Delays in the diagnosis of Alzheimer’s disease, and, therefore, delays in treatment, may have a detrimental effect on a patient’s long-term well-being. This studyassessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer’s disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer’s disease. These data support the long-term efficacy and safety of donepezil.

The costs and consequences of donepezil versus placebo treatment in patients with mild to moderate Alzheimer’s disease (AD) were evaluated as part of a 1-year prospective, double-blind, randomized, multinational clinical trial. Patients received either donepezil (n = 142; 5 mg/day for 28 days followed by 10 mg/day according to the clinician’s judgement) or placebo (n = 144). Unit costs were assessed in 1999 Swedish kronas (SEK) and converted to US dollars (USD). Donepezil-treated patients gained functional benefits relative to placebo on the Progressive Deterioration Scale (p = 0.042) and Instrumental Activities of Daily Living scale (p = 0.025) at week 52. Caregivers of donepezil-treated patients spent an average of 400 h less annually providing care than caregivers of placebo-treated patients. Mean annual healthcare costs were SEK 137,752 (USD 16,438) per patient for the donepezil group and SEK 135,314 (USD 16,147) in the placebo group. With the average annual cost of donepezil at SEK 10,723 (USD 1,280) per patient, the SEK 2,438 (USD 291) cost difference represented a 77% cost offset. When caregiver time and healthcare costs were included, mean annual costs were SEK 209,244 (USD 24,969) per patient in the donepezil group and SEK 218,434 (USD 26,066) in the placebo group, a total saving associated with donepezil treatment of SEK 9,190 (USD 1,097) per patient [95% CI of SEK –43,959 (USD –5,246), SEK 25,581 (USD 3,053); p = 0.6]. The positive effects on the efficacy outcome measures combined with no additional costs from a societal perspective indicate that donepezil is a cost-effective treatment, representing an improved strategy for the management of patients with AD.

Objective: To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD. Methods: Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year. Results: The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Brsne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7%, of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population. Conclusion: As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.

The results of this 1-year, multinational, double-blind, placebo-controlled study of an acetylcholinesterase inhibitor confirm the beneficial effects of donepezil on cognition, activities of daily living and behavioral symptoms over 1 year in the treatment of patients with mild to moderate Alzheimer's disease. Indeed, the data are consistent with those from the previously reported pivotal studies that led to the widespread marketing approval of donepezil. Data suggest that to maximize the benefits of donepezil, treatment should begin as early as possible, ideally in patients with mild Alzheimer's disease. Further, the determination of the benefits of therapy should be made by the physician and caregiver in conjunction with the patient, if possible, on the basis of improvement, stabilization, or a slowing of the deterioration in symptoms in any of the three areas commonly affected with Alzheimer's disease: cognition activity of daily living and behavior.

Data from the Cochrane meta-analysis (2006) 1 have confirmed that treatment with donepezil 5 or 10 mg/day in patients with Alzheimer's disease was more effective than the placebo in terms of evolution of cognitive function and the overall impression of carers (14 clinical studies) after 3 months, 6 months and 1 year of treatment. It should be noted that, according to the authors of this work, this benefit was established in patients with Alzheimer's disease at a level of severity qualified as mild to severe (outside of scope of current Marketing Authorisation). A benefit in performing everyday activities and associated behavioural issues was also observed. This modest impact is less well documented. The impact on quality of life was not documented. The level of effect attributed to donepezil at doses of 5 or 10 mg/ day was not significant across all assessment criteria, and the clinical relevance of the effects observed was called in to question, given the size of the effect, and the true impact for patients: as an illustration, a difference of 2.8 points on a composite score on the ADAS-Cog scale of 70 points for cognitive function was seen. The choice of giving a dosage of 10 mg/day of donepezil over that of 5 mg/day may be discussed based on the results observed: overall marginal additional clinical benefit for 10 mg/day (no difference observed between the two doses on the CIBIC plus, CDR-SB or MMSE scales and a difference of 1 point on the ADAS-Cog scale) but with improved tolerance for the 5 mg/day dosage. It should be noted that more recent studies have not investigated the 5 mg/day dosage. There are no data available which allows the longer-term effect of donepezil to be determined. The authors of the meta-analysis recall the need to investigate the optimum treatment duration and the indicators for stopping treatment due to an absence of benefits (implications for research). In the symptomatic treatment of Alzheimer's disease, no new randomised studies comparing donepezil to placebo have been presented by the laboratory. The authors state that no new systematic or meta-analysis with good quality methodology, according to PRISMA 2 recommendations, has been found since 2004. Five new randomised clinical studies versus placebo were taken into consideration. Their study plan, the patient characteristics and an assessment of their internal validity are 1 Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. and donepezil: …