The quality of evidence is downgraded by indirectness of evidence (short follow-up, surrogate outcomes).
A treatment attempt with the combination of cholinesterase inhibitors and memantine is recommended for patients with moderate to severe Alzheimer's disease.
The recommendation is strong because of possible positive effect on activities of daily living and behavioral disturbances. The cost of cholinesterase inhibitors and memantine is low.
In a double-blind RCT 1 of patients with moderate to severe AD (MMSE scores of 5 to 14), already receiving donepezil, 404 participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n=203) or placebo (n=201) for 24 weeks.
The change in total mean scores favored memantine vs placebo treatment for SIB (Severe Impairment Battery; score range 0-100), 0.9 vs -2.5, respectively (p<0.001); for ADCS-ADL19 (19-item AD Cooperative Study-Activities of Daily Living Inventory, score range 0-54), -2.0 vs -3.4, respectively (p=0.03); and for the CIBIC-Plus (Clinician's Interview-Based Impression Change Plus Caregiver Input; score range 1-7), 4.41 vs 4.66, respectively (p=0.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively.
A meta-analysis 2 included 7 studies with a total of 2182 patients with Alzheimer's disease. Combination therapy significantly affected behavioral disturbance scores (SMD −0.13, 95% CI −0.24 to −0.02), activity of daily living scores (SMD −0.10, CI −0.19 to −0.01), and global assessment scores (SMD −0.15, CI −0.28 to −0.01). In addition, cognitive function scores (SMD −0.13, 95% CI −0.26 to 0.01) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer's disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects.
Although the clinical benefits in the included studies were small, a treatment attempt is warranted due to the debilitating nature of the disease and its impact on the patient's quality of life.
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