Adding Second Drug No Help in Alzheimer's

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In moderate-to-severe Alzheimer's disease, continuing treatment with donepezil, a cholinesterase inhibitor, had some benefits, but adding memantine (Namenda) did not.
Note that memantine yielded similar benefits compared with placebo but the combination of memantine and donepezil was no better than donepezil alone.

For patients with moderate-to-severe Alzheimer's disease, continuing treatment with donepezil -- a cholinesterase inhibitor -- has some benefits, but adding memantine (Namenda) does not, a randomized trial showed.

Compared with stopping donepezil, continuing treatment for a year resulted in significant improvements in cognition and performance of the activities of daily living (P<0.001 for both), according to Robert Howard, MD, of King's College London, and colleagues.

Memantine yielded similar benefits compared with placebo but the combination of memantine and donepezil was no better than donepezil alone, the researchers reported in the March 8 issue of the New England Journal of Medicine.

In an accompanying editorial, Lon Schneider, MD, of the University of Southern California in Los Angeles, said the results with donepezil in the trial may not apply to other cholinesterase inhibitors because of differences in pharmacokinetics and mechanisms of action.

"Nor should the ... results be interpreted as evidence of the efficacy of indefinite treatment with donepezil," he noted. "More research is needed to assess the long-term benefits, the potential for harm and physiological tolerance, and the safe discontinuation of cholinesterase inhibitors as Alzheimer's disease progresses."

Cholinesterase inhibitors -- including donepezil -- have shown some benefits in patients with mild-to-moderate Alzheimer's disease, although no treatments have been able to halt disease progression.

When the disease worsens, clinicians must make a decision about continuing treatment, which is complicated by a greater risk of adverse outcomes, the need for permanent pacemakers, and hip fractures when treatment is not stopped.

In the DOMINO study, Howard and colleagues evaluated the effects of continuing donepezil with or without the addition of memantine in 295 patients with moderate-to-severe Alzheimer's disease who had been treated with donepezil for at least three months.

The patients were living in the community and either had a live-in caregiver or someone who visited them at least once a day.

The researchers assigned the patients to one of four groups for one year:

Continue donepezil at a dose of 10 mg daily and start placebo memantine
Continue donepezil and start memantine at a dose increasing to 20 mg daily
Gradually discontinue donepezil and receive placebo donepezil and placebo memantine
Gradually discontinue donepezil, receive placebo donepezil, and start memantine
The coprimary outcomes of the trial were changes on the Standardized Mini-Mental State Examination (SMMSE) and on the caregiver-rated Bristol Activities of Daily Living Scale (BADLS). The minimum clinically important differences were defined as 1.4 points and 3.5 points, respectively.

Compared with patients who stopped donepezil, those who continued treatment scored 1.9 points better on the SMMSE and 3 points better on the BADLS. Only the difference on the SMMSE exceeded the minimum clinically important threshold.

In his editorial, Schneider said the 1.9-point difference "is potentially important because many of the patients were severely impaired, on the cusp for needing nursing home care, and slightly worse cognitive function could affect their ability to remain at home."

Compared with patients who received placebo memantine, those who started the drug scored 1.2 points better on the SMMSE and 1.5 points better on the BADLS (P≤0.02 for both), although both figures fell short of being clinically important.

Combining donepezil and memantine was not superior to donepezil alone.

"Although memantine appears to be helpful for the treatment of moderate-to-severe Alzheimer's disease when used alone or when replacing donepezil, the results of the DOMINO trial do not support the typical use in the U.S., and an FDA-approved use, as add-on therapy to established donepezil treatment," according to Schneider, who noted that the finding conflicts with a previous, shorter trial.

Howard and colleagues pointed out that neither donepezil nor memantine halted the overall loss of cognitive function and functional abilities.

Compared with the changes in patients who received placebo for both drugs, the gains seen in the SMMSE score with donepezil and memantine represented just 32% and 20%, respectively, of the total decline during the study. The figures for the BADLS scores were 23% and 11%, respectively.

There were 188 serious adverse events, but only six were considered possibly related to the study drugs. Rates did not differ between groups.