Increased risk of incident dementia following use of anticholinergic agents: A systematic literature review and meta-analysis

Abstract

Background/rationale: Long-term treatment with anticholinergic agents may increase the risk of cognitive impairment or dementia. This systematic literature review and meta-analysis aimed to assess the impact of ≥3 months of exposure to anticholinergics as a class on the risk of dementia, mild cognitive impairment, and change in cognitive function. The impact of anticholinergic agents specifically used to treat overactive bladder was also evaluated.

Materials and methods: A systematic literature review was conducted to identify English language articles evaluating the impact of anticholinergic use for ≥3 months on dementia or cognitive function in adult patients. Databases searched included PubMed, Embase, and the Cochrane Library. Meta-analyses were conducted using random-effects models; 95% confidence intervals (CIs) and 95% prediction intervals (PIs) were reported.

Results: A total of 2122 records were identified. Out of those, 21 studies underwent qualitative synthesis and 6 reported endpoints relevant for inclusion in a meta-analysis assessing the risk of incident dementia. The overall rate ratio for incident dementia was 1.46 (95% CI: 1.17-1.81; 95% PI: 0.70-3.04; n = 6). The risk of incident dementia increased with increasing exposure (n = 3). In addition, two studies from the meta-analysis reported an increased risk of dementia with ≥3 months of use of bladder antimuscarinics (adjusted odds ratios ranged from 1.21 to 1.65, depending on exposure category).

Conclusion: Anticholinergic use for ≥3 months increased the risk of dementia on average by an estimated 46% versus nonuse. This relationship was consistent in studies assessing overactive bladder medications. The risk of developing dementia should be carefully considered in the context of potential benefit before prescribing anticholinergics.

Keywords: bladder antimuscarinics; cognitive dysfunction; cognitive impairment; incontinence; overactive bladder.

Figure 1

PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐Analyses

Figure 2

Forest plot of estimated rate ratios for the association between ≥3 months of anticholinergic use and incident dementia. The CI reflects a random error in estimating the mean but does not reflect the spread of the random‐effects distribution. The PI reflects heterogeneity and random estimation error and maybe informally interpreted as the interval within which we expect the true value estimated from a future study to lie. CI, confidence interval; PI, prediction interval; RR, rate ratio. *95% PI = 0.70–3.04

Figure 3

Stratified analysis and meta‐regression of three observational studies investigating the relationship between ≥3 months of anticholinergic use assessed by total standardized daily dose/defined daily dose and dementia. Daily dose indices were assumed to be equivalent. CI, confidence interval; DDD, defined daily doses, defined as the number of maintenance daily doses prescribed during the drug exposure period. The World Health Organization's (WHO) Collaborating Centre for Drug Statistics Methodology assigns daily dose values to drugs based on the average maintenance daily dose for the drug's primary indication in adult patients. ²⁹  RR, rate ratio; TSDD, total standardized daily doses, defined as the sum of standardized daily doses (tablet strength * number of dispensed tables divided by minimum recommended dose per day for older adults) from all anticholinergic pharmacy fills in the exposure assessment period. ⁸ , ¹³