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Risk of Serious Adverse Events Associated With Individual Cholinesterase Inhibitors Use in Older Adults With Dementia: A Population-Based Cohort Study

Abstract

Background and Objective

Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk.

Methods

This was a retrospective cohort study using 2013–2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs.

Results

The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03–1.33) and galantamine (aHR 1.51; 95% CI 1.24–1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06–1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17–2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses.

Conclusion

The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

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Authors and Affiliations

Authors

Corresponding author

Correspondence to Rajender R. Aparasu.

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Funding

No funding was received for this research.

Conflict of Interest

Dr Aparasu has received research funding from Astellas Inc., Incyte Corp., Gilead and Novartis Inc. for projects unrelated to the current work. Prajakta P. Masurkar, Satabdi Chatterjee, Jeffrey T. Sherer, Hua Chen, and Michael L. Johnson declare no conflicts of interest for this article.

Ethical approval

This study was approved by the Institutional Review Board for the Protection of Human Subjects at the University of Houston under the exempt category (Exemption approval #STUDY00002792).

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Not applicable.

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Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Code availability

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Author contributions

Masurkar and Aparasu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition of data: Masurkar and Aparasu. Analysis of data: Masurkar. Interpretation of data: All authors. Drafting of the manuscript: Masurkar. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Masurkar, Johnson, Aparasu. Administrative, technical, or material support, and study supervision: Aparasu.

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Masurkar, P.P., Chatterjee, S., Sherer, J.T. et al. Risk of Serious Adverse Events Associated With Individual Cholinesterase Inhibitors Use in Older Adults With Dementia: A Population-Based Cohort Study. Drugs Aging 39, 453–465 (2022). https://doi.org/10.1007/s40266-022-00944-z

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