Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review
Lucy E Farrimond1, Emmert Roberts, Rupert McShane
1University of Oxford Medical School, Oxford, UK.
Background:
Memantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer.
Objectives:
To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results.
Design:
Systematic review and meta-analysis of randomised controlled trials.
Data Sources:
The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011.
Data Synthesis:
Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine.
Results:
Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=-0.29, 95% CI -0.45 to -0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=-0.20, 95% CI -0.31 to -0.09), cognition (SMD=-0.25, 95% CI -0.36 to -0.14) and behaviour and mood (SMD=-0.17, 95% CI -0.32 to -0.03) but not on function (SMD=-0.04, 95% CI -0.21 to 0.13) at 6 months. No clinical data have been reported from a 1-year trial, although this found 'no significant benefit' on any clinical measures at 1 year.
Conclusions:
These results suggest that there may be a small benefit at 6 months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1 year. Legislation on the form and content of registry posted results is needed in Europe.
Insights
Adding memantine to cholinesterase inhibitors may offer a small, short-term benefit for Alzheimer's disease patients. However, this combination therapy shows no significant functional improvement at 6 months and no benefit at 1 year compared to monotherapy.
Area of Science:
- Neuroscience
- Pharmacology
- Geriatrics
Background:
- Memantine is approved for moderate-to-severe Alzheimer's disease (AD).
- National Institute for Clinical Excellence (NICE) guidelines do not recommend combining memantine with cholinesterase inhibitors (AChEIs).
- The manufacturer disputed the meta-analysis underpinning NICE guidance.
Purpose of the Study:
- To compare the efficacy of AChEI monotherapy versus combination therapy (memantine + AChEI) in moderate-to-severe AD.
- To assess the impact of including unpublished data on treatment outcomes.
- To evaluate effects across clinical global impression, cognition, function, and behavior/mood domains.
Main Methods:
- Systematic review and meta-analysis of randomized controlled trials.
- Searched the Cochrane Dementia Group trial register (ALOIS) up to May 3, 2011.
- Conducted sensitivity analyses to evaluate the influence of data restrictions and unpublished trials.
Main Results:
- Pooled data for moderate-to-severe AD showed a small effect of combination therapy on cognition (SMD=-0.29).
- Including an unpublished trial (1317 participants) revealed small benefits at 6 months in global scores, cognition, and behavior/mood, but not function.
- A 1-year trial reported no significant benefit on any clinical measures.
Conclusions:
- Adding memantine to AChEIs may provide a small, short-term benefit at 6 months, particularly for global impression and cognition.
- The clinical relevance is uncertain due to a lack of functional improvement and inconsistent global impression results.
- Current randomized controlled trial data indicate no benefit of combination therapy over monotherapy at 1 year.
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