Cholinesterase inhibitors called too expensive
and ineffective to prescribe

Study sets existing data on its head. Some say we shouldn't pay it any mind

By Graham Furness

This study tracked 486 community-resident patients with mild to moderate AD, who were randomized to either donepezil (5 or 10mg/day) or placebo. Primary endpoints were set as entry to institutional care and progression of disability. These criteria were defined as loss of either two of four basic or six of 11 instrumental activities on the Bristol activities of daily living scale (BADLS). The study aimed "to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, caregivers' psychological wellbeing, or delay in institutionalization." Cognitive performance -- the yardstick by which donepezil has usually been measured -- was conspicuously absent from these core criteria, although it was calculated.

Essentially, donepezil produced no benefits over placebo in any of the primary endpoints. Forty-three percent of the donepezil group had been institutionalized by the three year point, compared to 44% of the placebo group. Likewise, 58% of the donepezil group showed progression of disability, compared to 59% of the placebo group.

Similarly, no significant differences were seen in behavioural and psychological symptoms, caregiver mental wellbeing, care costs, unpaid caregiver time, adverse events or deaths, or between 5 and 10mg doses of donepezil.

This is not to say that no differences were found at all. During the first two years, donepezil did produce small but significant improvements in cognition and functionality as measured by the mini-mental state exam (MMSE) and BADLS. This finding mirrors previous trials, and is highly consistent and reproducible. Nonetheless the authors argue that the improvement in cognition is typically only three points on the 70-point cognitive section of the AD assessment scale. This, they say, "might not be associated with worthwhile clinical and social benefits." In particular, they believe that the cost of donepezil is not recouped in terms of lower nursing home or caregiver costs.

Lead author Richard Gray, PhD commented: "Based on our results, clinicians and healthcare funders can validly question whether other uses of the scarce resources allocated to dementia care would provide better value than routine prescription of cholinesterase inhibitors."

These economic criteria are, of course, rather brutal, since they overlook the fact that Alzheimer's patients are generally desperate for every extra bit of help they can get. Moreover, they're out of synch with previous studies, particularly the original clinical trials.

In an accompanying commentary, Dr Lon Schneider from the University of Southern California notes that "results [of the study] are incompatible with many drug-company-sponsored observational studies and advertisements claiming remarkable effects for cholinesterase inhibitors. For example, claims that donepezil stabilizes cognitive decline, or delays nursing-home placement by two to five years now can be seen as implausible in the light of AD2000."

But others argue that the Lancet study is way off the mark. Dr Jack Diamond, scientific director of the Alzheimer Society of Canada, states: "The experience and observations of many clinicians and caregivers and the basic science theory behind donepezil and other cholinesterase inhibitors have testified to the apparent effectiveness of these drugs, particularly in the earlier stages of the disease. More studies and especially full scale clinical trials are needed before abandoning a therapeutic approach that's still supported by many people with the disease, clinicians and caregivers alike."