OBJECTIVES: There is limited research evaluating the safety of Cholinesterase inhibitors (ChEIs) based on real-world data. Additionally, the moderating effect of sex on outcomes is not well-studied in dementia. This study evaluated the sex-based effects on the risk of serious events with individual ChEIs in older adults with dementia.

METHODS: This was a retrospective cohort study of patients ≥65 years with a dementia diagnosis using 2013-2015 Medicare claims data. Patients were selected with incident use of ChEIs, namely donepezil, galantamine, or rivastigmine, with a six-month washout period. The primary outcome of interest was serious events defined as Emergency Department visits, inpatient hospitalizations, or death within six months of ChEI initiation. Cumulative incidence functions curves, Gray’s test, and Fine and Gray’s proportional sub-distribution hazard model with inverse probability of treatment weighting(IPTW) generated using generalized boosted models(GBM) were used to assess sex-based effects on the risk of serious events across individual ChEIs.

RESULTS: The study included 767,684 older adults with dementia who were incident users of ChEIs (donepezil 79.42%, rivastigmine 17.67 %, galantamine 2.91%). There were 68.29% women and 31.70% men in the cohort. Fine and Gray’s proportional sub-distribution hazard model revealed that Rivastigmine(aHR 1.14; 95% CI, 1.09-1.18) and galantamine(aHR 1.52; 95% CI, 1.26 - 1.75) were associated with an increased risk of serious events compared to donepezil. However, sex-based interaction effects with ChEIs were significant. The stratified analysis found that women using rivastigmine (aHR 1.18; 95% CI, 1.06 - 1.31) were at increased risk of serious events compared to women using donepezil. Men using galantamine (aHR 1.71; 95% CI, 1.17-2.51) were at increased risk of serious events compared to men using donepezil.

CONCLUSIONS: This study found that the risk of serious events differs across sex. The study findings highlight the moderation effect of sex on ChEIs to assist providers in delivering personalized care in dementia