2. Methods
2.1 Study design and data
source
We carried out a repeated cross-sectional study over five years
(2012-2016) to assess trends in polypharmacy and the prevalence of PIM
in patients with polypharmacy in the Netherlands. The data were obtained
from the University of Groningen community pharmacy database IADB.nl.
This database contains anonymized information of dispensed
prescriptions, including the Anatomical Therapeutic Chemical code (ATC
code) of the drug, the date of dispensing, the number of units
dispensed, and the prescribed daily dose. The IADB.nl does not include
information on medical conditions or on medication dispensed during
hospitalization. The IADB.nl has been validated and used for many
studies in the pharmacoepidemiology field [13,14]. Ethical approval
is not required for studies using anonymous data in The Netherlands.
2.3 Study
population
The study population consists of all adults known in the IADB.nl
database, aged 45 years or older in 1 January of each study year and
receiving at least two prescriptions for medication used for diabetes
treatment (ATC codes: [A10A, insulin and analogues] and/or A10B
[blood glucose lowering drugs, excluding insulin]) in the calendar
year, and with follow-up data for at least 12 months.
2.4 Polypharmacy
Definition
Polypharmacy was defined as the chronic use of at least five drugs
concurrently [15]. Chronic use was defined as a drug being dispensed
for at least 90 days or at least three times in a four-month period
between 1 September and 31 December in the study year. Given the
definition of the Dutch guideline [15], all drugs intended for
topical use, contrast media, radiopharmaceuticals, surgical dressings,
and general nutrients (ATC codes belonging to D, V, Y, Z), as well as
records with invalid ATC codes were excluded from the calculation of
polypharmacy prevalence. To determine the number of different drugs for
chronic use, the third level of the ATC code (ATC3), which describes
pharmacological subgroups, was used following the Dutch guideline on
polypharmacy [15]. This implies that dispensing of different
substances within the same pharmacological subgroup, e.g. beta-blocking
agents, are counted as one chronic drug.
2.5 Potentially inappropriate
medication (PIM) Criteria
We used the American Geriatrics Society (AGS) Beers 2015 criteria for
assessment of PIM for patients of 65 years and older [16], and the
PRescribing Optimally in Middle-aged People’s Treatments (PROMPT)
criteria for patients 45-64 years old [17]. We included only those
criteria for the assessment of a PIM that can be applied in a pharmacy
database without clinical information. Beers criteria consist of a list
of therapeutic classes and individual drug substances which should be
avoided in people aged 65 and older in most circumstances or with some
specified medical conditions [16]. The PROMPT criteria were in part
derived from the Beers criteria but in addition include criteria related
to drug-drug interactions [17]. Since such drug-drug interactions
are not included in Beers, we excluded them from our PIM assessment. In
total, 14 criteria from Beers and nine criteria from PROMPT were
excluded because: (a) they could not be assessed with information
available in the IADB database, (b) the drugs were not available on the
Dutch market during the study period, or (c) they concerned drug-drug
interactions. This resulted in a total of 15 PIMs for therapeutic
classes and 15 PIMs for individual drug substances from Beers and PROMPT
criteria that were used in our study (Figure 1). There were 24 PIMs from
Beers applied for patients of 65 years and older, and 13 PIMs from
PROMPT applied for patients between 45 and 64 years of age. In addition,
there were nine PIMs from PROMPT that were not part of the Beers
criteria, which we considered also of relevance for older patients. For
comparison, these nine PIMs were also applied for patients of 65 years
and older (Appendix Table 1).
2.6
Outcome
The primary outcome was polypharmacy prevalence per calendar year,
stratified by age (45-54 years, 55-64 years and ≥65 years). Secondary
outcomes were the prevalence of any PIM and the prevalence of the
individual PIMs in polypharmacy patients. For the outcome of any PIM,
patients were categorized as having no PIM or at least one PIM, using
the 24 PIM criteria from Beers, and the 13 PIM criteria from PROMPT.
2.7
Analysis
The prevalence of polypharmacy and PIM were assessed for each year and
expressed as percentages with 95% Confidence Intervals (CI).
Additionally, absolute differences in these prevalences over the study
period are presented. The prevalence of polypharmacy was calculated by
dividing the number of people with diabetes on polypharmacy (numerator)
by the total number of diabetes patients in each year (denominator). The
prevalence of PIM was calculated by dividing the number of people with
diabetes and polypharmacy who had at least one PIM by the total number
of people with diabetes and polypharmacy. Linear-by-linear association
with Chi-square analysis and regression analysis were used to test for
significant linear or quadratic trends of the prevalence rates.
Statistical significance was evaluated at the 2-sided α=0.05 level. All
statistical analyses were carried out using SPSS software (version 23.0;
IBM, Armonk, NY, USA).