Systematic review and meta-analysis of combination therapy with cholinesterase inhibitors and memantine in Alzheimer's disease and other dementias

Abstract

Background: N-methyl-D-aspartic acid antagonists (memantine) and cholinesterase inhibitors (ChEIs) are the only two approved classes of drugs to treat dementia; this paper explores the evidence for using these two treatments in combination.

Objective: To determine the efficacy and safety of using combination therapy with memantine and a ChEI to treat dementia in comparison to monotherapy with either memantine or a ChEI.

Methods: In March 2012, we systematically searched MEDLINE/PubMed, EMBASE, Cochrane library, and grey literature databases. All study types were included, except for case series or reports, which looked at combination therapy versus monotherapy in various dementing disorders. Data was pooled for blinded randomized controlled trials (RCTs) only; mean differences and standardized mean differences were used to determine effect sizes.

Results: Thirteen studies were included in this review; 3 were blinded RCTs, with a total of 971 Alzheimer's disease (AD) patients, which were included into the meta-analysis. No papers were found that primarily addressed combination therapy in other dementias. In the meta-analysis, small but statistically significant effect sizes were seen in favor of combination therapy among patients with moderate to severe AD on the scales of cognition (0.45-0.52; p < 0.0001), scales of functional outcomes (0.23-0.3; p < 0.01), and the neuropsychiatric inventory (3.7-4.4; p < 0.0001). Among the open-label studies, 3 out of 6 suggested benefits, as did the 4 included cohort studies. However, the high risk of bias encountered in the latter two study designs limits deducing any conclusions about benefit.

Conclusion: Although there were statistically significant changes in favor of combination therapy in moderate to severe AD, heterogeneity in scales and patient characteristics exists. However, it is unclear if clinically significant outcomes can be achieved using the combination therapy. More studies are required before a recommendation for combination therapy can be made.

Keywords: Alzheimer; Cholinesterase inhibitors; Combination treatment; Dementia; Dementia therapy; Memantine; Side effects.

Fig. 1

Flow chart of the results of the search process.

Fig. 2

Metagraphs of cognitive outcomes of mild to severe (3 studies) and moderate to severe (2 studies) subgroups. DMvsD = Combination therapy with donepezil and memantine versus monotherapy with donepezil, denoted by Roman numeral I; DMvsM = combination therapy with donepezil and memantine versus monotherapy with memantine, denoted by Roman numeral II. In Porsteinsson et al. [20], MMSE scores were pooled in the results, denoted as ‘a’. ADAS-cog scores were pooled in the analysis, denoted as ‘b’. Howard et al. [21] used the MMSE, Tariot et al. [13] used the SIB.

Fig. 3

Metagraphs of functional outcomes of mild to severe (3 studies) and moderate to severe (2 studies) subgroups. DMvsD = Combination therapy with donepezil and memantine versus monotherapy with donepezil, denoted by Roman numeral I; DMvsM = combination therapy with donepezil and memantine versus monotherapy with memantine, denoted by Roman numeral II. Scales used in each study: ADCS-ADL₂₃ in Porsteinsson et al. [20], ADCS-ADL₁₉ in Tariot et al. [13], and BADLS in Howard et al. [21]. Standardized mean differences were used to calculate effect sizes.

Fig. 4

Metagraphs of behavioral outcomes of mild to severe (3 studies) and moderate to severe (2 studies) subgroups. DMvsD = Combination therapy with donepezil and memantine versus monotherapy with donepezil, denoted by Roman numeral I; DMvsM = combination therapy with donepezil and memantine versus monotherapy with memantine, denoted by Roman numeral II. NPI scale was used in each study and mean differences were used in determining effect sizes.

Fig. 5

Metagraph of performance on CIBIC-Plus, available from 2 studies.

Fig. 6

Metagraphs of adverse outcomes of mild to severe AD (3 studies). DMvsD = Combination therapy with donepezil and memantine versus monotherapy with donepezil, denoted by Roman numeral I; DMvsM = combination therapy with donepezil and memantine versus monotherapy with memantine, denoted by Roman numeral II. The only significant results were from the analysis shown in ‘Dropouts II’, IIa denoting mild to severe and IIb denoting moderate to severe subgroups.