David S. Geldmacher

Donepezil (Aricept®) for treatment of Alzheimer´s disease and other dementing conditions

Alzheimer´s disease is common, incurable and disabling. It is expected to grow dramatically in prevalence over the next 50 years. At current, the standard of care for patients with mild and moderately severe Alzheimer´s disease includes the use of acetylcholinesterase inhibitors. Donepezil (Aricept®) is a highly selective acetylcholinesterase inhibitors with a pharmacokinetic profile allowing once-daily dosing. There is an extensive knowledge base derived from published clinical trials of donepezil in Alzheimer´s disease, revealing consistent efficacy in cognition, global clinical ratings and daily function. Donepezil is also associated with additional meaningful outcomes such as reduced risk for, or delay to, nursing home placement. Despite a sense of limited efficacy of this drug class among prescribers, number needed-to-treat analyses suggest donepezil is highly effective at reducing the long-term adverse outcomes associated with Alzheimer´s disease.

Alzheimer disease prevention: focus on cardiovascular risk, not amyloid?

Autosomal dominant (early-onset) Alzheimer disease and the much more common sporadic Alzheimer disease share a common pathology but not necessarily a common pathophysiology. Common cardiovascular comorbidities are associated with increased risk for Alzheimer disease and offer opportunities for intervention. Class I evidence for prevention is extremely limited. The overall body of evidence suggests the best time to intervene is in midlife, not in old age. Efforts to modify the course of Alzheimer disease have, until now, been based on altering the production or clearance of beta-amyloid. Results have been disappointing.

RESPONSE TO DR. FINUCANE

To the Editor: Lopez et al. report that ‘‘cholinesterase inhibitor (CEI) use had a clinically meaningful effect on the natural history of Alzheimer Disease (AD),’’ slowing disease progression and lowering risk of nursing home admission after 2 years. The design of the study is worrisome. Of 1,139 patients who enrolled in the AD Research Center over 7 years, 270 were selected; 135 began taking CEIs ‘‘immediately after enrollment, and continued to take them throughout the following 12 months,’’ and 135 never took the drug. How these individuals were selected is not otherwise described. They were matched on a few characteristics, such as age, Mini-Mental State Examination score, and education. This study resembles a study by Dr. Geldmacher et al. that showed that patients who took a CEI faithfully (80% of pills or more) had a significant delay in nursing home placement (NHP). Both of these nonrandomized studies failed to report important baseline characteristics of the groups being studied. In the Geldmacher article, for example, nonadherent patients were far less likely to have a spouse caregiver than faithful users, yet the authors, who claimed it was the donepezil that ‘‘resulted in significant delays in NHP,’’ omitted this fact. Both papers are easily distinguished from AD 2000, a properly randomized, controlled trial with the largest number of placebo-controlled patient-years of any cholinesterase study. In AD 2000, ‘‘no significant benefits were seen with donepezil compared with placebo in institutionalization or progression of disability . . . [or] in behavioral and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events, or death or between 5 mg and 10 mg of donepezil.’’ In the United Kingdom, the National Institute for Clinical Excellence Appraisal Committee has recently issued the following preliminary recommendation: ‘‘Donepezil, rivastigmine and galantamine are not recommended for use in the treatment of mild to moderate Alzheimer’s disease (AD).’’ Would Dr. Lopez modify the discussion of his paper, where he emphasizes the important benefits of donepezil, in view of the results from AD 2000, a larger, better-designed trial that failed to show any meaningful difference at all?

Donepezil in vascular dementia: a viewpoint by David S. Geldmacher.

patients with mild and moderately severe attributable to the higher rate of co-morbid condiAlzheimer’s disease (AD). Its use in AD is strongly tions and concomitant medications among those supported by the well recognised loss of cholinergic with cerebrovascular disease associated with decells in the basal forebrain and associated cholinermentia. Drop out due to adverse events was nearly gic markers in the cerebral cortex. The rationale for twice as common in the 10mg once daily group its use in vascular dementia (VaD) is less clear, but compared with the 5mg once daily group (19% vs some evidence suggests a potential basis for cortical 11%, respectively). This potentially explains the acetylcholine deficiencies in patients with the typifailure of 10mg once daily to achieve significance cal types of cerebrovascular lesions associated with on global measures, since adverse events might negimpaired cognition.