Anticholinergic burden and adverse outcomes in dementia

AUSTRALIA, like many countries around the world, has an ageing population. This ageing population brings additional complexities in managing their health.

Older people are more likely to experience multimorbidity than younger people, and more than a third of older adults are taking five or more medications. Health professionals are required to consider not only the potential impact of the individual medications they prescribe, but the cumulative impact of the entire medication regimen. Seemingly innocuous medications have the potential to cause adverse effects when taken in addition to other medications. Additionally, not all medications have the same impact on every individual, with pre-existing conditions such as dementia potentially altering their effects.

Thus, before prescribing a new medication, there is a need to step back and assess the entire person and the complex interacting medication regimen to truly understand and predict the impact the addition will have on an individual.

The use of anticholinergics, such as tricyclic antidepressants and antimuscarinics, have long required careful consideration before prescribing. Increasing evidence suggests that the cumulative impact on a person taking one or more medications with anticholinergic effects, including those with only mild anticholinergic properties, hold greater adverse effects than first thought. Research into anticholinergic burden has identified an associated increased risk of cognitive impairment, dementia and mortality in older people (here and here).

However, the impact of anticholinergic burden in people with pre-existing cognitive impairment remains unclear. With more than 485 000 Australians currently living with dementia and with this number set to increase to over 1 million in the next 30 years, there is a need for greater evidence to understand the risk and guide prescribing of anticholinergic medications in this vulnerable population.

To help assist in determining the risk of anticholinergic burden in dementia, we published a Cochrane review in August 2022. Our review sought to evaluate the available evidence on whether anticholinergic burden predicts adverse outcomes in people with mild cognitive impairment or dementia.

The review identified 18 observational studies involving over 100 000 adults aged 50 years or more. We identified five distinct measurement scales used to quantify anticholinergic burden. The most prevalent scale was the Anticholinergic Cognitive Burden (ACB) scale (used in 12 studies), which quantifies the anticholinergic properties of each medication a person takes by assigning a score ranging from 0 to 3. The score for each medication is then tallied to give an overall score for the regimen. Other scales identified were the Anticholinergic Risk Scale (ARS), Anticholinergic Drug Scale (ADS), Anticholinergic Effect on Cognition (AEC) scale and a scale developed by Tune and Egeli.

We found that higher anticholinergic burden was associated with increased risk of death in people with cognitive impairment. High ACB scores (≥ 3), relative to those with no or minimal ACB scores, were associated with a 15% increased risk of death. This finding alone, despite it being of low certainty, warrants increased caution when prescribing anticholinergic medications in this population.

The low certainty evidence stems in part due to the over-reliance on pre-existing datasets that were not designed to investigate the association between anticholinergic burden and clinical outcomes. People living with dementia are often under-represented in clinical trials and in the evidence that informs prescribing guidelines.

There is a clear need for more prospectively designed research studies in this area to definitively determine whether anticholinergic burden increases mortality risk in people living with dementia.

For similar reasons to mortality risk, the evidence was unclear as to whether increasing anticholinergic burden leads to greater cognitive decline. This finding is surprising and conflicts with an earlier Cochrane review looking at anticholinergic burden in cognitively healthy older adults.

One potential explanation for this contradictory finding is that deterioration of the cholinergic system that occurs in dementia may limit some of the adverse impact that anticholinergic medications have on cognition. Thus, the impact of anticholinergic medications may be more pronounced in individuals with mild cognitive impairment or early-stage dementia rather than later stages of dementia.

This has practice implications for GPs in particular, as patients presenting with early signs of cognitive impairment are mostly managed in primary care and may not have had the comprehensive medication review that can be associated with receiving a formal diagnosis of dementia. However, further research is needed to confirm this finding and explore possible mechanisms underpinning it.

Our review found no evidence of high anticholinergic burden leading to increased risk of admission into a residential aged care facility, and minimal evidence of association with decline in physical function. Disappointingly, we also found a serious gap in the literature with no studies identified that evaluated the impact of anticholinergic burden on neuropsychiatric symptoms, an important factor to consider when determining risks associated with use of medications in people living with dementia.

In summary, our findings suggest that the use of anticholinergic burden as a tool to predict outcomes in people with cognitive impairment is questionable. However, our review has highlighted some potential considerations for the impact of anticholinergic burden in this population.

With no gold standard way of measuring, or quantifying anticholinergic burden, and the inconclusive nature of the majority of the evidence, it remains difficult to make firm conclusions about the impact of high anticholinergic burden on individuals living with dementia. From the data that we could find, it is clear that we should advocate for caution when prescribing anticholinergic medications in people with cognitive impairment, and we recommend using non-pharmacological interventions and non-anticholinergic medications wherever possible.

If no appropriate alternatives exist and anticholinergic medications are to be prescribed in people living with mild cognitive impairment or dementia, then there needs to be a person-centred care approach. Ideally, the medication regimen needs to be reviewed regularly by a multidisciplinary team to assess the ongoing benefits, and potential harm, of individual medications and the regimen as a whole.

Dr Amanda Cross is a Research Fellow with the Centre for Medicine Use and Safety at Monash University.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.

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