A review of published anticholinergic scales and measures and their applicability in database analyses

Background/objectives: Available metrics for characterizing cumulative anticholinergic exposure over time may not be well suited for use across all US data sources. In this review, the properties of existing anticholinergic scales and measures were evaluated to determine their suitability for implementation in observational studies relying on administrative data.Methods: A targeted literature review was conducted to identify available anticholinergic scales and measures. Suitability of the identified scales and measures for quantification of anticholinergic exposure was evaluated based on pre-defined criteria. Agreement between selected scales was characterized by the percentage overlap of included drugs and inter-scale Spearman’s correlation of scores.Results: Sixteen scales were identified; six were relevant and suitable for the quantification of anticholinergic exposure. When implemented on administrative data the Anticholinergic Drug Scale and Anticholinergic Cognitive Burden scale demonstrated the most agreement, with an inter-scale correlation coefficient of 0.82. Scale performance varied by outcome of interest, and underlying disease profile of the population of interest. Variability across the two measures (“average daily dose” and “cumulative dose”) was observed, with neither considering both dose and anticholinergic potency in score calculations.Conclusions: Accurate quantification of anticholinergic burden is important in assessing relative risks versus benefits of prescribing anticholinergic medications. In this review, the Anticholinergic Drug Scale and the Anticholinergic Cognitive Burden scale and the average daily dose and cumulative dose measures, were determined to be well suited for the quantification of anticholinergic exposure, particularly in the context of administrative data analyses; however, methods to characterize anticholinergic burden through consideration of both anticholinergic dose and potency are needed.     

Impact of anticholinergic burden on emergency department visits among older adults in Korea: A national population cohort study

ObjectivesThis study aimed to evaluate the impact of high anticholinergic burden on overall emergency department (ED) visits and ED visits related to adverse effects of anticholinergic drugs among older adults.MethodsFor this retrospective cohort study, we used claims data from older adults with high representativeness. The average daily Anticholinergic Risk Scale (ARS) score was calculated based on the dosage, treatment duration, and potency of anticholinergic drugs during three months. A high-exposure group (ARS ≥ 2) and a non-exposure group were included in this analysis. The primary outcome was the first ED visit during the follow-up period. Anticholinergic ED visits were defined as ED visits with a main diagnosis of a fall, fracture, dizziness, delirium, constipation, or urinary retention.ResultsIn total, 118,750 subjects (43.6% male) were included in this study. The mean age was 75.4 ± 6.6 years. The adjusted hazard ratios (aHRs) for all-cause and anticholinergic ED visits among those with high ARS scores were 1.28 (95% CI: 1.20–1.36) and 1.55 (95% CI: 1.38–1.74), respectively. The high-exposure group was at higher risk than the non-exposure group for ED visits for falls or fractures (aHR: 1.31, 95% CI: 1.07–1.60), dizziness (aHR: 1.71, 95% CI: 1.36–2.14), delirium (aHR: 2.05, 95% CI: 1.13–3.73), constipation (aHR: 1.65, 95% CI: 1.35–2.02) and urinary retention (aHR: 1.66, 95% CI: 1.30–2.12).ConclusionsThis study demonstrated that a high anticholinergic burden in older adults increased the risk of all-cause ED visits, anticholinergic ED visits and specific-cause ED visits.     

The anticholinergic risk scale and anticholinergic adverse effects in older persons

BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.     

Associations between drug burden index and falls in older people in residential aged care

OBJECTIVES: To evaluate the association between the Drug Burden Index (DBI), a measure of a person's total exposure to anticholinergic and sedative medications that includes principles of dose‐response and maximal effect and is associated with impaired physical function in community‐dwelling older people, and falls in residents of residential aged care facilities (RACFs). DESIGN: Data were drawn from participants in a randomized controlled trial that investigated falls and fractures. SETTING: RACFs in Sydney, Australia. PARTICIPANTS: Study participants (N=602; 70.9% female) were recruited from 51 RACFs. Mean age was 85.7 ± 6.4, and mean DBI was 0.60 ± 0.66. MEASUREMENTS: Medication history was obtained on each participant. Drugs were classified as anticholinergic or sedative and a DBI was calculated. Falls were measured over a 12‐month period. Comorbidity, cognitive impairment (Mini‐Mental State Examination) and depression (Geriatric Depression Scale) were determined. RESULTS: There were 998 falls in 330 individuals during a follow‐up period of 574.2 person‐years, equating to an average rate of 1.74 falls per person‐year. The univariate negative binomial regression model for falls showed incidence rate ratios of 1.69 (95% confidence interval (CI)=1.22–2.34) for low DBI (<1) and 2.11 (95% CI=1.47–3.04) for high DBI (≥1) when compared with those who had a DBI of 0. After adjusting for age, sex, history of falling, cognitive impairment, depression, use of a walking aid, comorbidities, polypharmacy, and incontinence, incident rate ratios of 1.61 (95% CI=1.17–2.23) for low DBI and 1.90 (95% CI=1.30–2.78) for high DBI were obtained. CONCLUSION: DBI is significantly and independently associated with falls in older people living in RACFs. Interventional studies designed for this population are needed to determine whether reducing DBI, through dose reduction or cessation of anticholinergic and sedative drugs, can prevent falls.     

Drug Burden Index Score and Functional Decline in Older People

Background

The Drug Burden Index (DBI), a measure of exposure to anticholinergic and sedative medications, has been independently associated with physical and cognitive function in a cross-sectional analysis of community-dwelling older persons participating in the Health, Aging and Body Composition study. Here we evaluate the association between DBI and functional outcomes in Health, Aging and Body Composition study participants over 5 years.

Methods

DBI was calculated at years 1 (baseline), 3, and 5, and a measure of the area under the curve for DBI (AUCDB) over the whole study period was devised and calculated. Physical performance was measured using the short physical performance battery, usual gait speed, and grip strength. The association of DBI at each time point and AUCDB with year 6 function was analyzed in data from participants with longitudinal functional measures, controlling for sociodemographics, comorbidities, and baseline function.

Results

Higher DBI at years 1, 3, and 5 was consistently associated with poorer function at year 6. On multivariate analysis, a 1-unit increase in AUCDB predicted decreases in short physical performance battery score of .08 (P = .01), gait speed of .01 m/s (P = .004), and grip strength of .27 kg (P = .004) at year 6.

Conclusion

Increasing exposure to medication with anticholinergic and sedative effects, measured with DBI, is associated with lower objective physical function over 5 years in community-dwelling older people.     

Anticholinergic drug exposure at intensive care unit admission affects the occurrence of delirium. A prospective cohort study

BackgroundAnticholinergic drugs may increase the risk of delirium in non-critically ill patients, but it is unclear whether exposure to these drugs is also a risk factor for Intensive Care Unit (ICU) delirium. In this study the hypothesis was tested that anticholinergic drug exposure at ICU admission increases the risk to develop delirium during ICU stay, particularly in patients with advanced age and severe sepsis.MethodsA prospective cohort study was performed in the mixed 32-bed medical-surgical ICU of the University Medical Center Utrecht, the Netherlands in the period from January 2011 till June 2013. Included were nonneurological patients that were consecutively admitted for more than 24 hours. The presence of delirium was evaluated each day using a validated algorithm based on the Confusion Assessment Method for the ICU (CAM-ICU), the initiation of delirium treatment as well as chart review by researchers. Anticholinergic drug exposure at ICU admission was assessed using the Anticholinergic Drug Scale (ADS). To evaluate the association between anticholinergic drug exposure at ICU admission and the risk of developing delirium, we performed multivariable competing risk Cox proportional hazard analysis corrected for confounding factors.ResultsApproximately half (47%, n=513) of the 1090 included patients developed delirium during ICU admission. The absolute risk for delirium development increased with more anticholinergic drug exposure: 42% in patients with ADS score=0, 49% in patients with ADS score=1, and 53% in patients with ADS higher than 1. Taking competing events (death and discharge) and potential confounding factors into account, the subdistribution hazard ratio (SHR) was 1.13 (95% CI: 0.91-1.40) for ADS score=1 point and 1.35 (95% CI: 1.09-1.68) for ADS ≥2 compared with an ADS score=0 (no anticholinergic drug exposure). The effect was strongest during the first days of ICU admittance and was strongest in patients above 65 year without severe sepsis and/or septic shock (SHR 2.15, 95% CI 1.43-3.25).ConclusionsAnticholinergic drug exposure at ICU admission increases the risk of delirium in critically ill patients. This effect was most pronounced in patients older than 65 years without severe sepsis and/or septic shock, and declining over time.     

Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study

OBJECTIVES: To determine whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative. DESIGN: A 2‐year longitudinal study of participants enrolled in the Medical Research Council Cognitive Function and Ageing Study between 1991 and 1993. SETTING: Community‐dwelling and institutionalized participants. PARTICIPANTS: Thirteen thousand four participants aged 65 and older. MEASUREMENTS: Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini‐Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years. RESULTS: At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33‐point greater decline in MMSE score (95% confidence interval (CI)=0.03–0.64, P=.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI=?0.14–0.11, P=.79). Two‐year mortality was greater for those taking definite (OR=1.68; 95% CI=1.30–2.16; P<.001) and possible (OR=1.56; 95% CI=1.36–1.79; P<.001) anticholinergics. CONCLUSION: The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality.     

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults

BackgroundAnticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.ObjectiveCompare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.DesignProspective cohort study.SettingPrimary care (Australia and USA).Participants19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.MeasurementsBaseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.ResultsAt baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1–2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.LimitationsResidual confounding and reverse causality are possible. Assessment of dose or duration was not possible.ConclusionsHigh anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06550-2.KEY WORDS: anticholinergic burden, dementia, stroke, potentially inappropriate medication     

Trospium chloride for overactive bladder may induce central nervous system adverse events

BackgroundAnticholinergic drugs constitute the first-line pharmacologic treatment for overactive bladder (OAB). Of the various anticholinergic agents available, trospium chloride appears to have potentially favorable chemical and pharmacologic properties leading to reduce the incidence of central nervous system (CNS) adverse reactions, since their ability to cross the blood-brain barrier is reduced (relative to other drugs in this therapeutic class).ObjectiveThe objective of the present survey was to establish whether or not CNS adverse reactions may be associated with trospium exposure by evaluating spontaneous reports made to the French pharmacovigilance database (FPVD).MethodsAll serious adverse drug reactions, specifically confusion, hallucinations, agitation and cognitive impairment, associated with trospium (the immediate-release form only) recorded in the FPVD between September 2005 to September 2011 were identified and analyzed.ResultsWe identified 15 cases of CNS adverse events, according to at least one of the following terms: confusion (n = 9), hallucinations (n = 6), cognitive impairment (n = 4) and agitation (n = 2) and in which trospium chloride was suspected to have a causal link according to their imputability evaluation. The reports concerned 10 women and 5 men, with a mean age of 81 years (range: 62 to 96 years). The symptoms varied from relatively acute states of confusion and/or hallucinations to more progressive cognitive changes. In all these cases, CNS symptoms resolved rapidly after treatment discontinuation.ConclusionDespite the drug's favorable physiochemical properties, we have found pharmacovigilance data indicating that trospium chloride prescribed for OAB can induce CNS adverse reactions, such as confusion, hallucinations, agitation and/or cognitive impairment. Physicians should consider withdrawing trospium chloride if CNS symptoms suggestive of anticholinergic adverse effects occur in patients treated with this drug.     

Prolonged anticholinergic therapy of duodenal ulcer

Summary and Conclusions The treatment of acute or uncomplicated ulcer with anticholinergic drugs is effective and gratifying. Anticholinergic drugs, chiefly through their effect on gastrointestinal motility, are helpful in relieving ulcer pain and possibly in facilitating healing. In the present study of 116 patients, those receiving potent anticholinergic drugs in the dosage prescribed fared significantly better than those receiving atropine or placebos. However, recurrences, hemorrhage, perforation, and obstruction were not prevented by the constant administration of these drugs in the dosage used.In all probability, rigid diets followed over prolonged periods have no major effect. More important are the patient's dietary habits and his schedule of eating.Anticholinergic drugs should be used as adjuncts to conventional therapy, and never as substitutes for the time-proved measures. Treatment must continue to be based on a rational approach which has a reasonable likelihood of producing a favorable effect in each instance. Duodenal ulcer continues to be a therapeutic problem, and the development of new drugs has not obviated the need for rest, reassurance, sedation, antacids, diet, and other measures.The author wishes to acknowledge the assistance of Drs. Malcolm P. Tyor, Lonnie A. Waggoner, M. Frank Sohmer, and Ozmer Henry who participated in this study while Fellows in Gastroenterology.     

A high sense of coherence protects from the burden of caregiving in older spousal caregivers

ObjectivesCaregiving is often associated with burden and chronic stress. Sense of coherence (SOC) may help the caregivers in coping with their stress and was identified as a positive factor for health outcomes and quality of life. We aimed to study the links between SOC, burden, depression and positive affects among caregivers of frail older patients.MethodsSeventy-nine spousal caregivers were recruited via the geriatric outpatient clinic. Data collected: Zarit Burden Inventory, SOC-13, Geriatric Depression Scale, Caregiver Reaction Assessment (CRA), sleep, time of supervision, Katz Index, Global Deterioration Scale and Neuropsychiatric Inventory. Analyses: Caregiver’s characteristics were analyzed by burden severity and SOC level. Multivariable logistic regressions were used in order to identify the variable that best predict caregiver burden and high SOC.ResultsThe mean age was 79.4 ± 5.3; 53% were women. Among care-recipient, 82% had cognitive impairment and the median Katz Index was 3. Caregivers with a high SOC and an older age reported a lower burden (Odds Ratio (OR) 0.18, 95% confidence interval (CI) 0.04–0.65 and OR 0.87, 95% CI 0.76–0.98, respectively). A higher burden was associated with patient functional limitations (OR 8.69, 95% CI 2.28–40.46).DiscussionHaving a high sense of coherence seems to be a protective factor against the burden. To support caregivers, health providers should recognize the expertise of the caregivers and the meaningfulness of this care situation.     

Confusion about measuring central nervous system effects

Anticholinergic therapy together with behavioral treatment are the mainstays of treatment for the overactive bladder. Successful therapy and patient compliance depend very much on side effects. In the past, little attention has been paid to anticholinergic side effects in the central nervous system (CNS), which can be critical, especially for elderly patients. Incidence and intensity of CNS effects depend on the pharmacokinetic and pharmacodynamic properties that are decisive whether anticholinergics pass the blood-brain barrier as a result of passive and active transport mechanisms. To measure potential CNS side effects of anticholinergic drugs, rapid eye movement sleep analysis, quantitative-topographic electroencephalogram studies, and psychometric tests were performed. Structural changes in brain morphology (resulting from anticholinergics) also were analyzed in a postmortem study. However, the data of these studies do not always correlate with clinical experience. The results of clinical studies in elderly patients are also controversial mainly due to the different design of the studies. Spontaneous reporting may not be appropriate, but targeted tests for memory and cognitive function should be applied. Moreover, the treatment period must be adequate. Therefore, further clinical studies in patients with overactive bladder are mandatory, with adequate study design and adequate duration of anticholinergic therapy.     

Association Between Anticholinergic Drugs and Apolipoprotein E ɛ4 Allele and Poorer Cognitive Function in Older Cardiovascular Patients: A Cross-Sectional Study

OBJECTIVES: To clarify the association between anticholinergic drugs and apolipoprotein E ɛ4 allele carrier status ( APOE4 ) and cognitive dysfunction.
DESIGN: Cross-sectional analyses of current drug use and cognitive functioning according to the baseline assessments of the Drugs and Evidence-Based Medicine in the Elderly Study.
SETTING: Helsinki, Finland.
PARTICIPANTS: Four hundred community-dwelling people aged 75 to 90 without clinical dementia but with a history of stable atherosclerotic disease.
MEASUREMENTS: Cognitive function according to the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDR). Participants' use of anticholinergic drugs was estimated using definitions from previous scientific literature. APOE alleles determined from peripheral blood leukocyte deoxyribonucleic acid using standard polymerase chain reaction–based methods.
RESULTS: There was an association between anticholinergic drugs and lower MMSE scores ( P for trend <.001). The higher the number of anticholinergic drugs, the lower the MMSE score. Subjects with the APOE4 allele and using drugs with anticholinergic properties had the lowest median MMSE score (26), whereas those without the APOE4 allele and not using drugs with anticholinergic properties had the highest median MMSE score (28). When adjusted for age, sex, and education, the difference between the groups remained significant. The finding was similar for CDR scores.
CONCLUSION: Use of drugs with anticholinergic properties was associated with lower cognitive function irrespective of APOE4 carrier status. Having lower cognitive function as a group, APOE4 carriers may be more vulnerable to this undesirable effect, but a follow-up study is needed to demonstrate this.     

The effects of atropine or benzilonium on pelvic pouch and anal sphincter functions

Anticholinergic drugs are used on an empirical basis for treatment of functional disturbances after restorative proctocolectomy, but their mode of action on ileal pouch performance is mainly unknown. We studied the acute effects of atropine or benzilonium on pouch characteristics and anal sphincter function in 20 patients with a pelvic pouch. Pouch volume was increased by 27% by atropine at distension with 20 cm H2O (p less than 0.01). Benzilonium tended to have a similar effect, but the changes did not reach statistical significance (p = 0.06). Pouch contractility, as reflected by volume fluctuations and pressure changes during distension, was almost abolished by both drugs. Sensory thresholds for sense of filling and, particularly, urge were raised. Resting anal pressure was slightly lowered, whereas no significant effect was found on maximal squeeze pressure. In conclusion, anticholinergics appear to have specific properties of action on small-intestinal reservoirs, constituting possible explanations for the empirically observed beneficial effects of anticholinergic treatment of functional disturbances after restorative proctocolectomy.