP	NP
7. Did the review authors provide a list of excluded studies and justify the exclusions?	Yes	Yes	No	No	Partial Yes	Partial Yes
8. Did the review authors describe the included studies in adequate detail?	Yes (n=363)	Yes (n=110)	No (n=34)	No (n=11)	Yes (n=16)	Yes (n=143)
9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?	NA
10. Did the review authors report on the sources of funding for the studies included in the review?
11. If meta-analysis was performed, did the review authors use appropriate methods for statistical combination of results?
12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?
13. Did the review authors account for RoB in primary studies when interpreting/discussing the results of the review?
14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?	Yes	Yes	Yes	Yes	Yes	Yes
15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?	NA
16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?	Yes	Yes	No	No	No	No

Table 2 Definitions of Polypharmacy

Author/ Year/ Country/	Title /Aim/Purpose	Sources/Method/ Period/ Number of Studies	Population	Polypharmacy Definitions
Bakaki et al^Citation9 2018 (USA) PLoS ONE	Defining pediatric polypharmacy: A scoping review. To describe definitions and terminology of pediatric polypharmacy.	(Conforms to the PRISMA checklist.) MEDLINE, PubMed, EMBASE, CINAHL, PsycINFO, Cochrane CENTRAL, and the Web of Science Core Collection databases were searched for English language articles with the concepts of “polypharmacy” and “children”. Data were extracted about study characteristics, polypharmacy terms and definitions from qualifying studies, and were synthesized by disease conditions. From inception to October 2016 and was updated on July 11, 2017 (n= 363 studies included)	Children	324 studies provided numeric definitions, 131 specified duration of polypharmacy, and 162 explicitly defined it. Over 81% (n = 295) of the studies defined polypharmacy as two or more medications or therapeutic classes. The most common comprehensive definitions of pediatric polypharmacy included: two or more concurrent medications for 1 day (n = 41), two or more concurrent medications for 31 days (n = 15), and two or more sequential medications over one year (n = 12). Commonly used terms included polypharmacy, polytherapy, combination pharmacotherapy, average number, and concomitant medications. The term polypharmacy was more common in psychiatry literature while epilepsy literature favored the term polytherapy. This review found 162 studies that offered 203 distinct definitions of polypharmacy in the text: Only 19% (n = 35 outpatient, 3 inpatient) of the text definitions provided both a medication threshold number and a period A list of all 203 text definitions is available at the journal website
Masnoon et al^Citation3 2017 (Australia) BMC Geriatrics	What is polypharmacy? A systematic review of definitions. To explore the definitions in existing literature. Additionally, to explore whether articles differentiated between appropriate and inappropriate polypharmacy and how this distinction was made.	(Conforms to the PRISMA checklist).MEDLINE (Ovid), EMBASE and Cochrane. Grey literature. Between 1st January 2000 and 30th May 2016 Published in English, (n=110 studies included)	All	A total of 138 definitions and associated terms. Definitions were categorised as: 111 Numerical only (using the number of medications to define polypharmacy): a wide range of variability in the definitions as well as associated terms (minor, moderate, major), the most commonly used term was “polypharmacy” but there was variation with regard to the actual definition of polypharmacy, which ranged from 2 or more medications to 11 or more medications. The most commonly used definition was 5 or more medication daily (51 studies). The second most common definition was 6 or more medications (10 studies). Only one study defined polypharmacy as the number of drug classes used by patient. 15 Numerical with an associated: Duration of therapy (11 studies): 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. or healthcare setting (4 studies): included the use of five or more medications at hospital discharge, and the use of 10 or more medications during hospital stay. 12 Descriptive (using a brief description to define polypharmacy) as: Patients visiting multiple pharmacies to obtain medications; Co-prescribing multiple medications; Simultaneous and long term use of different drugs by the same individual; Polypharmacy definition ranges from the use of a large number of medications, to the use of potentially inappropriate medications, medication underuse and medication duplication; Potentially inappropriate medications; Use of multiple medications concurrently and the use of additional medications to correct adverse effects; Use of medications which are not clinically indicated. More drugs being prescribed or taken than are clinically appropriate in the context of a patient’s comorbidities. (Some studies used different wording but conveyed the same definition ex: Coprescribing multiple medications and Simultaneous and long term use of different drugs by the same individual).
				7 studies defined appropriate or rational polypharmacy, or recognised the distinction between appropriate and inappropriate medications: defined polypharmacy using a brief description only (3 studies) or used a brief description and polypharmacy tools such as the Beers criteria and the Medication Appropriateness Index (MAI) (4 studies). (None of the studies explicitly identified the need to distinguish between appropriate and inappropriate polypharmacy based on the pharmacology of medications involved, how they interact with each other and comorbidities for a specific patient). Only one of the 110 studies included in the review highlighted the inconsistencies in the definitions of polypharmacy in the literature and suggested that polypharmacy 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”.
Monégat et al^Citation8 2014 (France) Questions d’économie de la Santé	Polypharmacy: Definitions, Measurement and Stakes Involved Review of the Literature and Measurement Tests Based on a review of the literature, different definitions of polypharmacy were identified and the measurement of polypharmacy was examined according to different thresholds.	The review of the literature was carried out using the Medline and Gediweb databases. Completed with research based on references included in selected articles. The following key words were used to designate polypharmacy: “polypharmacy”, “polymedication”, “polyprescription”, “multimedication”, “multiprescription”. Inclusion criteria were: articles or literature reviews on the definition and measurement of polypharmacy, studies on the prevalence of polypharmacy (excluding polypharmacy centered on a single therapeutic class or pathology) and articles in French or in English. Between 2000 and 2013 (n= 34 studies included)	All	Defined by the World Health Organisation as “the administration of many drugs at the same time or the administration of an excessive number of drugs” Notion of drug misuse: Polypharmacy refers to the administration of more drugs than clinically necessary. By extension, polypharmacy is said to be “appropriate” when the prescription of numerous medications is justified, and “inappropriate” when wrongly or indiscriminately prescribed. According to the time slots used to measure polypharmacy: Simultaneous polypharmacy: Corresponds to the number of drugs concurrently taken by a patient on a given day. A variant of this definition imposes that the simultaneous use of numerous medications should be prolonged through time; at least 60 consecutive days quarterly, for example.
				Cumulative polypharmacy (also known as multiple medication): is defined by the sum of different medications administered over a given period of time. Numerous studies use a three-month period, the time necessary to take into account 95% of prescriptions based on the standard prescription renewal time (three months). Other periods (six months, twelve months) have also been used. Continuous polypharmacy: it is similar to cumulative polypharmacy but limited to medications taken for prolonged and regular periods. It only takes into account medications present in two given time periods spaced by an interval of six months, for example. Or by taking into account only medications present in the preceding quarter and the following quarter. According to a defined thresholds: Numerous thresholds have been identified - Essentially 5 or more medications - 10 medications or over - Other thresholds: “5 to 7”; “8 and over”; Threshold of 8 medications; “6 medications and over” According to the number of medications administered: Minor polypharmacy: the administration of 2 to 4 medications – Major polypharmacy: the use of 5 medications and over. hyperpolypharmacy or excessive multi-medication: the consumption of 10 or more medications. In an article published in 2014: The consumption of over 10 medications is now considered as major 20 medications or over is considered excessive. The consumption of 5 medications or under is now considered as “non-polypharmacy” or “oligopharmacy”
Bushardt et al^Citation5 2008 (USA) Clinical Interventions in Aging	Polypharmacy: Misleading, but manageable To identify a consensus definition for polypharmacy and evaluate its prevalence among elderly outpatients.	A review conducted within OVID for original articles. Using the following search terms and phrases: “polypharmacy,” “elderly,” “geriatrics,” “inappropriate medication,” and “multiple medication use.” English language articles available in local holding, which described “polypharmacy” or the issue of the simultaneous use of multiple medications in elderly patients, were evaluated. Discrete definitions of polypharmacy were identified and recorded. Between January 1997 and May 2007 (n=11 studies included)	Elderly	Several different definitions involved one of the following concepts (24 définitions): Medication does not match the diagnostic (the most commonly cited, in 4 articles); Many medications; Duplication of medication; Drug/drug interactions; Inappropriate dosing frequency (excessive, too low, too long); Medication prescribed to treat the side effect of another medication (except for case where there is no other option); Two or more agents with the same chemical class; Two or more meds to treat the same condition; Two or more agents with the same or similar pharmacologic actions to treat different conditions; Minor polypharmacy = 2–4 meds/Major polypharmacy ≥5 meds; 3, 5 or 6 different medications; Two or more medications; Greater than 5 medications; Excessive use of medication; Unnecessary use of medication; Medications prescribed greater than twice per day; Complicated drug regimen effecting compliance; Contraindicated in the elderly; Taking an OTC medication, an herbal product or another person’s medication; Availability of an equally effective, lower-cost alternative; Patient misunderstanding of the use of the medication (purpose, how to take it, side effects possible, toxicity signs, etc.); Dosage does not reflect age/renal/liver status; Improvement after discontinuation of medication; Diagnosis no longer present. The term “inappropriate” was part of definitions used in six articles. Some definitions for polypharmacy place a value on the number of concurrent medications; the most commonly referenced number was 6 medications or more.
Fulton et al^Citation7 2003 (USA) Journal of the American Academy of Nurse Practitioners	Polypharmacy in the elderly: a literature review. To review the body of literature addressing polypharmacy in individuals aged 60 years and older to (a) determine primary care providers’ definition of polypharmacy, (b) explore how polypharmacy was assessed in primary care, and (c) seek tested interventions that address polypharmacy.	A systematic review; Bibliographic databases: EBSCOHost, InfoTrac, OVID, FirstSearch, and FirstSearch Deluxe. The search terms “polypharmacy,” “polypharmacy and elderly,” “polypharmacy and research,” and “multiple medications”. Between January 1991 and October 2003 (n=16 studies included)	Elderly (≥60 years)	Multiple definition are utilized: - Two or more drugs for 240 days or more - Concurrent use of two or more drugs - Use of for or more medications -Use of five or more different prescription medications Additional definitions include regular daily consumption of multiple medication as well as the use of high-risk medications and questionable dosing “Untoward iatrogenic sequel of the use of multiple, interacting medications” European studies defined polypharmacy according to the number of medications taken, whereas the studies conducted in the United states defined polypharmacy according to whether a medication was clinically indicated
Veehof et al^Citation6 2000 (Netherlands) European Journal of General Practice	Polypharmacy in the elderly – A literature review. To define polypharmacy; to determine the extent and nature of polypharmacy in the elderly; and to discover the problems which may result from polypharmacy in general practice.	A Medline search from 1985 to 1998 yielded. Entries: polypharmacy and aged (=65 years and older) in combination with: adverse drug reactions, drug interactions, drug combinations. (n= 143 articles included)	Elderly (≥65 years)	Defined in two ways in the literature: Quantitative vs Qualitative. In quantitative descriptions the emphasis lies mainly on the amount of drugs, and qualitative descriptions focus on polypharmacy as a problem. For instance, polypharmacy defined as the prescription, administering or use of more drugs than is clinically indicated for a certain patient. The term polypharmacy was also applied when several drugs are used with one of the following characteristics: Drug use with no apparent indication; Use of two identical drugs; Concurrent use of interacting drugs; Use of contraindicated drugs; Use of drugs to treat adverse drug reactions; Improvement after stopping or interrupting medication. When mentioning polypharmacy some authors describe a regime in which there is at least one drug that is superfluous or the use of any drug that is not essential to the management of a medical problem. When approaching polypharmacy quantitatively, the criterion often used is the simultaneous use of more than five drugs (But it must be remembered that situations exist where the simultaneous prescription of several drugs is necessary and has to be considered effective pharmacotherapy). For the purpose of this study: polypharmacy means simply the simultaneous use of two or more drugs; the use of more than five drugs is defined as major polypharmacy.

Abbreviations: OTC, over the counter; PIM, potentially inappropriate medication; WHO, World Health Organization.

Bakaki PM, Horace A, Dawson N, et al. Defining pediatric polypharmacy: a scoping review. PLoS One. 2018;13(11):e0208047. doi:10.1371/journal.pone.0208047

 PubMed Web of Science ®Google Scholar

Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE What is polypharmacy? A systematic review of definitions. BMC Geriatr [Internet]. October 10, 2017 [cité juill 9, 2018].;17. Disponible sur: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635569/. Accessed December 12, 2019.

 Google Scholar

Monégat M, Sermet C. (IRDES), In collaboration with Perronnin M. (IRDES) and Rococo E. (Institut Gustave Roussy – IGR). Polypharmacy: definitions, measurement and stakes involved. Review of the literature and measurement tests. Questions d’économie de la santé: 2014 (état de santé, protection sociale, enquête, analyses économiques, comparaisons internationales) - IRDES [Internet]. [cité November 29, 2018]. Disponible sur: http://www.bdsp.ehesp.fr/Base/492692/.

 Google Scholar

Bushardt RL, Massey EB, Simpson TW, Ariail JC, Simpson KN. Polypharmacy: misleading, but manageable. Clin Interv Aging. 2008;3(2):383–389. doi:10.2147/CIA.S2468

 PubMed Web of Science ®Google Scholar

Fulton MM, Allen ER. Polypharmacy in the elderly: a literature review. J Am Acad Nurse Pract. 2005;17(4):123–132. doi:10.1111/jaan.2005.17.issue-4

 PubMedGoogle Scholar

Veehof LJG, Meyboom-De Jong B, Haaijer-Ruskamp FM. Polypharmacy in the elderly – a literature review. Eur J Gen Pract. 2000;6(3):98–106. doi:10.3109/13814780009069956

 Google Scholar