Martin Taylor-Rowan1, Olga Kraia1, Christina Kolliopoulou1, Anna H Noel-Storr2, Ahmed A Alharthi3, Amanda J Cross4, Carrie Stewart5, Phyo K Myint6, Jenny McCleery7, Terry J Quinn1. 1. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. 2. Radcliffe Department of Medicine, University of Oxford, Oxford, UK. 3. Department of Clinical Pharmacy, Umm Al Qura University, Makkah, Saudi Arabia. 4. Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Australia. 5. ACER, IAHS, University of Aberdeen, Aberdeen, UK. 6. Division of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK. 7. Oxford Health NHS Foundation Trust, Banbury, UK.
Abstract
BACKGROUND: Medications with anticholinergic properties are commonly prescribed to older adults with a pre-existing diagnosis of dementia or cognitive impairment. The cumulative anticholinergic effect of all the medications a person takes is referred to as the anticholinergic burden because of its potential to cause adverse effects. It is possible that a high anticholinergic burden may be a risk factor for further cognitive decline or neuropsychiatric disturbances in people with dementia. Neuropsychiatric disturbances are the most frequent complication of dementia that require hospitalisation, accounting for almost half of admissions; hence, identification of modifiable prognostic factors for these outcomes is crucial. There are various scales available to measure anticholinergic burden but agreement between them is often poor. OBJECTIVES: Our primary objective was to assess whether anticholinergic burden, as defined at the level of each individual scale, was a prognostic factor for further cognitive decline or neuropsychiatric disturbances in older adults with pre-existing diagnoses of dementia or cognitive impairment. Our secondary objective was to investigate whether anticholinergic burden was a prognostic factor for other adverse clinical outcomes, including mortality, impaired physical function, and institutionalisation. SEARCH METHODS: We searched these databases from inception to 29 November 2021: MEDLINE OvidSP, Embase OvidSP, PsycINFO OvidSP, CINAHL EBSCOhost, and ISI Web of Science Core Collection on ISI Web of Science. SELECTION CRITERIA: We included prospective and retrospective longitudinal cohort and case-control observational studies, with a minimum of one-month follow-up, which examined the association between an anticholinergic burden measurement scale and the above stated adverse clinical outcomes, in older adults with pre-existing diagnoses of dementia or cognitive impairment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and undertook data extraction, risk of bias assessment, and GRADE assessment. We summarised risk associations between anticholinergic burden and all clinical outcomes in a narrative fashion. We also evaluated the risk association between anticholinergic burden and mortality using a random-effects meta-analysis. We established adjusted pooled rates for the anticholinergic cognitive burden (ACB) scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales. MAIN RESULTS: We identified 18 studies that met our inclusion criteria (102,684 older adults). Anticholinergic burden was measured using five distinct measurement scales: 12 studies used the ACB scale; 3 studies used the Anticholinergic Risk Scale (ARS); 1 study used the Anticholinergic Drug Scale (ADS); 1 study used the Anticholinergic Effect on Cognition (AEC) Scale; and 2 studies used a list developed by Tune and Egeli. Risk associations between anticholinergic burden and adverse clinical outcomes were highly heterogenous. Four out of 10 (40%) studies reported a significantly increased risk of greater long-term cognitive decline for participants with an anticholinergic burden compared to participants with no or minimal anticholinergic burden. No studies investigated neuropsychiatric disturbance outcomes. One out of four studies (25%) reported a significant association with reduced physical function for participants with an anticholinergic burden versus participants with no or minimal anticholinergic burden. No study (out of one investigating study) reported a significant association between anticholinergic burden and risk of institutionalisation. Six out of 10 studies (60%) found a significantly increased risk of mortality for those with an anticholinergic burden compared to those with no or minimal anticholinergic burden. Pooled analysis of adjusted mortality hazard ratios (HR) measured anticholinergic burden with the ACB scale, and suggested a significantly increased risk of death for those with a high ACB score relative to those with no or minimal ACB scores (HR 1.153, 95% confidence interval (CI) 1.030 to 1.292; 4 studies, 48,663 participants). An exploratory pooled analysis of adjusted mortality HRs across anticholinergic burden scales also suggested a significantly increased risk of death for those with a high anticholinergic burden (HR 1.102, 95% CI 1.044 to 1.163; 6 studies, 68,381 participants). Overall GRADE evaluation of results found low- or very low-certainty evidence for all outcomes. AUTHORS' CONCLUSIONS: There is low-certainty evidence that older adults with dementia or cognitive impairment who have a significant anticholinergic burden may be at increased risk of death. No firm conclusions can be drawn for risk of accelerated cognitive decline, neuropsychiatric disturbances, decline in physical function, or institutionalisation.
BACKGROUND: Medications with anticholinergic properties are commonly prescribed to older adults with a pre-existing diagnosis of dementia or cognitive impairment. The cumulative anticholinergic effect of all the medications a person takes is referred to as the anticholinergic burden because of its potential to cause adverse effects. It is possible that a high anticholinergic burden may be a risk factor for further cognitive decline or neuropsychiatric disturbances in people with dementia. Neuropsychiatric disturbances are the most frequent complication of dementia that require hospitalisation, accounting for almost half of admissions; hence, identification of modifiable prognostic factors for these outcomes is crucial. There are various scales available to measure anticholinergic burden but agreement between them is often poor. OBJECTIVES: Our primary objective was to assess whether anticholinergic burden, as defined at the level of each individual scale, was a prognostic factor for further cognitive decline or neuropsychiatric disturbances in older adults with pre-existing diagnoses of dementia or cognitive impairment. Our secondary objective was to investigate whether anticholinergic burden was a prognostic factor for other adverse clinical outcomes, including mortality, impaired physical function, and institutionalisation. SEARCH METHODS: We searched these databases from inception to 29 November 2021: MEDLINE OvidSP, Embase OvidSP, PsycINFO OvidSP, CINAHL EBSCOhost, and ISI Web of Science Core Collection on ISI Web of Science. SELECTION CRITERIA: We included prospective and retrospective longitudinal cohort and case-control observational studies, with a minimum of one-month follow-up, which examined the association between an anticholinergic burden measurement scale and the above stated adverse clinical outcomes, in older adults with pre-existing diagnoses of dementia or cognitive impairment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and undertook data extraction, risk of bias assessment, and GRADE assessment. We summarised risk associations between anticholinergic burden and all clinical outcomes in a narrative fashion. We also evaluated the risk association between anticholinergic burden and mortality using a random-effects meta-analysis. We established adjusted pooled rates for the anticholinergic cognitive burden (ACB) scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales. MAIN RESULTS: We identified 18 studies that met our inclusion criteria (102,684 older adults). Anticholinergic burden was measured using five distinct measurement scales: 12 studies used the ACB scale; 3 studies used the Anticholinergic Risk Scale (ARS); 1 study used the Anticholinergic Drug Scale (ADS); 1 study used the Anticholinergic Effect on Cognition (AEC) Scale; and 2 studies used a list developed by Tune and Egeli. Risk associations between anticholinergic burden and adverse clinical outcomes were highly heterogenous. Four out of 10 (40%) studies reported a significantly increased risk of greater long-term cognitive decline for participants with an anticholinergic burden compared to participants with no or minimal anticholinergic burden. No studies investigated neuropsychiatric disturbance outcomes. One out of four studies (25%) reported a significant association with reduced physical function for participants with an anticholinergic burden versus participants with no or minimal anticholinergic burden. No study (out of one investigating study) reported a significant association between anticholinergic burden and risk of institutionalisation. Six out of 10 studies (60%) found a significantly increased risk of mortality for those with an anticholinergic burden compared to those with no or minimal anticholinergic burden. Pooled analysis of adjusted mortality hazard ratios (HR) measured anticholinergic burden with the ACB scale, and suggested a significantly increased risk of death for those with a high ACB score relative to those with no or minimal ACB scores (HR 1.153, 95% confidence interval (CI) 1.030 to 1.292; 4 studies, 48,663 participants). An exploratory pooled analysis of adjusted mortality HRs across anticholinergic burden scales also suggested a significantly increased risk of death for those with a high anticholinergic burden (HR 1.102, 95% CI 1.044 to 1.163; 6 studies, 68,381 participants). Overall GRADE evaluation of results found low- or very low-certainty evidence for all outcomes. AUTHORS' CONCLUSIONS: There is low-certainty evidence that older adults with dementia or cognitive impairment who have a significant anticholinergic burden may be at increased risk of death. No firm conclusions can be drawn for risk of accelerated cognitive decline, neuropsychiatric disturbances, decline in physical function, or institutionalisation.
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