Long-term effect of discontinuing anticholinesterase treatment on cognitive decline and mortality in Alzheimer's disease in France: a quasi-experiment and target trial emulation study

TL;DR

A study in France found that stopping cholinesterase inhibitors in Alzheimer's patients led to faster cognitive decline over four years, suggesting these drugs may still be beneficial.

Contribution

The study provides real-world evidence of the long-term cognitive benefits of cholinesterase inhibitors in Alzheimer's disease.

Findings

Discontinuing cholinesterase inhibitors led to a 1.81-point greater decline in MMSE scores after four years.

No significant difference in mortality was observed between groups over five years.

The study supports the clinical relevance of cholinesterase inhibitors for mild-to-moderate Alzheimer's.

Abstract

In 2018, France withdrew reimbursement for cholinesterase inhibitors (ChEIs) in Alzheimer's disease, citing modest efficacy, lack of long-term benefit, and safety concerns. This policy shift provided a unique opportunity to assess ChEI effectiveness in real-world settings, by evaluating, among patients treated with ChEI between 01/08/2017 and 01/08/2018, the impact of treatment discontinuation on cognitive decline (MMSE score) and survival.

Using the French National Alzheimer's Database (BNA) and Meotis databases, we emulated a pragmatic, intention-to-treat trial comparing patients who discontinued ChEIs after delisting to those who continued treatment, under quasi-experimental conditions. To model cognitive trajectories, we used the inverse probability treatment-weighted (IPTW) cohort and applied mixed-effects models with random intercepts across all follow-up visits. Survival was estimated with a pooled logistic regression including treatment group, follow-up time, and an interaction between treatment and time.

The mean difference in MMSE decline between discontinuers and continuers after one year was 0·97 points (95% CI 0·68–1·27, p < 0·001), reaching 1·81 points (0·91–2·71, p < 0·001), after four years. No significant difference in mortality (RR 1·10, 95% CI [0·95–1·29]) was observed over a five-year period.

Our findings confirm and extend prior trials by demonstrating the sustained cognitive benefits of ChEIs in a real-world setting. While acknowledging the limitations associated with its retrospective nature, our study argues for reconsidering the 2018 delisting decision, as ChEIs remain safe and clinically relevant for mild-to-moderate Alzheimer's disease.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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