Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality

Abstract

Objective: To investigate whether cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer dementia and decreased risk of severe dementia or death.

Methods: Patients with Alzheimer dementia from the Swedish Dementia Registry starting on ChEIs within 3 months of the dementia diagnosis were included and compared to nontreated patients with Alzheimer dementia. In a propensity score-matched cohort, the association between ChEI use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores was examined with a mixed model, and severe dementia (MMSE score <10) or death as an outcome was assessed with Cox proportional hazards models.

Results: The matched cohort included 11,652 ChEI users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year; 95% confidence interval [CI] 0.06-0.20). ChEI users had a 27% lower risk of death (0.73, 95% CI 0.69-0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65-0.76) and lower risk of severe dementia (0.69, 95% CI 0.47-1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07-0.28).

Conclusions: ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia.

Classification of evidence: This study provides Class III evidence that for patients with Alzheimer dementia ChEIs decrease long-term cognitive decline and risk of death and that galantamine decreases the risk of severe dementia.

Figure 1. Flowchart of Included Patients

ChEI = cholinesterase inhibitors; MMSE = Mini-Mental State Examination.

Figure 2. Dose Response of ChEIs Using Cubic Splines With (A) MMSE Change and (B) All-Cause Death Risk Compared With Nonuse

Dose-response effect of increasing average cumulative daily dose of cholinesterase inhibitor (ChEI) compared to nonuse of ChEI: average (solid) and 95% confidence interval (dash lines). Horizontal axis represents the number of standard defined daily doses (DDDs) that patients took per day. For clarity, the DDD for each medication is shown with a vertical dotted line. For example, a patient taking galantamine 8 mg/d would be taking half the DDD of galantamine, which would be represented at the 0.5 point of the horizontal axis. In panel A, y-axis represents Mini-Mental State Examination (MMSE) score change. In panel B, y-axis represents adjusted hazard ratio for death. Model included ChEI treatment, visit time (class effect), interaction of ChEI treatment by visit, and baseline MMSE score. Reference was set at DDD 0. Cohort was matched for dementia diagnosis, age, sex, MMSE baseline score, comorbidity (hypertension, diabetes, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, renal disease, cancer, and atrial fibrillation), and medications (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blocking agents, calcium channel blockers, lipid-modifying agents, antipsychotics, and antidepressants).