Memantine, acetylcholinesterase inhibitors, and quality-of-care outcomes among patients with cognitive impairment: an emulated trial design.

INTRODUCTION: We evaluated the effect of acetylcholinesterase inhibitors (AChEIs) and memantine on non-cognitive outcomes by implementing emulated trials in electronic health records. METHODS: Individuals diagnosed with cognitive impairment who initiated AChEIs or memantine were matched to up to five non-initiators. Associations of medication initiation with 11 non-cognitive outcomes were estimated using Cox proportional hazards models. We calculated e-values for each hazard ratio (HR) and compared their magnitude to socioeconomic predictors of memantine and AChEI use in a US-based cohort. RESULTS: AChEI initiation was associated with nine of 11 adverse outcomes. For example, the HR for antipsychotic use = 1.67 (95% confidence interval [CI]: 1.51 to 1.84) and depression HR = 1.86 (1.67 to 2.06). Results for memantine were similar. E-values varied from 1.45 to 2.11 for memantine and 1.40 to 2.44 for AChEIs. Many potential confounders had odds ratios (ORs) > 1.4 for initiation, including marital status (ORs = 1.36 to 6.67). DISCUSSION: Memantine and AChEIs were associated with adverse outcomes, and residual confounding was unlikely to fully account for all the observed associations.