Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

A systematic literature review comparing methods

for the measurement of patient persistence and
adherence

Carol A. Forbes, Sohan Deshpande, Francesc Sorio-Vilela, Lucie Kutikova,

Steven Duffy, Ioanna Gouni-Berthold & Emil Hagström

To cite this article: Carol A. Forbes, Sohan Deshpande, Francesc Sorio-Vilela, Lucie Kutikova,
Steven Duffy, Ioanna Gouni-Berthold & Emil Hagström (2018): A systematic literature review
comparing methods for the measurement of patient persistence and adherence, Current Medical
Research and Opinion, DOI: 10.1080/03007995.2018.1477747

To link to this article: https://doi.org/10.1080/03007995.2018.1477747

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May 2018.

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A systematic literature review comparing methods for the measurement of patient persistence and
adherence 1

Carol A. Forbes1, Sohan Deshpande1, Francesc Sorio-Vilela2, Lucie Kutikova3, Steven Duffy1, Ioanna
Gouni-Berthold4, Emil Hagström5

1
Kleijnen Systematic Reviews Ltd, Unit 6, Escrick Business Park, Riccall Road, Escrick, York YO19 6FD,
United Kingdom
2
Global Health Economics, Amgen Europe and EEMEA, Dammstrasse 23, PO Box 1557, Zug, CH-6301,
Switzerland
3
Global Health Economics, Amgen (Europe) GmbH, Dammstrasse 23, Zug, 6301, Switzerland
4
Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Kerpener Str.
62, Cologne, 50937, Germany

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5
Uppsala Clinical Research Center (UCR), Department of Medical Sciences, University of Uppsala,

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Uppsala Science Park, Dag Hammarskjöldsv 38, Uppsala, 751 83, Sweden

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Corresponding author
Francesc Sorio-Vilela

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Global Health Economics, Amgen Europe and EEMEA, Dammstrasse 23, PO Box 1557, Zug, CH-6301,
Switzerland
Email Address: fsorio@amgen.com
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Transparency statement

Declaration of funding
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This study was funded by Amgen Europe GmbH

Declaration of financial/other interests

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CF, SD and SD are employees of KSR Ltd, an independent research company paid by Amgen to
conduct this research. IG-B is consultant to Amgen, Sanofi, Lilly and Regeneron and has participated
in Speakers Bureau for Amgen and Sanofi. EH is consultant to Amgen, Sanofi, Ariad and MSD; and
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has received research grants from Amgen, GSK, AstraZeneca and Sanofi. In addition, he has
participated in Speakers Bureau for Amgen, Boehringer Ingelheim, AstraZeneca, Sanofi and
NovoNordisk. Finally, he is the National Coordinator/ARO-coordinator for the following trials: Sanofi
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ODYSSEY outcomes; DalCore DAL310; Regeneron R1500-CL-1643; and Aegis II/Perfuse. LK and FS-V
are employees and stockholders of Amgen. Peer reviewers on this manuscript have received an
honorarium from CMRO for their review work, but have no other relevant financial relationships to
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disclose.

Author contributions
CF: concept and design; data inclusion assessment; data extraction and quality assessment; data
analysis and interpretation; drafting and final approval of the manuscript. SD: concept and design;
data inclusion assessment; data extraction and quality assessment; data analysis and interpretation;
manuscript draft and final approval. SD: concept and design, literature searching, drafting and final
approval of the manuscript. FS-V and LK: concept and design; data review; interpretation; drafting
and final approval of the manuscript.
Acknowledgements
The authors acknowledge the help of Kim Reid and Vanesa Huertas Carrera who assisted with data
extraction and quality assessment. Ioanna Gouni-Berthold and Emil Hagström - concept and design;
data review; interpretation; drafting and final approval of the manuscript.

Abstract

Objectives: A systematic literature review was conducted comparing different approaches

estimating persistence and adherence in chronic diseases with polypharmacy of oral and
subcutaneous treatments.
Methods: This work followed published guidance on performing systematic reviews. Twelve
electronic databases and grey literature sources were used to identify studies and guidelines for
persistence and adherence of oral and subcutaneous therapies in hypercholesterolemia, type 2
diabetes, hypertension, osteoporosis and rheumatoid arthritis. Outcomes of interest included pros:

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accurate, easy to use, inexpensive, and cons: inaccurate, difficult to use, expensive of each

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persistence and adherence data collection and calculation method.
Results: 4,158 records were retrieved up to March 2017. We included 16 observational studies, 5

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systematic reviews and 7 guidelines, in patients with hypercholesterolemia (n=8), type 2 diabetes
(n=4), hypertension (n=2), rheumatoid arthritis (n=1) and mixed patient populations (n=13).
Pharmacy and medical records offer accurate, easy and inexpensive data collection method. Pill

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count, Medication Event Monitoring Systems (MEMs), self-report questionnaires and observer
report are easy to use. MEMS and biochemical monitoring tests can be expensive. Proportion of
days covered (PDC) was recommended as a gold standard calculation method for long-term
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treatments. PDC avoids use of days’ supply in calculation hence, is more accurate compared to
medication possession ratio (MPR) to assess adherence to treatments in chronic diseases.
Conclusions: Decisions on what method to use should be based on considerations of the route of
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medication administration, the resources available, setting and aim of the assessment. Combining
different methods may provide wider insights into adherence and persistence, including patient
behaviour.
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Keywords: cardiovascular diseases, chronic disease, adherence, persistence, methodology,

systematic review
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Introduction

Treatment persistence and adherence are key factors associated with the effectiveness of all
pharmacological therapies, but are particularly important for medications that are prescribed for
chronic conditions which need to be taken on a long-term basis. This is the case of lipid lowering
therapies where good persistence and adherence have been associated with reductions in
cardiovascular events and mortality.1 In addition, more complex treatment regimens involving
polypharmacy with different dosages and less patient-friendly administration route (e.g.
subcutaneous therapies) are more likely to have problems with respect to patients failing to take
medications as prescribed.2, 3 Therefore it is important to evaluate persistence and adherence with
existing and new therapies in these groups of patients in the real world.

Patient support programs (PSPs) are powerful tools to enhance patient persistence and adherence in
real-world. The European Medicines Agency (EMA) increasingly consider and require data from PSPs
and disease management programmes, surveys of patients and healthcare providers, programmes
to gather information on patient compliance, or compensation/re-imbursement schemes.4

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This review is primarily aimed at comparing different approaches for collecting and measuring
patient persistence and adherence with subcutaneous and oral therapies for hypercholesterolemia.

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Methods

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This review adhered to methods recommended by the Cochrane Collaboration,5 and the Centre for
Reviews and Dissemination.6 Given the potentially limited evidence base within populations with
hypercholesterolemia, our review was also extended to include other diseases associated with
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cardiovascular (CV) morbidity and mortality (type 2 diabetes mellitus and hypertension). In addition,
studies of rheumatoid arthritis and osteoporosis were also considered, as these chronic diseases are
also likely to involve polypharmacy, and patients are likely to require treatment with long-term oral
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and/or subcutaneous therapies. Patients receiving other types of therapies including dietary changes
and supplements were excluded. Subgroups of particular interest included patients receiving
subcutaneous therapies, polypharmacy, and those taking part in PSPs.
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Where relevant, the interventions of interest were the methods of collecting data and calculating
patient persistence and adherence with drug therapies. Methods of collecting patient data to allow
estimating medication persistence and adherence included: pharmacy (refill claims data on
medication dispensed) and medical records (electronic or paper based information on prescription
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and dosing); pill counts (including simple pill count assessing number of pills remaining in relation to
number of pills prescribed and electronic devices such as Medication Event Monitoring Systems
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[MEMS] which record bottle opening at a given time); and questionnaires (including simple patient
recall and questionnaires, medication diaries, and recognized validated tools/scales). Persistence
was assessed as the number of patients remaining on the study drug for the entire follow-up period
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without discontinuation or switching after initiation of the index drug. Adherence was assessed
using medication possession ratio (MPR), proportion of days covered (PDC), cumulative medication
gap (CMG), daily average consumption (DACON) and new prescription medication gap (NPMG). Any
papers reporting on the validation of language adaptations of already available scales and tools were
excluded from the review.

The outcomes of interest were the pros and cons of each method of collecting patient level data
and/or calculating patient persistence and adherence. Pros were defined as accurate, easy to use,
and inexpensive; and cons were defined as inaccurate, difficult to use, and expensive.

For patients with hypercholesterolemia undergoing treatment with lipid lowering therapies (the
main focus of this review), we considered a broad range of evidence from randomised controlled
trials (RCTs), observational studies, systematic reviews, and guidelines. For patients with
hypertension, type 2 diabetes mellitus, rheumatoid arthritis and osteoporosis data, which were of
secondary interest to this review, we limited inclusion to only those study designs corresponding to
the highest levels of evidence, 7 i.e. systematic reviews and guidelines.

In addition, any guidelines/guidance documents recommending on best methodologies around

assessing adherence/persistence, not specifically related to any treatment were also included in
order to avoid missing relevant information from key organizations in the field such as ISPOR
(https://www.ispor.org/sigs/medication.asp).

Twelve electronic databases were searched from inception to March 2017. The search strategies
were developed specifically for each database and the keywords adapted accordingly. Search terms
included the following: adherence measurement methods, guidance, systematic reviews, RCTs, real
world evidence, CVD, hyperlipidaemia, diabetes, hypertension, osteoporosis and rheumatoid
arthritis. Searches were not limited by language, publication status (unpublished or published) or
date of publication. Supplementary searches were also undertaken for guideline resources, and grey

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literature was identified through searching organization websites such as that of the ISPOR

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Medication Compliance and Persistence (ISPOR MAP) Special Interest Group. A list of databases
searched, and the full Embase search strategy are reported in Supplemental File 1.

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Studies and systematic reviews initially identified were reference checked for any potentially
relevant additional studies. Studies were selected for inclusion by two independent reviewers. One

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reviewer extracted the study data and assessed the risk of bias using an adapted version of the
Downs and Black checklist7 for observational studies, the AGREE II tool8 for guidelines and Risk Of
Bias In Systematic reviews tool (ROBIS)9 for systematic reviews. A second reviewer independently
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checked these data. All discrepancies between reviewers were resolved through consensus or
consultation with a third reviewer.

Results
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A total of 4,158 titles and abstracts were screened for relevance according to the inclusion criteria
for the review. A summary of the identification and selection of studies for inclusion in this review is
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presented in Figure 1, in accordance with the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement.10

We identified 28 studies that compared different methods of collecting data or calculating

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persistence and adherence (see Table 1). Amongst the 28 included studies 14 were prospective
observational studies, 2 were retrospective observational studies, there were 5 systematic reviews
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and 7 guidance documents identified through the review of guidelines. Eight studies exclusively
included patients with hypercholesterolemia, 4 studies included patients with type 2 diabetes, 2
studies included patients with hypertension and 1 study included patients with rheumatoid arthritis.
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Six studies were conducted in patients with mixed disease types such as hypercholesterolemia, type
2 diabetes mellitus and/or hypertension. Six hypercholesterolemia studies11-16 assessed patients on
statins and two studies assessed patients on any oral lipid lowering therapy.17, 18 Six observational
studies were in populations with several diseases involving polypharmacy with multiple
administration routes.19-24 Only one systematic review reported on rheumatoid arthritis patients
who were on disease-modifying antirheumatic drugs (DMARDs).25 The seven guidelines were not
disease specific (Table 1).

Most of the studies identified in our review were observational studies. All of the observational
studies had limitations with respect to their methodologies and had at least two criteria were judged
to be at high risk of bias when assessed with the Down’s and Black tool for observational studies (see
Table 1). Observational studies are generally considered less robust study designs in comparison
with systematic reviews and guidelines, in the hierarchy of evidence. However, observational studies
are the prominent study design used when evaluating methodologies in patient persistence and
adherence in clinical practice.

Across the five included systematic reviews only one review in hypertensive patients, was assessed
as at a low risk of bias using the ROBIS assessment for systematic reviews (see Table 1).26 One review
in rheumatoid arthritis patients was judged to be at unclear risk of bias25 and two systematic reviews
conducted in patients with type 2 diabetes mellitus had a high risk of bias.27, 28

Using the AGREE II assessment tool (see Table 1) for guidelines, guidelines from NICE29, 30 and the
ISPOR Medication Compliance Working Group31 were judged at low risk of bias, whilst three
guidelines were judge at high risk of bias32-34 and one as unclear.35

Collection of persistence and adherence

Pharmacy/medical records review

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Most of the studies report pharmacy records to be accurate, easy and inexpensive for persistence

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and adherence assessment (Table 2). One systematic review and one guideline reported that
pharmacy records are reliable objective measures, which are well suited for accurately measuring

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persistence27, 35 and they are practical and easy to use.35 However they have some limitations such as
not capturing overuse accurately, and issues with early refills, changes in drug regimens,
combination therapies, or multiple dispensing.27 Only one prospective observational study reported

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that the pharmacy records are inaccurate compared to pill count as they are not sensitive to
temporal changes in adherence when carrying out longitudinal assessments.18 This prospective study
reports that, “twenty-four hour recall and refill history inaccurately measure medication adherence
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for both clinical trial and clinical practice pharmacotherapies” and that “pill count should be the
standard for monitoring medication adherence for both clinical trials and clinical practice.”
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Clifford 201427 was a systematic review in a diabetic population on multiple therapies administered
either orally or subcutaneously. This study reports that the medical records can be accurate as they
provide prescribing and dosing information. This review suggests that novel measures including
electronic monitoring and computerized logbook databases, could be evaluated in larger samples of
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patients taking insulin to get a better understanding of patterns of medication adherence and dosing
issues over time”. However, the authors also note that the documentation of prescribing and dosing
information is not equivalent to medication ingestion.27 Medical records can be time intensive to
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retrieve when data is not recorded in electronic format.27

Pill counts/MEMS
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Eight studies reported pros and cons for using simple pill count or MEMS (Table 2). One each
systematic review,27 guideline35 and observational study12 reported that MEMS was found to be
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more accurate compared to the simple pill count as it tracks patterns of taking medication and
records the time and date medication bottle was opened. Also, an observational study reported that
pill counts can significantly overestimate adherence compared to MEMS.13 Two observational
studies13, 18 and one systematic review27 reported that both measures are easy to use. One
observational study reported that compared to pill count MEMS was well accepted by patients.15 A
systematic review reported that MEMS is much more expensive compared to pill count, but
concluded that such methods “should be evaluated in larger samples of patients ….to get a better
understanding of patterns of medication adherence and dosing issues over time”.27 A further
observational study reported that compared to pill counts, the pros of using MEMS (used as the
“gold standard”) do not justify the associated increase in cost.23 However, two observational
studies,13, 17 one systematic review27 and one guideline35 reported that both measures are limited as
they do not confirm the ingestion of medication and can be easily altered by pill dumping.
Questionnaires

Twelve studies reported pros and cons of using patient and observer reported measures for
assessing adherence (Table 2). The patient reported measures included medication diaries, simple
patient questionnaires, patient recall and adherence scale/tools. All patient and observer reported
measures can potentially overestimate adherence27 and none of the scales can be considered as a
gold standard.26

The most commonly reported adherence scales were; Shea scale12, Adherence to Refills and
Medications Scale (ARMS)36 and Morisky Medication Adherence Scale (MMAS-4/8).11, 14, 19, 21, 26-28, 36
The Shea scale was reported as accurate and had 73.7% sensitivity when screening for poor
adherence and predicting cholesterol lowering.12 The Shea scale was preferred as a global or brief
estimate of adherence and was less complex when compared to some other scales.12 One
prospective observational study reported that MMAS is accurate (72% accuracy) when screening for
poor adherence to statins, however, another prospective study reported that MMAS did not
correlate with low density lipoprotein cholesterol (LDL-C) goal levels.14 ARMS scores showed

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stronger associations between measures of refill adherence and diastolic blood pressure control

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compared to MMAS, but not systolic blood pressure, the main predictor of outcomes.22 Scales like
MMAS are more complex to administer,28 but useful when assessing adherence in polypharmacy.19

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However one problem reported for self-report adherence scales like MMAS is that sometimes they
are not very accurate since they lead to overestimating adherence as the patients know that they
are being observed and can be dishonest with reporting.28 However, patient reported questionnaires

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can provide details on behaviour, are easy to administer and can be widely used.27 Simple
questionnaires can be inexpensive26, 27 as compared to scales like MMAS, which have an increased
cost of data collection.28 However, one observational study that compared the use of a simple visual
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analogue scale (VAS) in comparison with a validated questionnaire (the Adherence Self-Report
Questionnaire [ASRQ]) and MEMS, concluded that using simple self-report measures, “as the sole
means of assessing medication compliance is insufficiently accurate to detect poor adherence”.23
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This study in patients receiving cardiovascular medications, found that a majority of patients over-
report adherence to cardiovascular medication if asked to complete a visual analogue scale and a
validated questionnaire.
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Biochemical monitoring

Only one systematic review reported on biochemical monitoring which was defined as an objective
and direct measure (see Table 2).27 However, even these measures can be inaccurate as they can be
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influenced by other confounding factors e.g. glucose monitoring findings can be influenced by diet,
physical activity or absorption. The ease of use and expenses are dependent on the type of test for
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e.g. glucose monitoring is a simple less expensive method and easy to use whereas, HbA1c
monitoring can be expensive method as it requires blood collection and laboratory testing.27
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Calculation of adherence

Five studies reported on different methods of calculating adherence (see Table 3). These included
four studies reporting on the pros and cons of different ratio calculations for adherence including
medication possession ratio (MPR), proportion of days covered (PDC), cumulative medication gap
(CMG), daily average consumption (DACON) and new prescription medication gap (NPMG) (see
Table 4).24, 28, 33, 37 A systematic review by Stolpe (2016) reported the advantages of using PDC over
other calculation methods. According to this systematic review, PDC is more accurate compared to
other methods when calculating adherence to medication regimen.28 MPR use days’ supply in the
calculation (numerator) which can be a problem due to early refilling (does not account for
overlapping periods) and when using injectable medications with variable dosing schedules such as
insulin; PDC uses days covered instead in the calculation.28 PDC is recommended by Pharmacy
Quality Alliance (PQA)33 and may be useful for long-term treatments.28 However, PDC can be difficult
to use as it does not account for differences in pack size.28 MPR on the other hand was considered
easy to use and calculate however, it can overestimate adherence if patients refill a prescription
early.28

Despite all this, there seems to be some confusion in the definitions of MPR and PDC in the literature
and the difference dilutes in some manuscripts. In the end, it is recommended to adjust for
overlapping prescription (using days covered rather than adding all days supplied regardless of
whether there is an overlap which may result with a proportion higher than 100%). Additionally and
when dealing with chronic treatments with long-term follow-up periods available, when the
denominator includes a fixed observation period (i.e. one year) rather than number of days between
first and last refill, both adherence and persistence are accounted for.38 We have identified other
methods in the included studies that calculate adherence. For example, one retrospective study
reported that in comparison to CMG, NPMG is a valid, comprehensive measure that can be used in
addition to existing metrics and shows a significant relationship with self-reported adherence and
out-of-pocket costs.37 However, these are newer methods remaining be further explored.

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Calculations of persistence

Persistence rates were reported to be very sensitive to the method employed for the assigning non-

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persistence in a study reporting on chronic care medications such as statins (see Table 3).16 One
systematic review reported on persistence methods which were based on the time gap allowed

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between refills and proportion of patients not refilling in time.28 Persistence is difficult to use as it is
affected by wastage, stockpiling and reliance on days’ supply in calculation.28 The same systematic
review reported that persistence is a too crude calculation method and thus can be limited as it does
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not indicate whether the patient is adherent with the clinicians’ recommendations and treatment
regimen (see Table 4).28

Persistence and adherence assessment of subcutaneous therapies, polypharmacy and PSPs

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Two systematic reviews including patients with type 1 and 2 diabetes mellitus reported subgroup
data by route of administration (see Table 4).27, 28 Clifford 2014 reported that MEMS cannot be used
for subcutaneous treatments with variable dosing such as insulin.27 Stolpe 2016 reported that PDC is
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more accurate as it avoids use of days’ supply in calculation which is a problem when using MPR
with subcutaneous administration.28 The study also reported that the persistence rates may not be
appropriate for injectable medications with variable-dose titration schedules as a pre-defined
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treatment gap is not suitable.28

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Two systematic reviews and two prospective observational studies reported relevant data on
polypharmacy (see Table 4). Clifford 2014 reported that pharmacy records are difficult to use where
there are changes in drug regimen, polypharmacy or multiple dispensing.27 One prospective study
reported that MEMS is easy to use as it can identify patterns of non-adherence in polypharmacy
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drug regimen which are undetectable using pill count alone.15 Whereas, the other observational
study reported that in comparison with the MMAS, mMMAS (adapted from the Brief Medication
Questionnaire) is more useful when assessing adherence in polypharmacy.19 No studies reported
data regarding the best methods to use within the context of a PSP.

Discussion

Our review suggests there is evidence that some methods may offer advantages over alternative
methods dependent on the setting and aim of the research (Figure 2 and Table 5). Pharmacy records
from data sources such as pharmacy claims database are useful to determine the
adherence/persistence retrospectively to a particular treatment based on prescription refill.
Similarly, medical records can be used retrospectively to assess adherence/persistence based on
prescriptions and additionally allow the assessment of the clinical profile of the patient. MEMS and
pill counts may be used in clinical trials or prospective observational studies to assess medication
adherence and to describe patterns of medication intake. Questionnaires can be used in a variety of
study designs (e.g. surveys, clinical trials, prospective observational studies, patient support
programs, etc.) allowing the assessment of behaviours associated with lack of adherence and
assisting in the development of interventions to improve adherence and persistence. PDC seems
most up to date method to calculate adherence from medical or pharmacy records (Figure 2).

Our systematic review specifically focuses on the important area of persistence and adherence
within patients with chronic diseases. Many treatment and patient management guidelines across a
range of chronic conditions including coronary heart disease and other cardiovascular diseases have
stressed the importance of patient persistence and adherence with medications, but few provide
specific guidance as to the methods that should be employed.29, 30, 39-41

Simple self-report has been suggested as an easy approach to implement in clinical practice, by
asking patients to report if they have missed any medication doses over a specific period of time,

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such as the previous week.29 However, patient self-report has been shown in many cases to

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overestimate adherence and may also be associated with recall bias.17 Our review found similar
issues and also suggests that methods such as medical records, pharmacy records, MEMS, and

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medication diaries, are more accurate for measuring adherence/persistence compared to the other
methods. Medical records provide accurate prescribing and dosing information27 and pharmacy
records of medication dispensing provide an objective measure; both are well suited to calculating

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adherence/persistence.35 In countries where electronic databases of medical records and pharmacy
prescription records exist, these can be used to provide a simple and relatively inexpensive estimate
of persistence/adherence across a large number of patients, even across whole nations.42-45
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However, in countries where such databases are unavailable and only manual records are available,
accessing medical records and pharmacy prescription records can be a tedious and time consuming
process. Pill count and MEMS are also accurate measurement methods. MEMS in addition, tracks
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patterns of taking medication, through recording the times and dates the medication bottle is
opened.27 However, at present, the additional resources required to implement MEMs, may restrict
its widespread use in clinical practice.18, 27 We also found evidence that biochemical monitoring can
be an easy to use and cheap method of monitoring persistence, adherence and to confirm patient
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intake/injection, but this is dependent on the type of test used.

In our review, we also identified that in some cases, a simple estimate of persistence and/or
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adherence may not be sufficient and that researchers may also need to better understand patient
behaviour. This can also help to develop strategies to improve adherence and in these instances, the
application of specifically designed adherence scales and tools may be advantageous. Such scales
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may also be a useful addition to other methods such as pharmacy prescription records, medical
records and MEMs.46 We identified a number of examples of such tools including the commonly
used Shea, MMAS-4 and MMAS-8 scales.47-49 However, the use of such tools is likely to be more
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resource intensive and the information gathered may not always be reliable as the measurements
are more subjective.

In particular, we were interested in methods for use within the setting of a PSP, but found no
specific evidence. However, within the setting of a PSP adherence scales may provide an opportunity
to evaluate potential barriers and investigate patient behaviours and motivations. This in turn can
help to refine PSPs and so improve their effectiveness. We suggest that within the context of a PSP,
using a mixture of prescription records and scales may be helpful.

Assessing adherence to subcutaneous medications in chronic diseases was of particular interest to

our review and they pose a particular challenge.50 Most of the evidence identified in our review for
subcutaneous treatment was related to insulin administration and so the findings may not apply to
other subcutaneous treatments.27,28 Insulin administration uses a variable dosing scheme (dose and
frequency) dependent on blood glucose levels and so it is difficult to estimate how long each unit of
medication prescribed/dispensed will last. This adds another level of complexity to any calculations
of adherence/persistence.50

With respect to the types of calculations used to measure patient persistence and adherence, our
review, in line with other recent reviews,51 identified that the most commonly used methods were
PDC and MPR. PDC is recommended by the PQA33 and appears from the evidence gathered in our
review and by other recent studies,53 to be more accurate compared to other methods. When
calculating adherence to long-term medication regimen with available long-term follow-up, a pre-
defined period for the observation interval can be applied. This allows that both adherence and
persistence are incorporated in PDC at the same time.16 We suggest that PDC is perhaps the best
method also for measuring adherence with subcutaneous therapies (with fixed dosing schemes).
Similarly to our findings, a recent study by Malo 201753 recommended the use of more than one
measure to capture adherence and persistence fully. In this study, the authors concluded that
adherence and persistence are two distinct, but complementary parameters that need to be studied

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and interpreted in tandem.

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One of the key problems faced by almost all of the currently used methods of collecting data is that

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none of them provides evidence of actual medication ingestion by the patient. Although medical
records and prescription methods may show that the patients were prescribed and/or collected
their medication, there is no proof that the medicine was then consumed as directed by the

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clinician. Even more recent developments using electronic monitoring systems such as MEMs, do not
provide proof of ingestion and only show that the medicine container was opened at the
appropriate time. Direct observation of administration is perhaps one of the few methods of
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ensuring ingestion, but this method places a significant burden on resources and is unlikely in most
cases to be a feasible method to use in practice. An alternative is the direct measurement of the
drug, a metabolite, or its marker in a biological fluid.52 This provides objective confirmation that a
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dose of medication has been ingested by an individual. However, such as measure only provides a
snapshot of patient adherence at a specific point in time and may not be reflective of patient
behaviour over time, which is important in the case of long-term therapies in chronic diseases.52
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In summary, our review confirms that the measurement of persistence and adherence is complex
and needs to be tailored to individual circumstances in the absence of one gold standard
methodology. Ongoing work from the ISPOR Medication Adherence and Persistence Special Interest
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Group may also provide further insight.35, 51

Limitations
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The possibility of publication bias remains a potential limitation for all systematic reviews and
cannot be eliminated completely. However, we consider the risk of publication bias to be low in our
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review given our wide searches of grey literature and subsequent checking of references in included
studies, systematic reviews and guidelines/guidance. In addition, evidence was not excluded on the
basis of language, in order to keep the risk of language bias to a minimum.

Evidence relating to potential differences between methods used for oral versus subcutaneous
therapies was limited. In many cases details such as dose, route and frequency of administration,
were lacking.

The current development of standard reporting guidelines for studies evaluating persistence and
adherence (European Society for Patient Adherence, COMpliance, and Persistence [ESPACOMP]
Medication Adherence Reporting Guidelines [EMERGE]), should help to address this issue in future
studies.53
The findings of the review are also limited by the reliability of the included studies. In many cases a
high risk of bias was identified especially in the case of the included observational studies.
Consequently, we have tried to base our conclusions on those findings which include evidence from
other sources including systematic reviews and guidelines.

Conclusions

Decisions on the best methods to use for measuring patient persistence and adherence with long-
term medications for chronic diseases, should be based on the requirements of the individual
researcher and setting. Such decisions should consider the setting and the aims of the assessment,
the route of administration and any resource constraints.

Pharmacy records represent an accurate, easy to implement method of collecting persistence and
adherence data from a large number of patients. Medical records offer similar advantages, but also
allow for the clinical profiling of the patients. Adherence tools such as the MMAS and Shea scales
offer insight into patient behaviour though may be more subjective. PDC is considered a more

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appropriate method for assessing adherence to treatments in chronic diseases. Combining methods

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may gain wider insights into persistence and adherence, including patient behaviour.

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References

[1] Deshpande S, Quek RG, Forbes CA, de Kock S, Kleijnen J, Gandra SR, et al. A systematic review to
assess the adherence and persistence with statins. Curr Med Res Opin 2017;33(4):769-78.

[2] Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin Proc 2011;86(4):304-14.

[3] Webster R, Rodgers A. Polypill treatments for cardiovascular diseases. Expert Opin Drug Deliv
2016;13(1):1-6.

[4] Heads of Medicines Agencies, European Medicines Agency. Guideline on good pharmacovigilance
practices (GVP). Module VI – Management and reporting of adverse reactions to medicinal products

t
ip
(Rev 1). EMA/873138/2011 Rev 1* [Internet]. London: European Medicines Agency, 2014 [accessed
7.2.17]. Available from:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC50017

cr
2402.pdf

us
[5] Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions [Internet].
Version 5.1.0 [updated March 2011]: The Cochrane Collaboration, 2011 [accessed 2.2.17]. Available
an
from: http://handbook.cochrane.org/
M

[6] Centre for Reviews and Dissemination. Systematic Reviews: CRD’s guidance for undertaking
reviews in health care [Internet]. York: University of York, 2009 [accessed 2.2.17] Available from:
http://www.york.ac.uk/inst/crd/SysRev/!SSL!/WebHelp/SysRev3.htm
ed

[7] Downs SH, Black N. The feasibility of creating a checklist for the assessment of the
pt

methodological quality both of randomised and non-randomised studies of health care

interventions. J Epidemiol Community Health 1998;52(6):377-84.
ce

[8] Brouwers M, Kho ME, Browman GP, Cluzeau F, Feder G, Fervers B, et al. AGREE II: Advancing
Ac

guideline development, reporting and evaluation in healthcare. Can Med Assoc J 2010;182:E839-42.

[9] Whiting P, Savovic J, Higgins JP, Caldwell DM, Reeves BC, Shea B, et al. ROBIS: a new tool to
assess risk of bias in systematic reviews was developed. J Clin Epidemiol 2016;69:225-34.

[10] Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.
[11] Daly MW, Seaton T, Moore N, Wang F, Ralko A, Bailey T. Medication adherence in Medicaid
patients with dyslipidemia. Pharmacotherapy 2010;30(10):419e.

[12] Dunbar-Jacob J, Sereika SM, Houze M, Luyster FS, Callan JA. Accuracy of measures of medication
adherence in a cholesterol-lowering regimen. West J Nurs Res 2012;34(5):578-97.

[13] Kruse W, Nikolaus T, Rampmaier J, Weber E, Schlierf G. Actual versus prescribed timing of
lovastatin doses assessed by electronic compliance monitoring. Eur J Clin Pharmacol 1993;45(3):211-
5.

[14] Ladova K, Matoulkova P, Zadak Z, Macek K, Vyroubal P, Vlcek J, et al. Self-reported adherence by

t
MARS-CZ reflects LDL cholesterol goal achievement among statin users: validation study in the Czech

ip
Republic. J Eval Clin Pract 2014;20(5):671-7.

cr
[15] Schwed A, Fallab CL, Burnier M, Waeber B, Kappenberger L, Burnand B, et al. Electronic

us
monitoring of compliance to lipid-lowering therapy in clinical practice. J Clin Pharmacol
1999;39(4):402-9.
an
[16] LaFleur J, McAdam-Marx C, White GL, Lyon JL, Oderda GM. Comparing medication adherence
methods in lipid-modifying therapy. J Pharm Technol 2012;28(2):58-67.
M

[17] Cheng CWR, Woo KS, Chan JCN, Tomlinson B, You JHS. Assessing adherence to statin therapy
ed

using patient report, pill count, and an electronic monitoring device. Am J Health Syst Pharm
2005;62(4):411-5.
pt

[18] Lee JK, Grace KA, Foster TG, Crawley MJ, Erowele GI, Sun HJ, et al. How should we measure
ce

medication adherence in clinical trials and practice? Ther Clin Risk Manag 2007;3(4):685-90.
Ac

[19] Nori AY, Ali MSAK, Ibrahim B, Awang R, Hassali MA. Modifying the morisky medication
adherence scale by adapting two items from the brief medication questionnaire to fit assessing the
overall adherence to polypharmacy regimen of cardiac patients. Glob Heart 2014;9(1 Suppl 1):e313.

[20] Baruel Okumura PC, Okumura LM, Reis WC, Godoy RR, Cata-Preta BO, de Souza TT, et al.
Comparing medication adherence tools scores and number of controlled diseases among low
literacy patients discharged from a Brazilian cardiology ward. Int J Clin Pharm 2016;38(6):1362-6.
[21] Shalansky SJ, Levy AR, Ignaszewski AP. Self-reported Morisky score for identifying nonadherence
with cardiovascular medications. Ann Pharmacother 2004;38(9):1363-8.

[22] Kripalani S, Risser J, Gatti ME, Jacobson TA. Development and evaluation of the Adherence to
Refills and Medications Scale (ARMS) among low-literacy patients with chronic disease. Value Health
2009;12(1):118-23.

[23] Zeller A, Ramseier E, Teagtmeyer A, Battegay E. Patients' self-reported adherence to

cardiovascular medication using electronic monitors as comparators. Hypertens Res
2008;31(11):2037-43.

t
[24] Raebel MA, Carroll NM, Ellis JL, Schroeder EB, Bayliss EA. Importance of including early

ip
nonadherence in estimations of medication adherence. Ann Pharmacother 2011;45(9):1053-60.

cr
[25] Scheiman-Elazary A, Shourt C, Hay MC, Furst D. A meta-analysis and systematic literature

us
review: effect of the method used to measure adherence in rheumatoid arthritis on its rate, and
evaluation of associated factors. Arthritis Rheum 2013;65:S76-S77.
an
[26] Perez-Escamilla B, Franco-Trigo L, Moullin JC, Martinez-Martinez F, Garcia-Corpas JP.
Identification of validated questionnaires to measure adherence to pharmacological
M

antihypertensive treatments. Patient Prefer Adherence 2015;9:569-78.

ed

[27] Clifford S, Perez-Nieves M, Skalicky AM, Reaney M, Coyne KS. A systematic literature review of
methodologies used to assess medication adherence in patients with diabetes. Curr Med Res Opin
2014;30(6):1071-85.
pt
ce

[28] Stolpe S, Kroes MA, Webb N, Wisniewski T. A systematic review of insulin adherence measures
in patients with diabetes. J Manag Care Spec Pharm 2016;22(11):1224-46.
Ac

[29] National Institute for Health and Care Excellence (NICE). Medicines adherence: involving
patients in decisions about prescribed medicines and supporting adherence. Clinical guideline [CG76]
[Internet]. London: National Institute for Health and Care Excellence, 2009 [accessed 28.3.17]
Available from: https://www.nice.org.uk/guidance/cg76

[30] National Institute for Health and Care Excellence (NICE). Medicines optimisation. Quality
standard [QS120] [Internet]. London: National Institute for Health and Care Excellence, 2016
[accessed 28.3.17] Available from: https://www.nice.org.uk/guidance/qs120
[31] Hutchins DS, Zeber JE, Roberts CS, Williams AF, Manias E, Peterson AM, et al. Initial medication
adherence-review and recommendations for good practices in outcomes research: an ISPOR
Medication Adherence and Persistence Special Interest Group report. Value Health 2015;18(5):690-
9.

[32] ReHOT Investigators, Krieger EM, Drager LF, Giorgi DM, Krieger JE, Pereira AC, et al. Resistant
hypertension optimal treatment trial: a randomized controlled trial.[Erratum appears in Clin Cardiol.
2014 Jun;37(6):388 Note: Multiple investigator names added]. Clin Cardiol 2014;37(1):1-6.

[33] Nau DP. Proportion of days covered (PDC) as a preferred method of measuring medication
adherence [Internet]. Alexandria, VA: Pharmacy Quality Alliance, 2015 [accessed 2.2.17] Available

t
from: http://pqaalliance.org/resources/adherence.asp

ip
cr
[34] University of Michigan Health System. Secondary prevention of ischemic heart disease and
stroke in adults. Ann Arbor, MI: University of Michigan Health System, 2009 Available from:

us
https://www.guideline.gov/summaries/summary/48221
an
[35] Gwadry-Sridhar FH, Manias E, Zhang Y, Roy A, Yu-Isenberg K, Hughes DA, et al. A framework for
planning and critiquing medication compliance and persistence research using prospective study
designs. Clin Ther 2009;31(2):421-35.
M

[36] Nordstrom BL, Simeone JC, Zhao Z, Molife C, McCollam PL, Ye X, et al. Adherence and
ed

persistence with prasugrel following acute coronary syndrome with percutaneous coronary
intervention. Am J Cardiovasc Drugs 2013;13(4):263-71.
pt

[37] Karter AJ, Parker MM, Moffet HH, Ahmed AT, Schmittdiel JA, Selby JV. New prescription
ce

medication gaps: a comprehensive measure of adherence to new prescriptions. Health Serv Res
2009;44(5, Pt1):1640-61.
Ac

[38] Vink NM, Klungel OH, Stolk RP, Denig P. Comparison of various measures for assessing
medication refill adherence using prescription data. Pharmacoepidemiol Drug Saf 2009;18(2):159-65.

[39] American Association for Thoracic Surgery, American College of Cardiology Foundation,
American College of Physicians, American Heart Association, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, et al. 2012
ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with
stable ischemic heart disease, 2012 Available from:
https://www.guideline.gov/summaries/summary/39380/
[40] Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European
Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the
European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical
Practice (constituted by representatives of 10 societies and by invited experts). Developed with the
special contribution of the European Association for Cardiovascular Prevention & Rehabilitation
(EACPR). Eur Heart J 2016;37(29):2315-81.

[41] Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS
Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37(39):2999-3058.

[42] Medicines and Healthcare products Regulatory Agency (MHRA). Welcome to The Clinical

t
Practice Research Datalink [Internet]. London: MHRA, 2017 [accessed 18.12.17]. Available from:

ip
https://www.cprd.com/Home/

cr
[43] Kela. Reimbursements of medicine expenses: Number of recipients and prescription data

us
(Kelasto statistical database) [Internet]. Finland: Kela, n.d. [accessed 18.12.17]. Available from:
http://raportit.kela.fi/ibi_apps/WFServlet?IBIF_ex=NIT137AL&YKIELI=E
an
[44] Folkehelseinstituttet (Norwegian Institute of Public Health). Welcome to the Norwegian
Prescription Database (NorPD) [Internet]. Oslo, Norway: Folkehelseinstituttet, March 2017 [accessed
M

18.12.17]. Available from: http://www.norpd.no/

ed

[45] Sundhedsdata-Styrelsen (Danish Health Data Authority). Medstat.dk [Internet]. Copenhagen,

Denmark: Sundhedsdata-Styrelsen, [accessed 18.12.17]. Available from: http://www.medstat.dk/en
pt

[46] Shi L, Liu J, Koleva Y, Fonseca V, Kalsekar A, Pawaskar M. Concordance of adherence

ce

measurement using self-reported adherence questionnaires and medication monitoring devices.

PharmacoEcon 2010;28(12):1097-107.
Ac

[47] Shea S, Misra D, Ehrlich MH, Field L, Francis CK. Correlates of nonadherence to hypertension
treatment in an inner-city minority population. Am J Public Health 1992;82(12):1607-12.

[48] Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported
measure of medication adherence. Med Care 1986;24(1):67-74.
[49] Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive validity of a medication adherence
measure for hypertension control. J Clin Hypertens 2008;10(5):348-54.

[50] Cea-Calvo L, Carmona L, Calvo-Alén J. The Challenge of Assessing Adherence to Subcutaneous

Biological Drugs in Immune-Mediated Inflammatory Diseases. Letter to the Editor Regarding
Michetti P, Weinman J, Mrowietz U, et al. Adv Ther (2017);34:91-108. doi:10.1007/s12325-016-
0441-3. Adv Ther 2017;34(9):2173-6.

[51] Pednekar P, Malmenas M, Ágh T, Bennett B, Peterson A, on behalf of the Leadership Members
of the Multiple Medication Adherence Measurement Working Group of the ISPOR Medication
Adherence and Persistence Special Interest Group. Measuring multiple medication adherence–which
measure when? Value & Outcomes Spotlight 2017;3(6):17-20.

t
ip
[52] Jimmy B, Jose J. Patient Medication Adherence: Measures in Daily Practice. Oman Med J

cr
2011;26(3):155-159.

us
[53] Helmy R, Zullig LL, Dunbar-Jacob J, Hughes DA, Vrijens B, Wilson IB, et al. ESPACOMP Medication
Adherence Reporting Guidelines (EMERGE): a reactive-Delphi study protocol. BMJ OPEN
2017;7(2):e013496.
an
M

[54] Ma Q, Kao C, Miles G, Chen G. Measurement of adherence to anti-hypertensive drugs in Asia.

Value Health 2016;19(7):A868.
ed
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 Table 1: Characteristics and risk of bias of reviewed studies
Study ID Disease/therapy/administration route No of criteria (Low/High/Unclear
risk of bias)
Prospective studies (Downs and Black tool)
Daly 201011 Hypercholesterolemia/statin/oral adminstration 2/2/12
12
Dunbar-Jacob Hypercholesterolemia/statin/oral adminstration 13/2/1
Kruse 199313 Hypercholesterolemia/statin/oral adminstration 10/6/0
Ladova 201414 Hypercholesterolemia/statin/oral adminstration 10/3/0
15
Schwed 1999 Hypercholesterolemia/statin/oral adminstration 14/2/0
Cheng 200517 Hypercholesterolemia/lipid lowering therapy/oral 10/6/0
adminstration
Lee 200718 Hypercholesterolemia/lipid lowering therapy/oral 12/2/2
adminstration
Nori 201419 Hypercholesterolemia and cardiovascular 1/3/12
disease/polypharmacy/multiple administration routes

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20
Okumura Hypercholesterolemia, hypertension and cardiovasular 14/2/0

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disease/polypharmacy/multiple administration routes
21
Shalansky 2004 Hypercholesterolemia, hypertension and 5/4/4

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cardiovascular disease/lipid lowering therapy and
angiotensin-converting enzyme inhibitors/oral
adminstration
Kripalani 200922 Hypercholesterolemia, hypertension and type 2

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diabetes/lipid lowering therapy, anti-hypertensives
and anti-diabetics/oral adminstration
11/2/2
an
23
Zeller 2008 Hypercholesterolemia, hypertension and type 2 10/5/1
diabetes/lipid lowering therapy, anti-hypertensives
and anti-diabeticsoral adminstration
M

38
Vink 2009 Type 2 diabetes with hypercholestermia and 12/4/0
hypertension/lipid lowering therapy, anti-
hypertensive, anti-diabetics/oral
37
ed

Karter 2009 Type 2 diabetes with hypercholestermia and 13/3/0

hypertension/lipid lowering therapy, anti-
hypertensive, anti-diabetics/oral adminstration
Retrospective studies
pt

LaFleur 201216 Hypercholesterolemia/statin/oral adminstration 14/2/0

Raebel 201124 Hypercholesterolemia, diabetes, hypertension/lipid 13/3/0
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lowering therapy, anti-hypertensives, anti-

diabetics/oral adminstration
Systematic reviews (ROBIS tool) Risk of bias for Domain 1 to 4
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Clifford 201427 Diabetes/multiple therapies/oral and subcutaneous Low/High/High/High

administration routes
28
Stolpe 2016 Diabetes/insulin/subcutaneous administration Low/High/Low/Low
Perez-Escamilla Hypertension/anti-hypertensives/administration route Low/Low/Low/Low
201526 not reported
54
Ma 2016 Hypertension/anti-hypertensives/administration route Unclear/High/Unclear/Unclear
not reported
Scheiman-Elazary Rheumatoid arthritis/disease-modifying antirheumatic Unclear/Unclear/Unclear/Unclear
201325 drugs/administration route not reported
Guidelines (Agree 2 tool)
Study ID Disease/therapy/administration route No of criteria (Low/High/Unclear
risk of bias)
Economics of Disease not specified High risk
Medication Methods for Integrating Medication Compliance and
Compliance Persistence in Pharmacoeconomic Evaluations32
Working Group
(ISPOR)

ISPOR Medication Disease not specified Low risk

Adherence and Initial Medication Adherence—Review and
Persistence Special Recommendations for Good Practices in Outcomes
Interest Group Research.31 Relates specifically to the measurement of
initial medication adherence.
ISPOR Medication Disease not specified Unclear risk
Adherence and Framework for planning and critiquing medication
Persistence Special compliance and persistence research.35

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Interest Group
National Institute Disease not specified Low risk
for Health and Medicines Optimisation Overview30

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Care Excellence Clinical Guideline (CG76)29
(NICE)
Pharmacy Quality
Alliance (PQA)
Disease not specified

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Endorsement of proportion of days covered (PDC) for
the measurement of medication adherence33
High risk
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University of Ischemic heart disease and stroke High risk
Michigan Guidelines for prevention of ischemic heart disease
(Michigan and stroke34
Medicine Clinical
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Practice
Guidelines)
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 Table 2: Summary of pros and cons for collection of persistence and adherence
MEDICAL RECORDS/PHARMACY RECORDS
Study design Pros (Accurate/Easy to Cons (Inaccurate/Difficult to Use/Expensive)
Use/Inexpensive)
Prospective Inaccurate: Pharmacy records reporting medication
refill history (as compared with 24hr patient recall
and pill counts) are inaccurate as they
are not sensitive to temporal changes in adherence
when carrying out longitudinal assessments18
Systematic review Accurate: Medical record review Inaccurate: Pharmacy claims data doesn’t account
(Retrospective) provide accurate prescribing and for wastage and stockpiling28
27
dosing information Prescription refill from pharmacy records is not
Pharmacy records are a reliable equivalent to medication ingestion27, 28
27
measure of adherence Documentation of prescribing and dosing from
Inexpensive: Pharmacy records are medical records is not equivalent to medication
inexpensive in comparison with other ingestion27

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27

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records Difficult to Use: Using pharmacy records makes it
difficult to differentiate overuse, early refills, changes
in drug regimens, polypharmacy, or multiple

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dispensing27
Medical record review is time consuming27

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Medical record review requires a closed pharmacy
system27
Guidelines/guidance Accurate: Pharmacy records of refills Inaccurate: Pharmacy data may be inaccurate if
an
are objective measures of adherence35 prescriptions redeemed ouside pharmacy network,
Pharmacy records of refills are well missing dispensing events recorded in medical
suited to the measurement of records31
35
persistence Electronic databases e.g. pharmacy records and
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claim databases may miss events (e.g. patient paying

Easy to Use: Pharmacy records are for cheaper generic medications with cash rather
practical and easily quantifiable35 than through their pharmacy benefit scheme)31
ed

Pharmacy prescription data may be artificially low if

prescriptions are redeemed out of the pharmacy
network, missing dispensing events from medical
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records31
Pharmacy records of refills are limited by the fact
that the smallest unit of measurement is governed
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by the frequency of each refill35

PILL COUNT/MEMS
Study design Pros (Accurate/Easy to Cons (Inaccurate/Difficult to Use/Expensive)
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Use/Inexpensive)
Prospective Accurate: Medication Electronic Inaccurate: Pill count17 and MEMS13 do not assess
Monitoring System (MEMS) has high actual ingestion
sensitivity (78.9%) and detects poor MEMs may underestimate number of doses actually
12
adherence taken if patients open bottle and forget to close in a
MEMS predicts cholesterol lowering correct timely manner 17
12
(OR 5.35, 95% CI: 1.72 to 16.62) Pill counts (18.4%) has low sensitivity and fails to
Pill counts more accurate compared to detect lack of cholesterol lowering with poor
refill history18 adherence in comparison with the Shea scale12
MEMS can improve patient behavior Pill counts do not correlate well with clinical
and management.23 outcome such as cholesterol lowering (sensitivity
 Easy to Use: Pill count (as compared was 18.4% and specificity was 89.1%) and other
with 24hr patient recall and pharmacy measures12
records - refill history) should be the Pill counts significantly overestimate adherence
standard for monitoring medication compared to MEMS13
adherence for both clinical trials and Expensive: MEMS devices do not justify the
clinical practice18 increased costs compared with standard practices23
MEMS is useful in comparison with pill
counts for chronopharmacological
studies13
MEMS can identify patterns of non-
adherence (drug holidays, omission,
multiple daily doses, etc.) which are
undetectable using pill count alone15
MEMS well accepted by patients in
comparison with pill counts15
Systematic review Accurate: MEMS tracks patterns of Inaccurate: Pill count and MEMS data can be easily

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altered by the patient (e.g. pill dumping)27

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(Prospective) taking medication; records time and
date medication bottle opened27 Pill count and MEMs can over estimate medication
Easy to Use: Widespread use possible adherence27

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with pill counts27 Pill count and MEMS does not capture timing and
Pill count similar to adherence dosage patterns27

measured by interview, questionnaires
and drug level monitoring25
Inexpensive: Pill count is inexpensive
compared to MEMS27
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MEMS records bottle opening which is not the same
as medication ingestion27
Difficult to Use: Pill count requires patient
cooperation27
MEMS cannot be used to monitor subcutaneous
administration27
Expensive: MEMS is expensive compared to pill

count27
Guidelines/guidance Accurate: Electronic Monitoring Inaccurate: Validity of EMS (e.g. MEMS) assumes
System (EMS) (e.g. MEMS) provide patients took medication as required; that natural
ed

detailed, comprehensive and objective adherence level and behaviour is not affected; that
data35 patients using the device are representative35
EMS (e.g. MEMS) have lower risk of
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confounding than other measurement

methods35
EMS (e.g. MEMS) overcome problem
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of pill discarding (compared with pill

counts) as patients required to open
container in compliance with
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prescribers schedule35
QUESTIONNAIRES
Study design Pros (Accurate/Easy to
Use/Inexpensive)
Prospective Accurate: Shea scale (OR 2.68, 95% CI:
1.06 to 6.78) predicts cholesterol
lowering12
Shea scale is sensitive (73.7%) when
screening for poor adherence12
Modified Morisky Medication
Adherence Scale (MMAS) is
Cons (Inaccurate/Difficult to Use/Expensive)
Inaccurate: 24hr patient recall inaccurate compared
to pill counts18
Shea scale does not give detail on patient medication
taking behaviours12
Self-report can overestimate adherence17, 23
Patients may be dishonest when using self-reported
measures23
 satisfactory when screening for poor
adherence to statins11
Low Adherence to Refills and
Medications Scale (ARMS) scores
significantly associated with diastolic
blood pressure control22
Compared with MMAS, ARMS
correlated more strongly with
measures of refill adherence22.
Easy to Use: Shea scale is preferred for
global or brief estimate of adherence
and less complex12
In comparison with the Brief
Medication Questionnaire (BMQ),
Modified Morisky Medication
Adherence Scale (mMMAS) is more
useful when assessing adherence in
polypharmacy19
ARMS is easy to use and is understood
by patients with low literacy22
Systematic review Accurate: Patient diaries are the only
(Prospective) self-report method providing
medication regimen data27
Easy to Use: Easy to administer patient
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reported questionnaires in various
ways (phone, mail, electronic patient
reported outcome, inperson)27
Widespread use of patient reported
M
questionnaires possible27
Patient reported questionnaires can
provide additional detail on dose
ed
taking behavior27
Scales can gather information on
reasons for nonadherence, e.g. MMAS-
pt
4/MMAS-828
Scales such as MMAS can focus on
generic adherence or range of self-care
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adherence behaviors27
Observer reporting is acceptable to
physicians27
Ac
Inexpensive: Questionnaires can be
inexpensive26, 27
BIOCHEMICAL MONITORING
Study design Pros (Accurate/Easy to
Use/Inexpensive)
Systematic review Accurate: HbA1c monitoring is an
(Prospective) objective measure and direct measure
of longer-term outcomes27
MMAS-8 did not significantly correlate with low
density lipoprotein cholesterol (LDL-C) goal
achievement14
MMAS is of limited clinical value in comparison with
pharmacy refill records for identifying non-
adherence with cardiovascular medications21
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Inaccurate: Patient reported questionnaires may not
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correlate well with clinically objective measures27
Patient diaries, observer reporting and patient
reported questionnaires may overestimate
adherence27
Self report adherence scales (e.g. MMAS) may lead
to overestimation of adherence, as the individuals
know they are being observed28
Patients may be dishonest when using self-report
measures such as MMAS28
Usefulness of data from patient questionnaires and
scales are questionnaire dependent27
None of the scales (MMAS; BMQ; Morisky-Green-
Levine Scale; Hill-Bone Compliance to High Blood
Pressure Therapy Scale; Treatment Adherence Scale
for Patients with Hypertension and Martín–Bayarre–
Grau scale) can be considered as a gold standard in
hypertensive patients26
Difficult to Use: Medication diaries can be time
consuming27
Scales (e.g. MMAS) can be complex to administer 28
Medication diaries are reliant on patient
cooperation to complete and return27
Expensive: MMAS can increase the cost of data
collection28
Cons (Inaccurate/Difficult to Use/Expensive)
Inaccurate:
Findings from glucose monitoring can be misleading
as may be influenced by other factors (e.g. diet,
 Easy to Use: Glucose monitoring is
simple method that is easy to use27
Continous glucose monitoring offers
real-time measurement; may enable
better glucose control27
Inexpensive: Glucose monitoring is
less costly27
* RCT reporting on the prospective use of pill counts versus the retrospective monitoring of
pharmacy records
activity, absorption etc.)27
HbA1c levels poorly correlated with other measures
of adherence, suggesting may be subject to bias27
Continuous glucose monitoring not as accurate and
reliable as standard blood glucose meters27)
Difficult to Use: HbA1c monitoring is a complex
method requiring blood collection and laboratory
testing27
Expensive: Expense of continuous glucose
monitoring and HbA1c monitoring prevents
widespread use27

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 Table 3: Summary of pros and cons for calculation of persistence and adherence

CALCULATION OF ADHERENCE
Study design Pros (Accurate/Easy to
Use/Inexpensive)
Retrospective Accurate: In comparison with
Continuous Medication Gap (CMG), New
Prescription Medication Gap (NPMG) is a
valid, comprehensive measure that can
be used in addition to existing metrics
and shows a significant relationship with
self-reported adherence and out-of-
pocket costs37
Systematic review Accurate: PDC avoids use of days supply
(Retrospective) in calculation which is a problem when
using Medication Possession Ratio MPR
Cons (Inaccurate/Difficult to Use/Expensive)
Inaccurate: Proportion of Days Covered (PDC)
overestimates adherence by 9-18% when primary
non-adherent and early non-persistent patients are
excluded24
NPMG overestimates total adherence as it ignores
primary non-adherence37
Inaccurate: Daily Average Consumption (DACON)
affected by wastage and stockpiling and relies on
days supply in calculation28

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with injectables28 MPR can overestimate adherence if patients refill

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PDC is endorsed by the Pharmacy prescriptions early28
Quality Alliance (PQA) as preferred Inter- and intrapersonal variability could confound

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method for measuring adherence28 the results of DACON in large datasets28
PDC is more accurate compared to other Adjustment factors used in Adjusted PDC
calculations are not standardised28

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methods when calculating adherence to
medication regimens28 Difficult to Use: PDC does not account for
PDC can be adjusted (i.e. adjusted PDC) differences in pack size28
to account for overlapping prescriptions, DACON has no validated threshold for good
an
days in hospital and prescriptions for adherence28
polypharmacy, and for type of
administration when interpreting data)28
M

Easy to Use: MPR is easy to use and

calculate28
Adjusted MPR is a flexible method which
ed

accounts for differences in pack sizes

and correct for prescriptions dispensed
with 30-day supply period28
DACON is easy to calculate28
pt

Guidelines/guidance Accurate: PDC is endorsed as the

preferred method for measuring
ce

adherence by the PQA33

CALCULATION OF PERSISTENCE
Study Design Pros (Accurate/Easy to Cons (Inaccurate/Difficult to Use/Expensive)
Ac

Use/Inexpensive)
Retrospective Accurate: For chronic care medications
such as statins with long-term data
available, persistence can be calculated
using a defined period for the
observation interval rather than the last
fill date16
Systematic review Inaccurate: Persistence does not indicate whether
(Retrospective) patient is adherent with clinicians’
recommendations and treatment regimen28
Difficult to Use: Persisence may not be appropriate
 for injectable medications due to variable-dose
titration schedules so a pre-defined treatment gap
is not suitable28
Persistence is affected by wastage and stockpiling
and relies on days supply in calculation28

Table 4: Subgroup data

MEDICAL RECORDS/PHARMACY RECORDS

Study design Pros (Accurate/Easy to use/Inexpensive) Cons (Inaccurate/Difficult to
use/Expensive)Cons
Systematic Difficult to Use: Pharmacy records are
review difficult to use where there are changes in

t
drug regimen, polypharmacy or multiple

ip
dispensing28
PILL COUNT (MEMS AND PILL COUNT)

cr
Systematic Easy to use: MEMS is easy to use as it can Difficult to Use: Medication electronic
review identify patterns of non-adherence in monitoring system (MEMS) cannot be
polypharmacy drug regimen which are used for subcutaneous administration27

us
15
undetectable using pill count alone.
QUESTIONNAIRES
Prospective Easy to use: Compared to the BMQ, mMMAS
an
is more useful when assessing adherence in
polypharmacy.19
RATIOS (MEDICATION POSSESSION RATIO [MPR], PATIENT DAYS COVERED [PDC], NEW PRESCRIPTION
M

MEDICATION GAP [NPMG])

Systematic Accurate: PDC avoids use of days supply in Difficult to Use: Pre-defined treatment
review calculation which is a problem when using gap may not be not suitable for measuring
MPR with injectables28
ed

persistence with injectables due to

PDC is a more accurate measure as it accounts variable-dose titration schedules28
for prescriptions with polypharmacy
regimens28
pt
ce
Ac
 Table 5: Summary of evidence for pros and cons of different collection and calculation methods
METHOD OF DATA PROS CONS
COLLECTION/CALCULATION
Accurate Easy to use Inexpensive Inaccurate Difficult to use Expensive
DATA COLLECTION METHODS

Pharmacy records -

Medical records - - -

Pill count - - -

MEMS - -

Questionnaires

t
Observer report - - - -

ip
Biochemical monitoring

cr
DATA CALCULATION METHODS
Medication Possession Ratio
- - -
(MPR)

us
Proportion of Days Covered
- - -
(PDC)
Adherence rate - - - - -
an
Persistence rate - - - -
M

Systematic Review Guideline Retrospective design Prospective design - No

information
ed
pt
ce
Ac
Figure 1: Study inclusion process according to PRISMA10

RECORDS RETRIEVED AND SCREENED

(TITLE/ABSTRACT SCREENING)

TOTAL: 4,158 records

EXCLUDED PAPERS
(TITLE/ABSTRACT
SCREENING)
TOTAL: 3990 records
excluded

t
ip
cr
FULL PAPERS ASSESSED
(FULL PAPER SCREENING)
TOTAL: 168 papers

us
an
EXCLUDED PAPERS
M

(FULL PAPER
SCREENING)
Not a relevant population: 21
ed

Not relevant comparison: 20

No relevant outcome: 44
No relevant study design: 41
Unobtainable: 10
pt

Duplicate: 1
Translations of adherence scales: 3
ce

TOTAL: 140 papers excluded

Ac

STUDIES MEETING INCLUSION CRITERIA

TOTAL: 28 papers
Observational studies (n=16)
Systematic review (n=5)
Guidelines and guidance documents (n=7)
Figure 2: Summary of findings

t
ip
cr
us
an
M
ed
pt
ce
Ac