Cholinesterase Inhibitors and Memantine in More Advanced Alzheimer's Disease

The Debate Continues

Tzvi Dwolatzky; A Mark Clarfield

Disclosures

Aging Health. 2012;8(3):233-237. 

In This Article

Summary of Methods & Results

Howard et al. present the results of the DOMINO study,[1] designed as a multicenter, double-blind, placebo-controlled clinical trial. Subjects were resident in the community and had caregivers who either lived with them or visited them daily. All subjects had a diagnosis of moderate-to-severe Alzheimer's disease based on clinical criteria, and had scores ranging from 5 to 13 (of a maximum of 30, with lower scores indicating more impaired cognitive function) on the Standardized Mini-Mental State Examination (SMMSE). All patients were treated with donepezil for at least 3 months and were receiving a therapeutic dose of 10 mg daily for at least the past 6 weeks.

An important consideration in the design of this study was that the physician treating the patient was considering either stopping donepezil or adding memantine at the time of the study, based on the accepted guidelines of the UK NICE. Informed consent was obtained from those deemed to have the capacity to agree to participate in the study, and caregivers provided their own informed consent as well as their agreement for the patient to participate. The study was conducted in the UK and there were 15 participating centers.

Subjects were randomly assigned to one of four treatment arms. These included either continuation of treatment with donepezil at a dose of 10 mg daily, discontinuation of donepezil, discontinuation of donepezil and initiation of treatment with memantine, or continuation of donepezil with the addition of memantine. The authors determined two primary outcome measures, one evaluating cognitive function (SMMSE) and the other functional status, using the Bristol Activities of Daily Living Scale (BADLS). Secondary outcomes included behavioral and psychological symptoms of dementia as assessed by the Neuropsychiatric Inventory (NPI), health-related quality of life using the DEMQOL-Proxy and caregiver health status evaluated by the General Health Questionnaire 12 (GHQ-12). A strength of this study, as opposed to many previous studies in the field, was that minimum clinically important differences were predetermined based on data from the first 127 participants and prior to commencing data analysis. The predetermined change in scores was 1.4 points for SMMSE, 3.5 points for BADLS and 8 points for NPI.

While power calculations established that a sample size of 430 was required, only 295 subjects were enrolled. The authors explain this poor enrollment in the study as being the result of recruitment that was slower than anticipated, and the decision of the Medical Research Council, which provided public funds for the study, not to extend the recruitment period. The Medical Research Council based their decision on the assessment that the disadvantages of a delay in reporting the results outweighed the possible benefits of increasing the power of the study.

Randomization succeeded in that baseline characteristics of the four groups were similar, with no significant differences between the groups, apart from the total GHQ-12 score (p = 0.03). Mean age of the subjects was 77.1 years (standard deviation = 8.4) and the majority were female (65%). Subjects were almost entirely white (95%). The majority of participants (87%) had been receiving donepezil therapy for longer than 12 months. The mean SMMSE score was 9.1 (standard deviation = 2.6), and based on the SMMSE, 48% were determined to have moderate Alzheimer's disease, and 52% severe disease.

Cognitive outcomes were better in those subjects continuing treatment with donepezil by an average of 1.9 points on the SMMSE compared with those who discontinued the drug (95% CI: 1.3–2.5; p < 0.001). This level of improvement was deemed to be clinically significant, based on the predetermined minimum clinically important difference of 1.4 points. In addition, these subjects had better functional outcomes by an average of 3.0 points on the BADL (95% CI: 1.8–4.3; p < 0.001). Treatment with memantine alone was associated with better scores on the SMMSE by an average of 1.2 points (95% CI: 0.6–1.8; p < 0.001) than those who received placebo. While this may reflect better cognitive outcome, it fell short of the predetermined minimum clinically important difference of 1.4 points. The memantine group also had a better functional outcome, with BADL scores 1.5 points lower than the placebo group (95% CI: 0.3–2.8; p = 0.02), but this difference was not deemed to be clinically significant. Memantine treatment was also associated with fewer behavioral and psychological symptoms, as reflected by a NPI score 4.0 points lower in the treated group than those receiving placebo (99% CI: 0.6–7.4; p = 0.002), but this was also not considered to be clinically significant. Combination therapy, by adding memantine to donepezil, conferred no extra benefit to the cognitive and functional status of the subjects.

The authors found greater benefits for donepezil on the cognitive function (SMMSE) of patients with moderate disease (2.6 points; 95% CI: 1.5–3.7; p < 0.001) than those suffering from severe disease (1.3 points; 95% CI: 0.2–2.4; p = 0.02). However, the authors emphasize that this finding should be regarded with caution.

Those subjects receiving donepezil were significantly less likely to withdraw from the study than those who discontinued the drug (hazard ratio: 0.51; 95% CI: 0.36–0.72; p < 0.001). This finding probably reflects either improved efficacy or drug tolerability. Also, those receiving memantine were less likely to withdraw from treatment than those who received placebo (hazard ratio: 0.66; 95% CI: 0.47–0.93; p = 0.02). With regard to adverse events, a total of 188 serious adverse events occurred, although only six were considered to be possibly related to the study drugs. There were no differences between the groups with regard to serious adverse events or death.

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