Changes in the Prevalence of Polypharmacy in People with and without Dementia from 2000 to 2014: A Nationwide Study

Abstract

Background:

Polypharmacy, the use of multiple medications, has become increasingly widespread. Information on time trends in polypharmacy in people with dementia is limited, although they may be more susceptible to risks associated with polypharmacy.

Objective:

To examine changes in the prevalence of polypharmacy and excessive polypharmacy in people with dementia compared to changes in people without dementia.

Methods:

Repeated cross-sectional study of the entire Danish population aged≥65 from 2000 (n = 790,717) to 2014 (n = 1,028,377) using linked register data on diagnoses, filled prescriptions, and demographic data. Multivariate analyses were performed to explore changes in the prevalence of polypharmacy and excessive polypharmacy (≥5 and≥10 different prescription drugs). This was done before and after 2011 to examine whether increasing awareness of potential problems associated with polypharmacy has altered the trend. Estimates for people with and without dementia were compared.

Results:

In people with dementia, the prevalence of polypharmacy increased from 47.3% to 69.4% from 2000 to 2011 and excessive polypharmacy from 7.4% to 20.9%. In people without dementia, polypharmacy increased from 22.7% to 36.1% and excessive polypharmacy from 3.5% to 7.7%. The increase was significantly more marked in people with dementia across all age groups. From 2011 to 2014, the prevalence of polypharmacy and excessive polypharmacy remained relatively stable: Polypharmacy decreased negligibly from 69.4% to 68.1% in people with dementia and from 36.1% to 35.2% in people without dementia.

Conclusion:

Although the increasing trend has halted, polypharmacy remains widespread in people with dementia. Further research is needed to explore possible implications.

Keywords

Dementia inappropriate prescribing pharmacoepidemiology polypharmacy

INTRODUCTION

The use of multiple medications, often termed polypharmacy, is widespread in older people. While polypharmacy can be necessary for the management of multiple chronic conditions, it is also potentially problematic, particularly in people with dementia. Our knowledge of the added effects of several medications, chronic conditions, and pharmacokinetic and pharmacodynamic changes occurring in the aging body is limited as older people and the multimorbid are often excluded from drug trials [1, 2]. However, studies have found associations between polypharmacy and various negative health outcomes, including decreased functional status, increased frailty, higher risk of adverse drug events, and even mortality [3 –5]. The prevalence of multimorbidity and frailty is high in people with dementia which may render them more susceptible to such risks [6]. Furthermore, the decline in cognitive function can affect adherence and the ability to report adverse effects which further challenges patient safety [7].

Knowledge on time trends of polypharmacy and excessive polypharmacy in people with dementia is limited. However, studies of the general older population have reported increasingly widespread polypharmacy [8 –11]. In recent years, awareness of potentially inappropriate drug use in the older population (including polypharmacy) has increased [4]. Consequently, initiatives have been introduced to improve the pharmacological management of older people. Examples of such initiatives include tools for deprescribing and lists of ‘potentially inappropriate medication’— medication to avoid in older people as risks associated with the use of these drugs outweigh potential benefits [12, 13]. In Denmark, examples of such initiatives include guidelines on medication review, and the Red-yellow-green list, a list of potentially inappropriate medication tailored toward use in Denmark, published in 2011 by the Institute of Rational Pharmacotherapy a part of the Danish health authorities [14].

The universal health coverage in Denmark facilitates linkage of information across nationwide registers which allows us to examine the entire older population and identify individuals with dementia and examine their use of prescription medication [15]. The primary aim of the study was to improve the understanding of the development of polypharmacy in people with dementia to guide new initiatives to improve the care of people with dementia. To this end, changes in the prevalence of polypharmacy and excessive polypharmacy in older people with dementia as compared to the general older population were examined from 2000 to 2014, by comparing data at different time points. Our hypothesis was that the prevalence of polypharmacy and excessive polypharmacy had increased in older people with dementia to a greater extent than in the general older population, possibly with improvements in recent years due to increased awareness of the risks associated with polypharmacy in older people; particularly around 2011 where a range of initiatives were launched by the Danish authorities.

MATERIALS AND METHODS

The registers

In Denmark, all residents are assigned a personal identification number (CPR number). The CPR number facilitates linkage of information across multiple registers on an individual level. This study used data from the Danish Civil Registration System, the Danish National Patient Register, the Danish Psychiatric Central Research Register, and the Danish National Prescription Registry [16 –18]. The Danish Civil Registration System includes basic sociodemographic information, including marital status, age, and sex. Information on all hospital admissions, discharges, and invasive procedures since 1977 is available in the Danish National Patient Register. Additionally, data on hospital-based outpatient clinic and emergency department contacts are available from 1995. The Danish Psychiatric Central Research Register contains data on all admissions to psychiatric hospitals since 1969 and all outpatient contacts since 1995, including data on discharge diagnoses [16]. Diagnosis codes are registered by use of the International Classification of Diseases (ICD) codes [19]. The Danish National Prescription Registry contains information on all dispensed prescription medication since 1995 including data on dispensing date, strength, and package size. Medication is classified according to the Anatomical Therapeutic Chemical (ATC) classification system [20]. Information on nursing home residency was provided by Statistics Denmark, however, this information was only available from 2008 and onwards.

This study was approved by the Danish Data Protection Agency (ID no: 2007-58-0015/30-0667), Statistics Denmark, and the Danish Health and Medicine Authority (ID no: 6-8011-907/1). Danish law did not require ethics committee approval or informed patient consent.

Measures of medication utilization

The number of different drugs used within a three-month period has previously been verified as a valid estimate of the number of drugs used concomitantly [21]. Consequently, polypharmacy was defined as filling prescriptions for≥5 different drugs and excessive polypharmacy as filling prescriptions for≥10 drugs on the substance level (ATC5) within the second quarter of each year. The second quarter was chosen to avoid potential irregularities in medication sales at the end of and the beginning of the year due to the Danish reimbursement system. In a sensitivity analysis, anti-dementia medication (N06D) was excluded when counting polypharmacy and excessive polypharmacy.

The most frequently used drug groups in 2000 and 2014 were examined in people with and without dementia to map changes in medication utilization. Drug groups were assessed on ATC level 3 (example N06A: antidepressants).

To explore the possibility that increasing awareness of potentially harmful effects of polypharmacy in older people could have influenced the change over time in the later years of the study period, the change in prevalence before and after 2011 were examined separately. The change in attitude and possible effects must be considered a gradual development; however, 2011 was chosen as a cut-off as this marked the year of several initiatives to improve drug utilization in the older population and in general in Denmark [22]. Furthermore, the red-yellow-green list, a Danish counterpart to lists of potentially inappropriate medication such as the Beers Criteria but applicable to the Danish setting, from the Institute of Rational Pharmacotherapy, part of the Danish Health Authority, was first published in 2011 [14]. The list contains information on 43 drugs or drug groups to avoid (red), use with caution (yellow), and drugs where evidence on long-term effects are still limited (green) in people aged 65 or above.

Study population

The study population included all residents in Denmark aged 65 or above, community-dwelling as well as nursing home residents. As polypharmacy was examined in the second quarter of each year, the study population was defined on April 1 (the index date) of each year from 2000 to 2014 and included everyone aged 65 or above on that date. Individuals who died before the end of the second quarter were excluded to avoid including people who did not fill prescriptions because they had died early in the study period. Dementia patients were identified as individuals who had received a dementia diagnosis at hospital discharge or at in-/outpatient visits (specific diagnosis codes available in Supplementary Material 1) or as individuals who had filled prescriptions for anti-dementia medication (N06D) before the index date. Individuals who had received a dementia diagnosis or filled their first prescription for anti-dementia medication before the age of 60 were excluded due to the low validity of diagnosis at a young age [23]. Time since dementia diagnosis and information on nursing home residency (available from 2008 and onwards) is presented in Table 1.

Table 1

Characteristics of the population in 2000, 2011, and 2014 stratified by dementia diagnosis

	2000		2011		2014
	No-dementia N = 770,294	Dementia N = 18,467	No-dementia N = 904,864	Dementia N = 33,038	No-dementia N = 992,141	Dementia N = 33,870
Age	74.2 (69.3–80.1)	82.0 (77.0–86.9)	72.7 (68.2–79.1)	83.1 (77.5–87.9)	72.5 (68.5–78.7)	83.0 (77.3–88.0)
Sex (female)	446,743 (58.0)	12,500 (67.7)	496,683 (54.9)	21,563 (65.3)	538,353 (54.3)	21,603 (63.8)
Married	383,431 (50.6)	5,761 (31.2)	508,964 (56.8)	11,171 (33.8)	572,892 (58.1)	12,066 (35.6)
Time since diagnosis (y)	NA	2.0 (0.9–4.1)	NA	2.6 (1.2–5.0)	NA	2.9 (1.3–5.2)
Nursing home	NA	NA	26,763 (3.0)	16,361 (49.5)	26,941 (2.7)	17,464 (51.6)
CCI score
0	478,969 (62.2)	8,416 (45.6)*	478,191 (52.9)	11,774 (35.6)*	507,150 (51.1)	11,527 (34.0)*
1	135,713 (17.6)	4,784 (25.9)*	165,800 (18.3)	7,931 (24.0)*	179,467 (18.1)	7,945 (23.5)*
2	92,456 (12.0)	2,760 (15.0)*	132,933 (14.7)	5,857 (17.7)*	152,705 (15.4)	6,060 (17.9)*
≥3	63,156 (8.2)	2,507 (13.6)*	127,940 (14.1)	7,476 (22.6)*	152,819 (15.4)	8,338 (24.6)*
Cardiovascular disease	146,567 (19.0)	6,661 (36.1)	205,218 (22.7)	13,722 (41.5)	226,758 (22.9)	13.899 (41.0)
Pulmonary disease	51,032 (6.6)	1,384 (7.5)	82,239 (9.1)	3,799 (11.5)	95,217 (9.6)	4,234 (12.5)
Any tumor	83,127 (10.8)	2,090 (11.3)	145,494 (16.1)	5,861 (17.7)	176,169 (17.8)	6,775 (20.0)
Diabetes	33,498 (4.4)	1,325 (7.2)	68,488 (7.6)	3,785 (11.5)	81,861 (8.3)	4,195 (12.4)

NA, not applicable; CCI score, Charlson Comorbidity Index score. NOTE: numbers are given as n (%) and median (25–75% interquartile range) as appropriate. *Charlson Comorbidity Index score calculated without dementia as one of the items.

Comorbidity

Comorbidity was assessed using the Charlson Comorbidity Index and was evaluated based on registered diagnosis codes of 19 chronic somatic diseases (diagnosis codes available in Supplementary Material 2) [24]. Dementia was excluded from the Charlson Comorbidity Index. All covariates were evaluated on April 1 of each year. The items on the Charlson Comorbidity Index were grouped into categories where relevant (for example cardiovascular disease: myocardial infarct, congestive heart failure, peripheral vascular disease, and cerebrovascular disease) and the most frequent groups were presented (Table 1) to show the comorbidity profiles of people with and without dementia.

Statistics

Characteristics of the study population were examined in 2000, 2011, and 2014. Normality of the data was examined graphically. Continuous data are expressed by medians and 25–75 percentiles as data were not normally distributed. Proportions are presented as percentages with 95% confidence intervals. The prevalence of polypharmacy and excessive polypharmacy in people with and without dementia were calculated for each year from 2000 to 2014. Furthermore, changes in drug utilization were examined by comparing the use of widespread pharmacological subgroups in 2000 and 2014 in people with and without dementia (ATC level 3).

Changes in the prevalence of polypharmacy and excessive polypharmacy were examined separately for two time periods. This was done exploratively, to examine whether the trend had changed in the later years of the study period. The year 2011 was chosen as this marked the year of nationwide initiatives to improve pharmacological management of older people in Denmark. To examine the trend of change before and after 2011, logistic regression analyses were performed comparing the odds of polypharmacy in 2011 versus 2000 and 2014 versus 2011 for people with and without dementia. To achieve the necessary independent observations, people were stratified into age groups at intervals corresponding to the period examined. Therefore, 11-year age (e.g., 65–75, 76–86, etc.) groups when examining the odds of polypharmacy in 2011 versus 2000 and 3-year age groups (e.g., 65–67, 68–70, etc.) when examining the difference between 2014 and 2011. This ensured that an individual was only included once in each age group. First, a crude analysis was conducted with no adjustment for covariates. Second, a multivariate analysis was conducted with adjustments for age and sex. Third, the Charlson Comorbidity Index score was added to the multivariate model as a supplemental sensitivity analysis.

People aged≥98 were excluded from the logistic regression due to the small size of this group. To determine whether the change in the prevalence of polypharmacy and excessive polypharmacy differed between people with and without dementia, a method described by Bland and Altman was used to test whether there were statistically significant differences between the odds ratios obtained in the logistic regression for people with and without dementia in corresponding age groups [25]. Joined multivariate analyses including an indicator for dementia, calendar year (for example 2011 versus 2000), and the interaction between year and dementia, were conducted to assess the statistical significance of the interaction. Odds ratios were accompanied by 95% confidence intervals. A p-value < 0.05 was considered statistically significant. Data analysis was performed using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC, USA).

RESULTS

Study population

A description of the selection of the population aged≥65 in 2000, 2011, and 2014 is available in Supplementary Material 3. On April 1, 2000, 18,467 people with dementia and 770,294 without dementia were included. In 2014, the number of people with dementia had increased to 33,870 and the group without dementia to 992,141. Table 1 presents the characteristics of the population in 2000, 2011, and 2014. People with dementia were older in 2014 than in 2000, while the opposite was true for people without dementia. Comorbidity scores increased from 2000 to 2014 in both groups.

Changes in polypharmacy from 2000 to 2011

Figure 1 displays the annual prevalence of polypharmacy and excessive polypharmacy in people with and without dementia. In people with dementia, the prevalence of polypharmacy increased from 47.3% [46.5–48.0] in 2000 to 69.4% [68.9–69.9] in 2011 and the prevalence of excessive polypharmacy almost tripled from 7.4% [7.0–7.7] to 20.9% [20.5–21.4]. In people without dementia, the prevalence of polypharmacy increased from 22.7% [22.6–22.8] to 36.1% [36.0–36.2] and excessive polypharmacy from 3.5% [3.4–3.5] to 7.7% [7.6–7.7] in the same period.

Fig.1

Annual prevalence of polypharmacy (use of≥5 different drugs) and excessive polypharmacy (use of≥10 different drugs) in people aged≥65 from 2000 to 2014 with and without dementia.

Figure 2 presents the results of the multivariate analysis. The increase in polypharmacy and excessive polypharmacy from 2000 to 2011 was significant across all age groups in people with and without dementia. Results from the multivariate analysis are shown in Table 2. Furthermore, the increase was larger for excessive polypharmacy than polypharmacy and more pronounced in the older age groups (Fig. 2). The largest increase was found in the prevalence of excessive polypharmacy in people with dementia aged 87–97 for whom excessive polypharmacy was 4 times more likely in 2011 compared to 2000 after adjustments for age and sex (adjusted odds ratio: 4.09 [3.58–4.68]) (Table 2). The increase was generally less pronounced for polypharmacy than excessive polypharmacy. Furthermore, there was a trend toward a smaller increase in the younger age groups: as an example, the odds ratio for polypharmacy in 2011 compared to 2000 in people without dementia aged 65–75 was 2.05 [2.03–2.07] (Table 2). The method by Bland and Altman to assess the difference between two estimates was used to calculate relative odds ratios to compare the change in polypharmacy and excessive polypharmacy in people with dementia to the change in people without dementia. This revealed that the increase in the prevalence of polypharmacy and excessive polypharmacy from 2000 to 2011 was significantly larger for people with dementia compared to people without dementia in all age-groups (Table 2). The interactions between calendar year and dementia were significant for all age groups in the joined analyses, further supporting that the development in polypharmacy and excessive polypharmacy from 2000 to 2011 was different for people with and without dementia.

Fig.2

Changes in polypharmacy and excessive polypharmacy prevalence from 2000–2011. The figure displays results of the logistic regression analysis comparing polypharmacy (A) and excessive polypharmacy (B) prevalence in people with (black) and without (gray) dementia in 2011 versus 2000 (reference), displaying adjusted odds ratios (ORs) and 95% confidence intervals (CI). Odds ratios were adjusted for age and sex.

Table 2

Multivariate logistic regression examining changes in the prevalence of polypharmacy (use of≥5 different drugs) and excessive polypharmacy (use of≥10 different drugs) in people aged≥65 with and without dementia from 2000 to 2014. Odds ratios with 95% confidence intervals are displayed. To obtain independent observations, 2000 to 2011 was examined in 11-year age groups and 2011 to 2014 was examined in 3-year age groups. The methods described by Bland and Altman was used to calculate relative odds ratios to compare the changes in people with and without dementia

		Polypharmacy			Excessive polypharmacy
	Age group	No-dementia Adjusted* OR	Dementia	Relative Adjusted* OR	p	No-dementia Adjusted* OR	Dementia Adjusted* OR	Relative OR	p
2000 versus 2011	65–75	2.05 [2.03–2.07]	2.30 [2.12–2.50]	1.13 [1.04–1.22]	0.005	2.23 [2.18–2.28]	3.03 [2.65–3.45]	1.36 [1.19–1.55]	<0.001
	76–86	2.26 [2.23–2.28]	2.57 [2.44–2.70]	1.14 [1.08–1.20]	<0.001	2.69 [2.63–2.75]	3.25 [2.99–3.52]	1.21 [1.11–1.31]	<0.001
	87–97	2.15 [2.10–2.20]	2.66 [2.47–2.86]	1.24 [1.14–1.34]	<0.001	2.87 [2.75–3.00]	4.09 [3.58–4.68]	1.42 [1.24–1.64]	<0.001
2011 versus 2014	65–67	0.98 [0.96–0.99]	0.88 [0.74–1.06]	0.90 [0.75–1.08]	0.271	0.94 [0.92–0.97]	0.83 [0.66–1.05]	0.88 [0.69–1.12]	0.294
	68–70	0.97 [0.96–0.99]	0.85 [0.74–0.98]	0.87 [0.76–1.01]	0.059	0.96 [0.93–0.99]	0.90 [0.75–1.08]	0.93 [0.78–1.12]	0.465
	71–73	0.94 [0.92–0.95]	0.89 [0.79–1.01]	0.95 [0.84–1.08]	0.441	0.89 [0.86–0.92]	0.82 [0.70–0.95]	0.92 [0.79–1.07]	0.254
	74–76	0.94 [0.92–0.95]	0.88 [0.80–0.98]	0.95 [0.85–1.05]	0.298	0.89 [0.86–0.91]	0.90 [0.80–1.02]	1.02 [0.90–1.16]	0.779
	77–79	0.95 [0.93–0.97]	0.94 [0.86–1.03]	0.99 [0.90–1.09]	0.897	0.89 [0.86–0.92]	0.97 [0.87–1.08]	1.09 [0.97–1.22]	0.134
	80–82	1.00 [0.98–1.02]	0.94 [0.86–1.03]	0.94 [0.85–1.04]	0.208	0.93 [0.90–0.96]	0.83 [0.75–0.92]	0.90 [0.80–1.00]	0.048
	83–85	0.98 [0.96–1.01]	1.02 [0.94–1.11]	1.04 [0.95–1.14]	0.390	0.92 [0.88–0.95]	0.99 [0.90–1.08]	1.08 [0.97–1.19]	0.150
	86–88	0.98 [0.96–1.01]	0.99 [0.90–1.08]	1.00 [0.91–1.10]	0.928	0.93 [0.89–0.97]	0.92 [0.83–1.01]	0.99 [0.89–1.10]	0.857
	89–91	1.01 [0.97–1.04]	1.00 [0.91–1.11]	1.00 [0.90–1.11]	0.968	0.93 [0.88–0.98]	0.95 [0.85–1.06]	1.02 [0.90–1.16]	0.711
	92–94	1.00 [0.95–1.05]	0.95 [0.83–1.08]	0.95 [0.82–1.10]	0.497	0.98 [0.91–1.05]	0.89 [0.76–1.05]	0.91 [0.76–1.08]	0.285
	95–97	1.01 [0.93–1.09]	1.05 [0.85–1.31]	1.04 [0.83–1.32]	0.711	0.96 [0.85–1.07]	0.77 [0.59–1.01]	0.81 [0.60–1.08]	0.147

*Adjusted for age and sex. OR, Odds ratio.

Sensitivity analysis: Anti-dementia medication excluded

Excluding anti-dementia medication did not change our findings significantly (data not shown). However, there was a trend toward a decrease: as an example, the odds ratio for excessive polypharmacy in 2011 versus 2000 for the group aged 87–97 decreased from 4.09 [3.58–4.68] to 3.57 [3.12–4.09] after excluding anti-dementia medication. The method for comparing two estimates revealed that after the exclusion of anti-dementia medication, the difference between the increase in polypharmacy and excessive polypharmacy in people with dementia compared to people without dementia was not as clear: The increase in the prevalence of excessive polypharmacy was still larger for people with dementia compared to people without dementia in those aged 65–75 (dementia versus non-dementia relative OR: 1.25 [1.09–1.43], p = 0.001) and 87–97 (dementia versus non-dementia relative OR: 1.24 [1.08–1.43], p = 0.003). For polypharmacy, however, the increase was slightly larger for people without dementia compared to people with dementia in those aged 76–86 (dementia versus non-dementia relative OR: 0.93 [0.88–0.98], p = 0.004), while the difference was not significant in the remaining age groups.

Sensitivity analysis: Comorbidity added to the multivariate analysis

Adding the Charlson Comorbidity Index score to the multivariate analysis did not change our findings significantly. There was a trend toward a slightly less pronounced increase in both polypharmacy and excessive polypharmacy in people with and without dementia (data available in Supplementary Material 4). Additionally, there was a trend towards a larger difference between the increase in people with dementia compared to people without dementia (Supplementary Material 4).

Changes in polypharmacy from 2011 to 2014

As seen in Fig. 1, the prevalence of polypharmacy and excessive polypharmacy reached its peak in 2011 and subsequently remained relatively stable from 2011 to 2014. In people with dementia, the prevalence of polypharmacy was 69.4% [68.9–69.9] in 2011 and 68.1% [67.6–68.6] in 2014 and the prevalence of excessive polypharmacy 20.9% [20.5–21.4] in 2011 and 19.3% [18.9–19.7] in 2014. The change in prevalence was similar in people without dementia (polypharmacy: 36.1% [36.0–36.2] to 35.2% [35.1–35.3]; excessive polypharmacy 7.7% [7.6–7.7] to 7.0% [7.0–7.1]). The difference between the odds of polypharmacy and excessive polypharmacy in 2011 and 2014 was largely insignificant in both groups; however, there was a slight trend towards a decrease in both groups (Table 2).

Differences in drug utilization

In people with dementia, the proportion filling at least one prescription for anti-dementia medication in the 2nd quarter of the year increased drastically from 9.2% in 2000 to 44.0% in 2014. The use of lipid-modifying agents (C10A) also increased (dementia: 0.8% to 26.7%; no-dementia: 3.0% to 27.2%). There was a decrease in the proportion of people with and without dementia filling prescriptions for anxiolytics (N05B) (dementia 19.0% -5.7%; no-dementia: 9.4–3.6%), and hypnotics/sedatives (N05C) (dementia: 14.3–7.1%; no-dementia: 11.7–6.4%). Furthermore, in people with dementia, there was a marked decrease in the use of antipsychotics (N05A) (24.1–14.4%). There was also a decrease from 10.4% in 2000 to 5.8% in 2014 in the proportion of people with dementia filling prescriptions for NSAIDs (M01A). In people without dementia, the decrease in the use of NSAIDs was less marked (9.7–8.4%).

DISCUSSION

To our knowledge, this is the first nationwide study to examine changes in the prevalence in polypharmacy (the use of 5 or more different drugs) and excessive polypharmacy (the use of ten or more different drugs) in people with dementia. From 2000 to 2011, in line with our hypothesis, there was a significant increase in the prevalence of polypharmacy and excessive polypharmacy in people with dementia across all age groups: the prevalence of polypharmacy increased from 47.3% to 69.4% and excessive polypharmacy almost tripled from 7.4% to 20.5%. After 2011, a plateau was reached, but the prevalence of polypharmacy and excessive polypharmacy remained high.

In our study, a significant increase in the prevalence of polypharmacy and excessive polypharmacy was observed in people with dementia from 2000 to 2011. Though no studies have examined the change in prevalence over time in people with dementia, the few existing studies that have reported a point-prevalence support this finding. Studies based on older data generally report a lower prevalence of polypharmacy than studies based on more recent data [6 , 26–28]: the prevalence of polypharmacy was 43% based on data from 2000–2002 in France [26], 57% based on data from 2007 in the UK [6], and 81.5% based on 2013-data in Northern Ireland [28]. However, while in line with our findings, this apparent increase could also be caused by diverse national settings, study periods, and definitions of polypharmacy. For instance, the recent study from Northern Ireland reported a rather high prevalence of polypharmacy. However, this could be attributed to their definition of polypharmacy as the use of 4 or more repeat prescriptions within a year [28]. In contrast, the French study based on data collected between 2000 and 2002, reported a lower prevalence. One explanation could be that they examined a selected population as they excluded patients with severe Alzheimer’s disease, institutionalized individuals, and those with a concomitant disorder that could affect the short-term prognosis were excluded [26].

The increase observed from 2000 to 2011 in our study is similar to published results on the time trend in polypharmacy in the general older population [10, 29]. In 2011, the prevalence of polypharmacy and excessive polypharmacy in people with and without dementia peaked and subsequently remained stable in our study. Only three time trend studies of polypharmacy cover the period after 2010 [11 , 30], and none of these studied the trend in people with dementia: Nishtala et al. examined the time trend from 2005 to 2013 in the general older population: Similar to our findings in people with dementia and the general older population, they noted a small drop in the use of 10 or more drugs (in their study referred to as ‘hyperpolypharmacy’) in the last year of the study [11].

There are several factors which may explain the increasing prevalence of polypharmacy and excessive polypharmacy across all age groups in the older population: the introduction of new treatments, including increasing use of long-term preventive treatments, and increasing comorbidity [31, 32]. The same explanations probably apply to the increasing polypharmacy observed in people with dementia in our study. However, we observed a greater increase in polypharmacy, and even more markedly in excessive polypharmacy, in people with dementia as compared to people without dementia in the period 2000 to 2011. Two recent studies have examined longitudinal changes in polypharmacy following diagnosis of dementia and found polypharmacy to increase in the first years following dementia diagnosis [33, 34]. Our findings suggest this trend could have increased in recent years, explaining why polypharmacy and excessive polypharmacy have increased more in people with dementia compared to people without dementia from 2000 to 2011. In a sensitivity analysis, adjustments were made for the increasing comorbidity scores observed in Table 1, to see whether this could explain either some of the increase in polypharmacy in both groups or the relatively larger increase in people with dementia when compared to people without dementia. The changes were insignificant and thus, increasing comorbidity as documented/detected during hospital contacts does not seem to be the explanation for the increase observed in polypharmacy. As evident from the sensitivity analysis where anti-dementia medication was excluded, much of the difference between the increase in polypharmacy and excessive polypharmacy in people with dementia compared to people without dementia is likely due to the introduction of anti-dementia medication. On the one hand, the increasing polypharmacy observed in the first part of the study period could reflect more focus on treatment and management of older people, including people with dementia: However, these rates could also be considered a cause for concern— particularly in people with dementia who are more frail and comorbid, possibly rendering them even more susceptible to the risks associated with polypharmacy [6, 35]. In our study polypharmacy and excessive polypharmacy peaked in 2011, hereafter the increasing trend halted in both people with and without dementia, which illustrates the possible effect of the increasing awareness of potential hazards associated with pharmacological management of older people. The increasing awareness has resulted in several initiatives to improve prescribing practice. As an example, several explicit quality indicators have been published worldwide to help guide prescribers avoid treatments that could cause harm in older patients [36, 37]. In Denmark, the red-yellow-green list was published in 2011 [14]: Not all the explicit quality indicators, including the red-yellow-green list, contain polypharmacy as an indicator. However, due to the close association between the use of potentially inappropriate medication and polypharmacy, it seems probable that initiatives to improve one would influence the other [38]. Additionally, in recent years, experts have pointed out the need for regular re-assessment of treatment schemes and guidelines to promote the holistic treatment of multimorbid older patients rather than guidelines focusing on single conditions [39, 40]. The halt in the increasing trend observed in this study could be an indication that initiatives to improve the pharmacological management of older people, including people with dementia, have had the intended effect. While a halt in the increasing trend is favorable, the prevalence remains high, especially in people with dementia, which calls for further efforts to enhance the safety of drug therapy in people with dementia. Furthermore, research is needed on the effects and risks of polypharmacy and excessive polypharmacy in people with dementia to support decision-making for clinicians as well as policymakers.

Though inconsistent, there was a small trend toward a decrease in the prevalence of polypharmacy and excessive polypharmacy in people with dementia after 2011. Contrarily, in people without dementia, though comparably small, the decrease was significant, possibly because each age group contained far more individuals. Consequently, continued monitoring is needed to investigate whether this implies the commencement of a slight decreasing trend in the prevalence of polypharmacy and excessive polypharmacy in people with and without dementia.

A major strength of the study is the use of nationwide registers, which allowed us to follow the development of polypharmacy specifically in people with dementia. Furthermore, the registers allow us to examine drug use in the entire older population irrespective of living situation, and therefore, the study population includes both nursing home residents and community-dwelling older people.

The study has several limitations: First, although the study was based on valid information on all filled prescriptions, we cannot know whether the medication was consumed. Furthermore, we have no information on the use of over-the-counter drugs. Second, even though the validity of a dementia diagnosis in the Danish registers has previously proven to be high, dementia is underdiagnosed in our registers [41]: In a report from 2003, it was estimated that 42–78% of dementia cases are documented in the hospital registers [42]. Consequently, we also included people who had filled a prescription for anti-dementia medication. Unavoidably, however, the group without dementia must still be assumed to contain a small but unknown number of dementia cases. Additionally, changes in the practice of diagnosing dementia and prescribing anti-dementia medication over the course of the study period could have led to a change in the composition of this group.

People diagnosed with dementia or filling their first prescription for anti-dementia medication before the age of 60 were excluded from this study as a previous study found a low validity of registered dementia diagnoses in younger age groups [23]. Consequently, our results do not cover the small group of people diagnosed with dementia at an early age.

We adjusted for comorbidity in a separate model to examine whether changes over time in the comorbidity profiles of each group could explain the more pronounced increase in polypharmacy and excessive polypharmacy in people with dementia when compared to people without dementia. However, changes in diagnosing practice and increased incitement to diagnose people due to new available treatments and new diagnostic tools could also explain the increasing comorbidity scores observed in both groups from 2000 to 2014 as shown in Table 1. It is therefore unclear whether an increase in comorbidity score reflects an actual increase in comorbidity burden. Furthermore, comorbidity and polypharmacy are too intertwined cause-and-effect-wise to consider comorbidity a real confounder, and therefore, results should be interpreted with care.

We chose to exclude people who died within the counting period as to avoid the possible bias of people not filling in prescriptions because they had died early in the counting period. However, this could have resulted in a survival bias as the results only reflect the use of medication among people who survive at least 3 months following the index date.

The peak and subsequent plateau of polypharmacy observed in our study imply a possible change in the previously ever-increasing prevalence. However, our study design does not allow for conclusions as to the effect of any specific interventions.

In this, the first nationwide study of changes in polypharmacy prevalence in people with dementia, the prevalence of polypharmacy and excessive polypharmacy increased from 2000 to 2011 and more in people with dementia compared to people without dementia. After 2011, the previously increasing trend stopped, which could be the result of the increased focus on appropriate drug therapy in older people in recent years. However, the prevalence remains high, especially in people with dementia, which potentially challenges patient-safety. Research on the consequences of polypharmacy is needed specifically for people with dementia to support prescribers in securing the appropriate care and avoiding potentially harmful treatments.

Footnotes

ACKNOWLEDGMENTS

The Danish Dementia Research Centre is supported by grants from the Danish Ministry of Health (file no. 2007-12143-112/59506, file no. 1604063, and file no. 0901110/34501).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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