Donepezil and memantine for moderate-to-severe Alzheimer's disease.
Author(s): Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening
T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I,
Macharouthu A, O'Brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R,
Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R,
Johnson T, Bentham P, Phillips P.
Affiliation(s): Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom.
robert.j.howard@kcl.ac.uk
Publication date & source: 2012, N Engl J Med. , 366(10):893-903
BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors
for the treatment of mild-to-moderate Alzheimer's disease. It is not known
whether treatment benefits continue after the progression to moderate-to-severe
disease.
METHODS: We assigned 295 community-dwelling patients who had been treated with
donepezil for at least 3 months and who had moderate or severe Alzheimer's
disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination
[SMMSE, on which scores range from 0 to 30, with higher scores indicating better
cognitive function]) to continue donepezil, discontinue donepezil, discontinue
donepezil and start memantine, or continue donepezil and start memantine.
Patients received the study treatment for 52 weeks. The coprimary outcomes were
scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS,
on which scores range from 0 to 60, with higher scores indicating greater
impairment). The minimum clinically important differences were 1.4 points on the
SMMSE and 3.5 points on the BADLS.
RESULTS: Patients assigned to continue donepezil, as compared with those assigned
to discontinue donepezil, had a score on the SMMSE that was higher by an average
of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS
that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3)
(P<0.001 for both comparisons). Patients assigned to receive memantine, as
compared with those assigned to receive memantine placebo, had a score on the
SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and
a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The
efficacy of donepezil and of memantine did not differ significantly in the
presence or absence of the other. There were no significant benefits of the
combination of donepezil and memantine over donepezil alone.
CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued
treatment with donepezil was associated with cognitive benefits that exceeded the
minimum clinically important difference and with significant functional benefits
over the course of 12 months. (Funded by the U.K. Medical Research Council and
the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).
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