Polypharmacy prescribing guidance - draft: consultation

6. Anticholinergic Burden

6.1 Introduction to anticholinergic adverse effects

The cumulative exposure to multiple medicines with anticholinergic properties is known as anticholinergic burden. Older people are commonly exposed to medicines that have anticholinergic properties. Higher anticholinergic burden in older people is associated with greater risk of morbidity and mortality, longer hospital length of stay (LOS), institutionalisation, functional and cognitive decline. ^[122]

Acetylcholine (Ach) functions in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections, from the basal forebrain to the cerebral cortex and hippocampus, support the cognitive functions of those target areas. In the PNS, Ach activates muscles and is a major neurotransmitter in the autonomic nervous system. Anticholinergic is used to refer to substances that block the action of Ach neurotransmitter at synapses in the CNS and PNS.

Medication with anticholinergic effects aid regulation of muscles in the intestines and bladder. 87 They are also used in the management of Parkinson’s disease and chronic obstructive pulmonary disease. Anticholinergic effects can however also impact on learning and memory.87 Anticholinergic effects can be the side effect of multiple different medications that are not primarily used for their anticholinergic effect, e.g. tricyclic antidepressants and antihistamines. Therefore a large range of medication can lead to adverse anticholinergic effects including impaired cognition, increased risk of falls, functional decline, cardiovascular events, and mortality. Blurred vision, urinary retention, and constipation are known peripheral adverse effects of anticholinergic medication. Sensitivity varies across individuals and is dose-dependent.[123]^{, [124],122, [125], [126]}

6.1.1 Why are anticholinergic adverse effects problematic?

Anticholinergics have long been recognised as causing symptoms such as dry mouth, constipation and urinary retention. Exposure to anticholinergic medication has more recently been linked to impaired cognition and physical decline. There may also be an association with falls, and increased mortality and cardiovascular events. The table below shows that anticholinergic effects are dose dependent,^[127] but there is significant inter-individual variability regarding anticholinergic dose and manifestations of signs and symptoms of toxicity.

Therefore, it is essential to take a person-centred approach when reviewing medications with anticholinergic side effects, to understand the individual’s perspective and experience as the impact will vary depending on individual sensitivity. At the time of writing this there is currently no commonly accepted measure of cumulative anticholinergic burden.^[128]

The table below sets out the potential anticholinergic effects that an individual may experience.127 The table shows that anticholinergic effects can be dose dependent noting there can be significant individual variability.127

Medicines with anticholinergic properties continue to be commonly prescribed to older people and those with mental health conditions, who are particularly susceptible to adverse effects, even at therapeutic doses.

Anticholinergic burden principles:

• Anticholinergic effect of medications vary greatly between individuals
• Anticholinergic effect of multiple medications are cumulative
• The comparative degree of anticholinergic medications are based partly on clinical evidence and partly on pharmacological theory

6.1.2 Measuring Anticholinergic Burden and Potential Risk

Several tools have been developed to estimate the anticholinergic load of an individual’s medicine regimen – the anticholinergic cognitive burden scale (ACBs) and the Anticholinergic Risk Scale (ARS). ^[129]

ARS is a means for ranking medicines with anticholinergic potential as very strong, strong, moderate, or low, sometimes by a numerical score, and attempts to predict both peripheral and central effects.129 In contrast, the anticholinergic cognitive burden scale grading of drugs is based on the potential to cause cognitive effects.^[130]

It might be possible that in delirium both central and peripheral anticholinergic effects play a role. Blurred vision, urinary retention, and constipation, known peripheral adverse effects of anticholinergic medication are risk factors for delirium and might explain why the ARS was associated with delirium.^[131] However, because the individual studies did not report on adverse effects, this remains speculative.

NICE (2018) noted the different validated scales for assessing anticholinergic burden, but that there was insufficient evidence to recommend a particular one. ^[132] There is limited evidence that anticholinergic risk assessment tools are equally valid for use in clinical practice or to inform policy decisions.

To support the prioritisation of patients for review, a national therapeutic indicator identifies people taking more than 10 items of strong or very strong anticholinergics using the modified ARS scale (mARS 2&3) per annum as a percentage of all people aged 75 years and over. ^[133] This can be used to support the prioritisation of people for review.

Various studies have highlighted the impact of anticholinergics burden and adverse events. These are described briefly below:

Delirium

Delirium describes a mental state which causes confusion, disorientation so that the individual may not be able to think or remember clearly. Causes include infections, medication and organ failure.

Egberts et al. investigated the possible association between ACB, measured with Anticholinergic Rating Scales, and delirium. ^[134] Studies looked at prevalence of delirium and reported an association between delirium and ACB. They concluded that the evidence suggested the anticholinergic risk scale (ARS) is a useful means for identifying people with ACB at risk of delirium. Welsh et al reviewed reported association between delirium and ACB using a range of ACB scales and found the association between adverse outcomes and anticholinergic burden varies between scores and has not been conclusively established. [135]

Mortality

Two SRs and a GL reported an association between anticholinergic burden (ACB) and mortality. Two were judged to be low quality. The third, the SR by Ali et al. was judged acceptable. ^[136] They examined the reported association between ACB and mortality, specifically in older adults. Twenty-seven studies looked at the association between ACB and mortality: 15 studies (56%) reported a positive correlation between ACB and mortality. Of the ten that reported a lack of positive association, 80% had a follow-up period of one year or less.

A 2019 NHS guideline concluded there is a need to be cautious when prescribing medicines with anticholinergic effects; and proposed the need to minimise their use where possible; to be cautious when prescribing in older adults, people with frailty, or those with complex multimorbidities. ^[137]

Cognitive impact

Medicines with anticholinergic effects are risk factors for a variety of cognitive disorders. Both the NICE (2018) guidelines on the diagnosis and management of dementia (including Alzheimer's disease)132 and NICE guidance on management of urinary continence and pelvic organ prolapse in women ^[138] noted that those with dementia are frequently prescribed medicines with a high ACB (either through individual medicines or by combinations). This puts the individual at risk of cognitive impairment, and so NICE recommended reducing medicines associated with increased anticholinergic burden.

NICE guidance to manage urinary incontinence reported how older adults taking medications with anticholinergic effect, have increased risk of cognitive impairment therefore there is a need to be cautious when prescribing medicines with anticholinergic effects. They recommended that:

• Prescribing medications with an anticholinergic effect should be minimised for older adults, people with frailty, or people with complex multimorbidities.
• Older people are at greater risk of constipation, urinary retention, dry mouth/eyes, sedation, confusion, delirium, and reduced cognition.
• If a person has a cognitive impairment/dementia, they should receive a medication review to minimise medication with ACB or identify alternatives.
• Women diagnosed with dementia, should be made aware of the risk of cognitive impairment from medication with ACB used for bladder control.

Welsh et al. reviewed a reported association between cognitive function and anticholinergic burden found that two-thirds of the studies reported an association with ACB and impaired cognitive function.135 Mehdizadeh et al. conducted a high-quality SR examining the association between anticholinergic exposure and cognitive dysfunction. ^[139] They reported older community-dwelling women living in the USA were at increased odds of impaired cognitive function, indicated by a MMSE score ≤ 26, but they were unable to make a definitive conclusion on whether this decline was solely attributable to medication with anticholinergic side effects.

The Cochrane Review by Taylor-Rowan et al. assessed the risk of cognitive decline/dementia from ACB. ^[140] They focused on the strength of association between ACB and future cognitive decline or dementia in different healthcare settings (primary care, secondary care, or community settings); different anticholinergic burden scales; and the effect of duration of exposure and duration of follow-up on risk. They found a significant increase in the risk of cognitive impairment or dementia for those taking anticholinergic medication compared to those who do not.

They found an association between increasing ACB and risk of dementia. The review suggests that careful consideration should be made before prescribing anticholinergic medication to older adults.

Fractures and falls

Evidence highlights the association between risk of fractures and falls, and ACB.135^,137^,139^,[141] There is no significant change in bone mineral density (BMD).[142] The EuGMS group on Fall-Risk Increasing Drugs conducted a modified Delphi based on metanalysis of national fall prevention guidelines in Europe.83 This is referred to the STOPPFall list. All of the medicines identified in this list have anticholinergic properties and these should be used to prioritise individuals for review and are shown in the table below. A person-centred approach needs to be taken in order to review the impact of anticholinergic burden score.

Frailty status

While anticholinergic burden does not alter frailty status,139 these guidelines recommend that the anticholinergic impact, on cognitive and peripheral effects, falls, delirium and mortality, should be minimised for people with any level of frailty.

6.1.3 Interventions to reduce anticholinergic burden

Nakham et al. aimed to determine the contents of the interventions designed to reduce ACB in older adults on polypharmacy mediation regimes, and the clinical and cost effectiveness of these. [143] The findings were mixed where one study showed statistically significant improvement in the Medication Appropriateness Index, and another found improvement in sedative side effect. Table 17 sets out the recommendations of action to be taken to address anticholinergic burden.25^{,132,134,135,137,139,140,143,136,138} (see Appendix G for recommendation methodology)

6.1.4 How to assess and reduce the anticholinergic burden

A single medicine with anticholinergic properties may not put a person at risk of severe adverse effects, but when used in combination, effects may accumulate. Reducing the anticholinergic burden may result in improvements in short-term memory, confusion, behaviours and delirium.

A scale or table that assigns a cumulative anticholinergic score to a patient’s prescribed medication can be used to assess anticholinergic burden. A number of these scoring systems are available. While this approach is valid, the overall aim is to reduce total anticholinergic exposure as much as possible. The table below is intended to be a guide to which areas anticholinergic burden is likely to be the highest. This information has been drawn from the modified anticholinergic risk scale mARS, which updates the guidance in 2018.133 This is a developing area with disagreements between different sources. Some of this table is based on incomplete or poor evidence, or on expert opinion. The anticholinergic effects of medication may become better understood with time. Some of these therapeutic areas are highly specialised (for example Parkinson’s disease) and would require expert advice before considering a change. As noted here, less anticholinergic alternatives often have other concerns. If an anticholinergic agent must be used, consider reducing the dose. ^{122,124,125,126,129,[144],[145]} or consider the cumulative effect of agents having anticholinergic effects.

For an example of an NTI for ACB, see Appendix M.