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NEWS FROM THE ANA ANNUAL MEETING: New Analysis Finds Benefit of Combination Memantine-Donepezil in Moderate-to-Severe Alzheimer's

Collins, Thomas R.

doi: 10.1097/
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In a pooled analysis of four separate randomized trials totaling about 1,500 patients — including 438 memantine-donepezil patients; 428 on donepezil alone; and 304 on memantine alone — patients taking the combination therapy fared significantly better than those taking monotherapy on an array of measures of cognition and daily living activities.

NEW ORLEANS — Patients with moderate-to-severe Alzheimer's disease (AD) who took combination memantine-donepezil therapy performed significantly better on an array of tests than those taking one drug or the other, according to a pooled analysis performed by Forest Pharmaceuticals, the manufacturer of Namenda, the memantine brand name.

The analysis is one of the largest to compare the combination therapy to monotherapy. Forest combined the results of four separate randomized trials totaling about 1,500 patients — including 438 memantine-donepezil patients; 428 on donepezil alone; and 304 on memantine alone. Assessments using scales for cognition, function, behavior and global status were done at baseline, week 12 and at the end of the studies at either 24 or 28 weeks.

Pooling the data allowed the company to compare the memantine-donepezil combination to memantine alone for the first time. It also allowed for a larger comparison of the combination and donepezil alone, the company said.

A clinician not associated with the study, though, said it is merely a “rehashing” without any new information and is essentially sophisticated marketing.

Treatment of Alzheimer's patients with a cholinesterase inhibitor like donepezil, followed by memantine when the disease advanced to the moderate-to-severe stage, is a standard practice. But there have been mixed results on whether adding memantine makes a difference in those patients.

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A 295-patient study by UK investigators, published in The New England Journal of Medicine in 2012, looked at changes in scores on the Standardized Mini-Mental State Examination and the Bristol Activities of Daily Living Scale. The investigators found that there was no significant difference after a year between moderate-to-severe patients on donepezil alone and memantine plus donepezil.

A study by Harvard researchers, including 143 moderate-to-severe AD patients, published in January in Alzheimer's Research and Therapy, found that combination therapy outperformed donepezil alone in cognition (using the Mini-Mental State Examination), function and global status.

Two of the trials used in Forest's analysis were comparisons of memantine immediate release (IR) and placebo, and another was memantine IR added to donepezil compared to donepezil. The fourth was memantine's extended release form added to a cholinesterase inhibitor compared to a cholinesterase inhibitor alone — most of the cholinesterase inhibitor used was donepezil, and only the subjects specifically on donepezil were included in the pooled analysis. [See “Breakdown of the Meta-Analysis Data.”]

Stephen M. Graham, PhD, study director at Forest Laboratories, said the size is a strength of the study — and large numbers are especially necessary in studies of AD.

“In clinical trials of Alzheimer's, you need several hundred patients per arm just because of the intrinsic variability that you get between patients because of the subjective nature of many of these tests,” he said.



He drew attention to the way in which the patients getting combination therapy either were about the same at the end of the study's 24 weeks as they were at baseline, or were better.

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David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN, who specializes in Alzheimer's, said Forest's original studies, on which the new analysis is based, did appear to show a benefit to combination therapy in severe-to-moderate disease.

But the use of the Severe Impairment Battery as the measure of cognition, he said, left room to wonder how meaningful the differences are. “The SIB was developed for more severe patients and the clinical relevance of a change on the SIB is not really well-established,” he said.

He said clinicians shouldn't put much stock into this new analysis. “My view of these meta-analyses is that they basically represent a sophisticated form of marketing, and that there's no additional data in these that isn't contained or wasn't contained in the original articles,” Dr. Knopman said.

Dr. Graham acknowledged that assessing what the differences mean clinically might be difficult. “It is still an area of great debate as to how to translate so many points into something that is clinically meaningful change,” he said.

The more important question, he said, is whether the patients, on average, show a difference over time.

“I think that's how you have to look at these data,” he said. “Not just simply in terms of the points themselves, because it may be very difficult to say this is a meaningful change of two or three or four points, but rather looking at the profile over time and seeing how they have either been able to maintain [cognition] or whether they have a reduced rate of decline.”

Dr. Knopman was also concerned that the presentation of these meta-analyses of prior studies, even though they're studies on moderate-to-severe AD, might boost interest in the use of memantine in mild forms, as well. A 2011 study in the Archives of Neurology by investigators at the University of Southern California, using data from the Alzheimer's Disease Neuroimaging Initiative, found that memantine was being used in 47.5 percent of patients with mild AD, even though the drug isn't approved by the Food and Drug Administration for that stage. And past studies by Forest attempted to show efficacy in mild AD, but failed, Dr. Knopman said.

“Practitioners are using it (in mild AD) because they're desperate for something to do. And when they start someone on donepezil or one of the other cholinesterase inhibitors, and they don't see a great deal of benefit — because the cholinesterase inhibitors themselves are modest in their benefit — then they say, ‘What else can we do?’”

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•. Howard R, McHane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012 Mar 8;366(10):893–903.
    •. Atri A, Molinuevo JL, Lemming O, et al. Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy. Alzheimers Res Ther 2013;5(1):6).
      •. Schneider LS, Insel PS, Weiner MW, et al. for the Alzheimer's Disease Neuroimaging Imitative. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol 2011 Jan;68(1):58–66.
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