Donepezil Effective, Safe in Late-Stage Alzheimer's Disease

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Donepezil Effective, Safe in Late-Stage Alzheimer's Disease


Caroline Cassels



August 1, 2007 — New research, published in the July 31 issue of Neurology, shows that donepezil improves memory and global function in patients with severe Alzheimer's disease (AD).

Led by Sandra Black, MD, from Sunnybrook Health Sciences Center in Toronto, Ontario, the randomized, double-blind, placebo-controlled trial found that donepezil improved or stabilized cognitive function in 63% of treated individuals, compared with 39% of placebo controls.

Patients taking the drug experienced improvement in memory, language, attention, and name recognition, compared with individuals taking placebo. In addition, the treated group showed less decline in social interactions than the placebo group.

"This study is good news. It shows that you can still do something to preserve function even in patients who are in the very late stages of this disease. This provides clinicians with solid evidence that treatment does make a difference," Dr. Black told Medscape.

Community-Based Study

The 6-month, community-based study involved 343 people with severe AD attending 98 outpatient clinics in the United States, Canada, France, Australia, and the United Kingdom.

Subjects were recruited for the study between May 1, 2001 and January 17, 2005. A total of 343 patients were randomized to receive 10 mg daily of donepezil (n=176) or placebo (n=167).

All men and women recruited for the study had probable AD, were ambulatory, and were 50 years or older. To be included in the study patients had to have a Mini-Mental State Examination (MMSE) score between 1 and 12, a modified Hachinski Ischemic score of 6 or less, and a Functional Assessment Staging (FAST) score of 6 or greater.

In addition, only subjects who had either not received previous AD treatment with cholinesterase inhibitors, memantine, or propentofylline, or who had discontinued such treatment a minimum of 3 months before assessment were eligible for the study. Experimental AD treatment had to be discontinued 1 month or 5 drug half lives before screening, whichever was longer.

The majority of patients (76.7%) lived in their own homes with their caregiver. The remainder resided in assisted-living facilities or retirement homes, but not full skilled nursing homes. In addition, all subjects had a caregiver for a minimum of 3 days per week and 4 hours per day during waking hours.

The study's primary endpoints were changes in the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus)

Positive Effect

Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resources Utilization for Severe Alzheimer Disease Patients (RUSP).

Safety was assessed by monitoring adverse events. Adverse events were considered severe if patients died, life was threatened, or patients were hospitalized.

At baseline, mean total SIB scores were similar for both groups — 64.6 for donepezil vs 65.2 for placebo. However, at study completion, donepezil-treated patients improved in 5 of the 9 SIB domains: language, attention, memory, praxis, and orienting to name. Orientation remained unchanged, and in the 3 remaining domains of social interaction, visuospatial function, and construction, donepezil-treated subjects showed significantly less decline than those in the placebo group.

"More patients [in the donepezil group] were stabilized or improved than in the placebo group. This demonstrates that even at a late stage in the disease it is possible, through manipulation of the cholinergic system — that is, by helping to restore and replace cholinergic function — to have a positive effect," she said.

In practical terms, said Dr. Black, this means patients could remain in a more independent living situation for a longer period of time, thereby reducing the substantial health costs associated with AD institutionalization.

In addition, CIBIC-Plus and MMSE scores also favored donepezil at study endpoint. However, the authors report that donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP outcomes.

Severe AD Subgroup?

Although the reasons for this are not clear and require further study, Dr. Black speculated that this finding might be due to the fact that the study group represents a subgroup of severe AD patients.

The fact that these individuals are able to be cared for at home or in an assisted-living situation suggests that they have fewer behavioral disturbances than their counterparts who are institutionalized. Therefore, said Dr. Black, treatment is less likely to demonstrate a dramatic benefit on behavioral outcomes.

Donepezil was well tolerated with adverse side effects, which included gastrointestinal upset, insomnia, infection, and bladder problems. However, said Dr. Black, subjects in the placebo group had more adverse events than those in the active-treatment group.

In the United States, memantine, an N-methyl-D-aspartate receptor antagonist, was the first approved treatment for severe AD. Results from our trial, along with those of 2 other recent studies of cholinesterase inhibitors, now give clinicians another treatment option for this patient group," said Dr. Black.

"It has always been a bit of a dilemma for clinicians as to whether or not to continue treatment when patients reach the severe stage of disease. I think a lot of physicians already continue to use these drugs in severe-stage patients, but I hope the benefit demonstrated in this study provides them with the evidence they need to confidently use the drug throughout the disease course," she said.

The study was sponsored by Eisai Inc and Pfizer Inc. Dr. Black reports receiving contract research grants not reported in this article in excess of $10,000 per year and receiving honoraria for ad hoc consulting and CME in excess of $10,000 per year during the course of the study. Disclosures for other coauthors appear in the paper.

Neurology 2007; 69:459-469.


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