Donepezil Beneficial in Moderate to Severe Alzheimer's

Caroline Cassels

March 07, 2012

March 7, 2012 — The cholinesterase inhibitor donepezil (Aricept, Pfizer), which is widely used to treat mild to moderate Alzheimer's disease (AD), also appears to be beneficial in patients with moderate to severe disease, new research shows.

Further, the N-methyl-d-aspartate-receptor antagonist memantine was also shown to be beneficial in this patient population, although its effect was more modest compared with donepezil.

The multicenter, double-blind, randomized controlled trial conducted by investigators at King's College London in the United Kingdom is the first study to demonstrate the value of continued drug intervention for those patients with moderate to severe AD who have deteriorated beyond the point where donepezil is currently recommended.

"For the first time, we have robust and compelling evidence that treatment with these drugs can continue to help patients at the later, more severe stages of the disease," lead author Robert Howard, MD, from the Institute of Psychiatry at King's College, said in a statement.

The study is published in the March 8 issue of the New England Journal of Medicine.

Limited Evidence, Difficult Decision

Most guidelines advocate treatment with a cholinesterase inhibitor. However, the investigators note that some recommend discontinuation of these agents when AD becomes severe.

In addition, memantine has been shown to be effective primarily in moderate or severe AD, and 1 study suggested that combination treatment with memantine and a cholinesterase inhibitor was more effective than treatment with a cholinesterase inhibitor alone. However, to date, this finding has not been replicated.

The researchers also point out that all trials examining cholinesterase inhibitors in severe AD have been conducted in patients residing in nursing homes. Further, none of these trials have investigated the strategy of continuing treatment with cholinesterase inhibitors in patients already taking these drugs.

"There is very limited evidence to guide the difficult decision regarding the continuation or discontinuation of treatment when the disease progresses, but continued treatment is associated with an increase in adverse outcomes, including syncope, the need for insertion of permanent pacemakers, and hip fractures," the investigators write.

The aim of the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO) trial was to determine whether continuation with donepezil vs discontinuation of the drug would be associated with better cognition and function over a period of 52 weeks.

The investigators also tested whether treatment with memantine vs placebo would be associated with better cognition and function. Finally, they examined whether combination treatment with donepezil and memantine would have additive or synergistic benefits.

Noticeable Clinical Improvement

The study included 295 patients living in the community who had moderate to severe AD, defined as a score of 5 to 13 on the Standardized Mini-Mental State Examination (SMMSE), who had been treated with donepezil for at least 3 months before trial entry.

Participants were randomly assigned to continue donepezil (n = 73), discontinue donepezil (n = 73), discontinue donepezil and start memantine (n=76), or continue donepezil and start memantine (n = 73) for a period of 52 weeks.

The study's co-primary endpoints were scores on the SSMSE and on the Bristol Activities of Daily Living Scale (BADLS). Scores on the SSMSE range from 0 to 30, with higher scores indicating better cognitive function. In contrast, higher scores on the BADLS, which range from 0 to 60, indicate greater impairment.

For the purposes of the study, the minimum clinically important change in SSMSE and BADLS scores were 1.4 points and 3.5 points, respectively.

The results showed that patients who continued donepezil had a score on the SMMSE that was higher by an average of 1.9 points vs those who discontinued the drug (95% confidence interval [CI], 1.3 - 2.5; P < .001) and a score on the BADLS that was lower by 3.0 points (95% CI, 1.8 - 4.3; P < .001).

Those assigned to receive memantine had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 - 1.8; P < .001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 - 2.8; P < .02) vs participants who received placebo.

The authors note that there was no significant benefit associated with the combination of donepezil and memantine over donepezil alone.

"We observed that patients who continued taking donepezil were better able to remember, understand, communicate, and perform daily tasks for at least a year longer than those who stopped taking the drugs. These improvements were noticeable to patients, their caregivers, and doctors," said Dr. Howard.

"As patients progress to more severe forms of Alzheimer's disease, clinicians are faced with a difficult decision as to whether to continue or not with dementia drugs, and until now, there has been little evidence to guide that decision," he added.

It is estimated that 18 million people worldwide suffer from AD, which is the most common cause of dementia. According to the World Health Organization, of the 35 million people currently living with dementia globally, 58% live in low- and middle-income countries, and this figure is projected to reach 71% of the total by 2050.

"Both donepezil and memantine will soon be off patent and available in very cheap generic preparations. These findings will greatly increase the numbers of patients in the developed and developing world," said Dr. Howard.

More Research Needed

In an accompanying editorial, Lon S. Schneider, MD, from the departments of psychiatry and neurology at the University of Southern California, notes that the fact that the average SMMSE was "1.9 points lower...in the group that discontinued donepezil than in the group that continued the drug is potentially important because many of the patients were severely impaired, on the cusp of needing nursing home care, and slightly worse cognitive function could affect their ability to remain at home."

However, Dr. Schneider cautions that the "results of the DOMINO trial should not be interpreted as evidence of the efficacy of indefinite treatment with the drug."

"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," Dr. Schneider writes.

Further, he notes, the results with donepezil in this study cannot necessarily be applied to other cholinesterase inhibitors, including galantamine and rivastigmine, because the pharmacokinetics, mechanisms, and other actions of these drugs may differ.

Disclosures for the authors and Dr. Schneider are available at  www.nejm.org.

NEJM. 2012; 366:893-903; 957-959. Abstract

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