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For patients with moderate to severe Alzheimer's disease, does continuing donepezil and/or adding memantine offer any clinically meaningful benefit?
Continuing donepezil (Aricept) in patients whose Alzheimer's disease (AD) is becoming more severe has a benefit that is statistically significant but unlikely to be clinically meaningful. (LOE = 1b)
Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012;366(10):893-903. [PMID:22397651]
Randomized controlled trial (double-blinded)
Donepezil is approved for use in patients with mild to moderate AD, and memantine is approved for those with moderate to severe disease. In both cases, benefits are modest, with statistically significant but clinically questionable differences in scores that measure cognition and function. In this study, 295 patients with AD who had received donepezil for at least 3 months and had a score on the Standardized Mini Mental State Examination (SMMSE) between 5 and 13 (out of 30) were included. All patients were at the point at which their physician was considering either stopping donepezil or changing to memantine. The mean age of participants was 77 years, and 64% had taken donepezil for 2 or more years. They were randomized into 1 of 4 groups, which is called a Latin square design: (1) donepezil 10 mg plus memantine 20 mg, (2) donepezil plus placebo, (3) placebo plus memantine, or (4) dual placebos. Doses given are final doses after gradual escalation over a 1-month period. Groups were balanced at the start of the study and analysis was by intention to treat. The primary outcomes were the Bristol Activities Daily Living Scale (BADLS, 0 to 60, with a 3.5-point difference considered clinically significant), the SMMSE (0 to 30 points, with 1.4 points considered clinically significant) and the Neuropsychiatric Inventory (NPI, 0 to 144 points, with 8 points considered clinically significant). I disagree that these differences are clinically significant; studies comparing scale scores with global assessment of improvement have shown that differences of at least 10% are needed before patients or caregivers note a meaningful improvement (Emerg Med J 2001;18:205-207). Withdrawals were similar between groups, with the exception of more withdrawals in the memantine-only group than in the donepezil plus memantine group or the donepezil-only group (15 vs 6 and 8, respectively, significance not reported). Patients were followed up for up to 1 year. Many patients stopped taking the medication prematurely or did not adhere well to the medication, taking it less than 70% of the time. There was no significant advantage to the combination of memantine and donepezil or to donepezil alone. There was also no advantage of memantine over placebo. For the comparison of continued donepezil versus placebo, there was a small benefit on the SMMSE (1.9 points; 95% CI, 1.3 - 2.5 points) and on the BADLS (3 points; 95% CI, 1.8 - 4.3 points), but not on the NPI. The only difference exceeding their prespecified level of "clinical significance" was on the SMMSE score, and that difference of 1.9 points on a 30-point scale is unlikely to be noticeable by anyone other than a neuropsychiatrist.