Galantamine for dementia due to Alzheimer's disease and mild cognitive impairment

 

Amanda Wei Yin Lim
Lon Schneider
Clement Loy




https://doi.org/10.1002/14651858.CD001747.pub4


Abstract


Background

Dementia leads to progressive cognitive decline, and represents a significant health and societal burden. Its prevalence is growing, with Alzheimer's disease as the leading cause. There is no cure for Alzheimer's disease, but there are regulatory‐approved pharmacological interventions, such as galantamine, for symptomatic relief. This review updates the 2006 version.
Objectives

To assess the clinical effects, including adverse effects, of 

galantamine in people with probable or possible Alzheimer's disease or mild cognitive impairment, and to investigate potential moderators of effect.
Search methods

We systematically searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register on 14 December 2022 using the term 'galantamine'. The Register contains records of clinical trials identified from major electronic databases (including CENTRAL, MEDLINE, and Embase), trial registries, grey literature sources, and conference proceedings. We manually searched reference lists and collected information from US Food and Drug Administration documents and unpublished trial reports. We imposed no language restrictions.
Selection criteria

We included double‐blind, parallel‐group, randomised controlled trials comparing oral galantamine with placebo for a treatment duration exceeding four weeks in people with dementia due to Alzheimer's disease or with mild cognitive impairment.
Data collection and analysis

Working independently, two review authors selected studies for inclusion, assessed their quality, and extracted data. Outcomes of interest included cognitive function, change in global function, activities of daily living, functional disability, behavioural function, and adverse events. We used a fixed‐effect model for meta‐analytic synthesis, and presented results as Peto odds ratios (OR) or weighted mean differences (MD) with 95% confidence intervals. We used Cochrane's original risk of bias tool (RoB 1) to assess the risk of bias in the included studies.
Main results

We included 21 studies with a total of 10,990 participants. The average age of participants was 74 years, and 37% were male. The studies' durations ranged from eight weeks to two years, with 24 weeks being the most common duration. One newly included study assessed the effects of galantamine at two years, and another newly included study involved participants with severe Alzheimer's disease.

Nineteen studies with 10,497 participants contributed data to the meta‐analysis. All studies had low to unclear risk of bias for randomisation, allocation concealment, and blinding. We judged four studies to be at high risk of bias due to attrition and two due to selective outcome reporting.

Galantamine for dementia due to Alzheimer's disease

We summarise only the results for galantamine given at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day), assessed at six months. See the full review for results of other dosing regimens and assessment time points.

There is high‐certainty evidence that, compared to placebo, galantamine improves: cognitive function, as assessed with the Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS‐cog) (MD‐2.86, 95% CI ‐3.29 to ‐2.43; 6 studies, 3049 participants; minimum clinically important effect (MCID) = 2.6‐ to 4‐point change); functional disability, as assessed with the Disability Assessment for Dementia (DAD) scale (MD 2.12, 95% CI 0.75 to 3.49; 3 studies, 1275 participants); and behavioural function, as assessed with the Neuropsychiatric Inventory (NPI) (MD ‐1.63, 95% CI ‐3.07 to ‐0.20; 2 studies, 1043 participants) at six months. Galantamine may improve global function at six months, as assessed with the Clinician's Interview‐Based Impression of Change plus Caregiver Input (CIBIC‐plus) (OR 1.58, 95% CI 1.36 to 1.84; 6 studies, 3002 participants; low‐certainty evidence). Participants who received galantamine were more likely than placebo‐treated participants to discontinue prematurely (22.7% versus 17.2%) (OR 1.41, 95% CI 1.19 to 1.68; 6 studies, 3336 participants; high‐certainty evidence), and experience nausea (20.9% versus 8.4%) (OR 2.89, 95% CI 2.40 to 3.49; 7 studies, 3616 participants; high‐certainty evidence) during the studies. Galantamine reduced death rates at six months: 1.3% of participants in the galantamine groups had died compared to 2.3% in the placebo groups (OR 0.56, 95% CI 0.33 to 0.96; 6 studies, 3493 participants; high‐certainty evidence).

Galantamine for mild cognitive impairment

We summarise results, assessed at two years, from two studies that gave participants galantamine at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day). Compared to placebo, galantamine may not improve cognitive function, as assessed with the expanded ADAS‐cog for mild cognitive impairment (MD ‐0.21, 95% CI ‐0.78 to 0.37; 2 studies, 1901 participants; low‐certainty evidence) or activities of daily living, assessed with the Alzheimer's Disease Cooperative Study – Activities of Daily Living scale for mild cognitive impairment (MD 0.30, 95% CI ‐0.26 to 0.86; 2 studies, 1901 participants; low‐certainty evidence). Participants who received galantamine were probably more likely to discontinue prematurely than placebo‐treated participants (40.7% versus 28.6%) (OR 1.71, 95% CI 1.42 to 2.05; 2 studies, 2057 participants) and to experience nausea (29.4% versus 10.7%) (OR 3.49, 95% CI 2.75 to 4.44; 2 studies, 2057 participants), both with moderate‐certainty evidence. Galantamine may not reduce death rates at 24 months compared to placebo (0.5% versus 0.1%) (OR 5.03, 95% CI 0.87 to 29.10; 2 studies, 2057 participants; low‐certainty evidence).

Results from subgroup analysis and meta‐regression suggest that an imbalance in discontinuation rates between galantamine and placebo groups, together with the use of the 'last observation carried forward' approach to outcome assessment, may potentially bias cognitive outcomes in favour of galantamine.
Authors' conclusions

Compared to placebo, galantamine (when given at a total dose of 16 mg to 24 mg/day) slows the decline in cognitive function, functional ability, and behaviour at six months in people with dementia due to Alzheimer's disease. Galantamine probably also slows declines in global function at six months. The changes observed in cognition, assessed with the ADAS‐cog scale, were clinically meaningful. Gastrointestinal‐related adverse events are the primary concerns associated with galantamine use in people with dementia, which may limit its tolerability. Although death rates were generally low, participants in the galantamine groups had a reduced risk of death compared to those in the placebo groups. There is no evidence to support the use of galantamine in people with mild cognitive impairment.

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001747.pub4/full