Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study

Abstract

Background: A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer's disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome.

Methods: Randomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints.

Results: Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores.

Conclusion: This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation.

Trial registration: ClinicalTrials.gov NCT00679627 . Registered 15 May 2008.

Keywords: Alzheimer’s disease; Baseline scores; Galantamine; Memantine; Mortality.

Fig. 1

Time to death by subgroup. DAD Disability Assessment for Dementia, MMSE Mini-Mental State Examination, hr hazard ratio, lcl lower confidence limit, ucl upper confidence limit

Fig. 2

a Mean difference of MMSE score by median age and memantine. Two sites (049134 and 049137) excluded from the analysis due to GCP noncompliance. Median age = 74. b Mean difference of MMSE score by DAD score and memantine. DAD Disability Assessment for Dementia, diff difference, MMSE Mini-Mental State Examination, lcl lower confidence limit, ucl upper confidence limit

Fig. 3

Mortality, cognitive, and functional outcomes of 24 months’ treatment with galantamine (dark green) or placebo (white or light green): a memantine nonusers and b memantine users. DAD Disability Assessment for Dementia, MMSE Mini-Mental State Examination

Fig. 4

a Mean difference of DAD score by MMSE score and memantine. Two sites (049134 and 049137) excluded from the analysis due to GCP noncompliance. b Mean difference of DAD score by median age and memantine. Two sites (049134 and 049137) excluded from the analysis due to GCP noncompliance. Median DAD score = 62.16. c Mean difference of DAD score by DAD score and memantine. DAD Disability Assessment for Dementia, diff difference, MMSE Mini-Mental State Examination, lcl lower confidence limit, ucl upper confidence limit