Continuing Donepezil Appears Best for Some Alzheimer’s Patients

Patients with moderate or severe Alzheimer’s disease who continued to worsen despite treatment with donepezil appeared to retain a small but significant benefit over those who added or switched to memantine or stopped taking medication for Alzheimer’s altogether in a randomized trial.

The patients in the 1-year study, DOMINO (Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease), who continued on donepezil (Aricept) showed improved cognitive and functional outcomes, compared with all other groups, Dr. Robert Howard of the Institute of Psychiatry, King’s College London, and his associates reported March 8 in the New England Journal of Medicine.

Patients who stopped donepezil and started memantine (Namenda) showed smaller but still significant benefits. Those who stopped donepezil and didn’t switch to memantine did not improve. And patients who continued donepezil and added memantine to their regimen did not improve further than those who simply continued donepezil.

However, “the improvements in cognition and function associated with donepezil and memantine were small relative to the overall size of the decline in cognitive and functional status that was seen in all patients,” the investigators noted.

Noting that there is little evidence to guide the difficult decision regarding continuing or changing treatment when Alzheimer’s disease (AD) progresses, Dr. Howard and his colleagues studied 295 community-living patients with moderate or severe AD who had already taken donepezil for 2-3 years and whose clinicians were considering changing medication.

All the patients scored between 5 and 13 on the Standardized Mini-Mental State Examination (SMMSE), which ranges in score from 0 to 30; higher scores indicate better cognitive function. The investigators randomly assigned them to continue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking a placebo (73 patients), discontinue donepezil and start taking memantine (76 patients), or continue donepezil and start taking memantine (73 patients).

During a 1-year follow-up period, 137 (46%) withdrew from the trial, usually because of a perceived lack of benefit from continued treatment.

Compared with patients who discontinued donepezil, those who continued the drug scored better by 1.9 points on the SMMSE. They also scored better by 3 points on the 60-point, caregiver-rated Bristol Activities of Daily Living Scale (BADLS), indicating less functional impairment, the investigators said (N. Engl. J. Med. 2012;366:893-903).

Patients who began taking memantine scored a mean of 1.2 higher on the SMMSE and a mean of 1.5 points better on the BADLS, compared with patients who did not start the drug. However, combined treatment with the drugs did not provide any significant benefits beyond treatment with donepezil alone for any of the primary or secondary outcomes.

This study was funded by the U.K. Medical Research Council and the Alzheimer’s Society. Pfizer-Eisai and Lundbeck donated the drugs and placebos used in the study. Many of the authors reported financial ties to Pfizer and Eisai, which together market donepezil in the United States, as well as other companies that manufacture drugs for Alzheimer’s disease.

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