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Objectives: The objectives of this research were to (1) Evaluate the prevalence and predictors of cumulative anticholinergic burden among older adults with Alzheimer’s disease (AD) initiating Cholinesterase inhibitors (ChEIs); (2) Assess the risk of delirium associated with cumulative anticholinergic burden in older adults with AD; (3) Evaluate the treatment modification among older adults with AD after a delirium event. Methods: This study involved a new-user retrospective cohort study design using multi-year (2013-2017) Medicare claims data involving parts A, B, and D. The study sample included community-dwelling older adults (age 65 and older) with a diagnosis of AD initiating any of the ChEIs (donepezil, rivastigmine, or galantamine). The cumulative anticholinergic burden was calculated based on the Anticholinergic Cognitive Burden scale and patient-specific dosing using the defined daily dose over the defined period after ChEIs initiation. For objective 1, the dependent variable of interest for objective one was the cumulative anticholinergic burden levels, dichotomized into moderate-high (total standardized daily anticholinergic exposure (TSDD) over a year score ≥ 90) versus low-no (score 0–89). The primary outcome of interest for objective two was delirium, and the exposure of interest was the monthly cumulative anticholinergic burden, calculated as the monthly total standardized daily dose of medications with anticholinergic effects and categorized as no (0), low (1-10), moderate (11-40), and high (>40) burden. The primary outcome measures of interest for objective three were changes in trend and level of cumulative anticholinergic burden, sedative load, and opioid load and were measured as monthly burden/load calculated based on standardized dosing during a 12-month baseline and follow-up period among patients who had a delirium event compared with patients who did not have a delirium event (control group). The conceptual framework of the Andersen Behavioral model was used to select the predisposing, enabling, and need factors. A multivariable logistic regression model was used to evaluate the predictors of high-moderate vs. low-no cumulative anticholinergic burden for objective one. A multinomial logistic regression model was also used to determine the factors associated with patients having moderate and high burden as compared to low-no burden. A multivariable Cox proportional-hazards regression model with inverse probability of treatment weighting (IPTW) generated using generalized boosted models was used to evaluate the risk of delirium associated with the cumulative anticholinergic burden for objective two. Separate patient-level segmented regression models were used for each outcome for objective three to evaluate changes in the cumulative anticholinergic burden, sedative load, and opioid load after the delirium event. In addition, propensity score-based stabilized weights were estimated to balance baseline predisposing, enabling, and need factors to compare the trend and slope of burden before and after the delirium event. Results: For the first objective, there were 222,064 older adults with AD with incident ChEI use. Overall, 80.48% had some anticholinergic burden, with 36.26% patients with moderate (TSDD scores 90-499), followed by 24.76% high (TSDD score>500), and 19.46% with low (TSDD score 1-89) burden categories. Predisposing factors such as age, African American, Asian, or Hispanic race, and need factors included comorbidities such as dyslipidemia, syncope, delirium, fracture, pneumonia, epilepsy, and claims-based frailty index were less likely to be associated with the moderate-high anticholinergic burden. The factors that increased the odds of moderate-high burden were predisposing factors such as female sex, enabling factors such as dual eligibility and diagnosis year, and need factors such as baseline burden, behavioral and psychological symptoms of dementia, depression, insomnia, urinary incontinence, irritable bowel syndrome, anxiety, muscle spasm, gastroesophageal reflux disease heart failure, and dysrhythmia. For the second objective, the study identified 143,320 older adults with AD who were incident users of ChEIs. Most patients were in the low-no burden (62.73%) group, followed by high burden (21.12%) and moderate burden (16.14%). Overall, delirium diagnosis was observed in 19.11% of the cohort within one year of ChEIs prescription. The Cox regression model with IPTW found that moderate (aHR, 1.56; 95% CI, 1.52–1.61; p< 0.0001) and high cumulative anticholinergic burden (aHR, 1.45; 95% CI, 1.42–1.49; p<0.0001) were associated with an increased risk of delirium compared to low-no burden. For the third objective, the study included 80,019 older adults with AD with incident ChEI use (mean age 81.06± 7.03, 68.72% females, 85.09% White). Of these, 13,690 patients had delirium events. There was an immediate decline in monthly cumulative anticholinergic burden after the delirium event (on average, -0.86, p-value:0.01). A similar decline was observed when examining sedative load (-0.06, p-value:0.002) after the delirium event. However, there was no decline in opioid load (-0.50, p-value:0.18) observed after the delirium event. However, the burden increased in each group over the one-year follow-up period compared to patients without delirium events. Conclusions: The study found that four out of five older adults with AD had some level of anticholinergic burden, with over 60% of them having a moderate-high anticholinergic burden. Several predisposing, enabling, and need factors were associated with the cumulative anticholinergic burden. Moderate and high levels of cumulative anticholinergic burden were associated with about 50% higher risk of delirium compared to low-no burden. Moreover, an immediate decline in burden levels was observed over the cumulative anticholinergic burden and sedative load outcomes; however, the trend over the one-year follow-up showed increasing burden/load across three groups (cumulative anticholinergic burden, sedative load, and opioid load). The study findings suggest a critical need to reduce the cumulative anticholinergic burden and load of other deliriogenic medications over the short- and long-term to minimize delirium risk and associated consequences in older adults with AD.

Cumulative anticholinergic burden, Alzheimer's Disease, Delirium, Medicare population