Donepezil or Memantine Improved Cognitive Functioning in Moderate-to-Severe Alzheimer Disease

David Burke, BMed, MRCPsych, FRANZCP

Ann Intern Med. 19 June 2012;156(12):JC6-10

Question: In community-dwelling patients with moderate-to-severe Alzheimer disease, what are the benefits of continuing donepezil and/or initiating memantine treatment?

Design: Randomized, 2 x 2 factorial, placebo-controlled trial (Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease [DOMINO] study). Current Controlled Trials ISRCTN49545035.

Allocation: Concealed.*

Blinding: Blinded* (patients, clinicians, outcome assessors, and {trialists}†).

Follow-up period: 30 weeks. Follow-up at 1 year was < 80% (results not reported in this abstract).

Setting: {14 clinical centers in the UK.}†

Patients: 295 community-dwelling residents (mean age 77 y, 65% women) who had probable or possible moderate or severe Alzheimer disease, had been prescribed donepezil for≥ 3 continuous months at a dose of 10 mg for≥ 6 previous weeks, and scored 5 to 13 on the Standardized Mini-Mental State Examination (SSMSE). Eligible patients had caregivers who lived with them or visited them daily, and their clinicians were considering changing their drug treatments. Exclusion criteria included severe or unstable medical conditions and use of memantine.

Intervention: Continuation of donepezil with placebo memantine (n = 73), continuation of donepezil plus memantine (n = 73), discontinuation of donepezil plus placebo memantine (n = 73), or discontinuation of donepezil plus memantine (n = 76). Memantine was initiated in week 1 at a dose of 5 mg and increased weekly by 5-mg increments to a dose of 20 mg in week 4.

Outcomes: Cognitive (SMMSE) and functional (Bristol Activities of Daily Living Scale [BADLS]) scores.

Patient follow-up: 83% (intention-to-treat analysis).

Main results: The main results are in the Table. Groups did not differ for serious adverse events or death (P = 0.77).

Conclusions: In community-dwelling patients with moderate-to-severe Alzheimer disease, continued donepezil improved cognitive functioning and activities of daily living at 30 weeks. Memantine improved cognitive functioning at 30 weeks.

Donepezil or memantine vs placebo in moderate-to-severe Alzheimer disease‡

Intervention (vs placebo)
Difference at 30 wk (95% CI)
SMMSE§ Donepezil 2.6 (1.6 to 3.7)
Memantine 1.5 (0.5 to 2.6)
BADLS|| Donepezil −3.9 (−6.3 to −1.5)
Memantine −1.9 (−4.3 to 0.5)

‡CI defined in Glossary.

§Standardized Mini-Mental State Examination (scores range from 0 to 30, higher scores indicate better cognitive functioning); minimum clinically important difference is 1.4 points.

||Bristol Activities of Daily Living Scale (scores range from 0 to 60, higher scores indicate greater impairment); minimum clinically important difference is 3.5 points.