Long-term rivastigmine treatment in a routine clinical setting

Objective – The aim of the study was to observe the effects of long‐term rivastigmine treatment in patients with mild to moderate Alzheimer’s disease (AD) in a routine clinical setting. Methods – This was a prospective, open‐label, observational, multicentre, non‐randomized study. Outcome measures included the Mini Mental State Examination (MMSE), the Clinician’s Interview‐Based Impression of Change (CIBIC) and the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS‐cog). Results – Of 217 patients initiated into rivastigmine treatment, 62% (n = 135) remained on treatment for 24 months. Most patients droped out due to nursing home placement or side effects. Eighty per cent and 67% of completers exhibited a symptomatic attenuation of cognitive decline (≤ 4‐point deterioration) as assessed by using the MMSE and ADAS‐cog respectively. Forty‐four per cent showed an unchanged/improved CIBIC rating. Conclusions – Over 60% of patients remained on treatment for 2 years in this routine clinical setting. In patients who remained on treatment, rivastigmine appeared to stabilize their condition and prevented or delayed symptomatic decline.     

Donepezil in the treatment of mild to moderate Alzheimer's disease: report of a Belgian multicenter study

In this report the results of a Belgian multicenter 24-week open-label study with donepezil in the treatment of mild to moderate Alzheimer's disease are described. Efficacy and safety were evaluated in a sample of 200 patients recruited in 25 Belgian centers. No significant changes could be found in cognition and behaviour over this 6-month period. Changes in daily functioning were small. Safety data were comparable to those reported in international trials. These results suggest that the findings of more robust double-blind, placebo-controlled studies can be confirmed in real life situations.     

Diagnosis of preclinical Alzheimer's disease in a clinical setting

INTRODUCTION: The aim of the study was to investigate whether the preclinical stage of Alzheimer's disease (AD) can be diagnosed in a clinical setting. To this end we investigated whether subjects with preclinical AD could be differentiated from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. METHODS: Twenty-three subjects with preclinical AD, 44 subjects with nonprogressive mild cognitive impairment, and 25 subjects with very mild AD-type dementia were selected from a memory clinic population. Variables that were used to differentiate the groups were demographic variables, the Mini-Mental State Examination score, performance on cognitive tests, measures of functional impairment, and measures of noncognitive symptomatology. RESULTS: Age and the scores for the delayed recall task could best discriminate between subjects with preclinical AD and subjects with nonprogressive mild cognitive impairment. The overall accuracy was 87%. The score on the Global Deterioration Scale and a measure of intelligence could best discriminate between subjects with preclinical AD and subjects with very mild AD-type dementia. The overall accuracy was 85%. CONCLUSIONS: Subjects with preclinical AD can be distinguished from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. This means that preclinical AD is a diagnostic entity for which clinical criteria should be developed.     

Donepezil in the treatment of Alzheimer's disease: long-term efficacy and safety

OBJECTIVES: The aim of this study was to evaluate the long-term efficacy, safety and tolerability of donepezil in the treatment of Alzheimer's disease (AD). METHODS: Twenty-five patients (15 females and 10 males) with mild to moderate AD, according to DSM IV criteria, were recruited in the study. The principal efficacy measures were Alzheimer Disease Assessment Scale-cognitive subscale score (ADAS-cog), Mini Mental State Examination (MMSE) and Physical Self-Maintenance Scale (PSMS). Patients were treated with donepezil 5 mg/day for 1 month, after which an increase to 10 mg/day was encouraged. Evaluations were carried out prior to the start of the treatment and every 3 months for a period of 1 year. RESULTS: A significant improvement from baseline score of cognitive performances was seen through Week 24. Beginning with Week 36, performances declined relative to baseline, indicating continued disease progression. CONCLUSIONS: Donepezil improved cognition and global functioning and was well tolerated especially considered the long duration of the observation period.     

Donepezil for the treatment of mild to moderate Alzheimer's disease in France: the economic implications

In the present study, the socioeconomic impact of the use of the acetylcholinesterase inhibitor donepezil in patients with mild to moderate Alzheimer's disease (AD) living in France was examined. A model was created to extrapolate over a 3-year period the results from placebo-controlled trials together with epidemiological and prevalence data. Costs considered in the model were net societal costs associated with paid and unpaid assistance, general medical consumption and institutional care. The model suggested that delays in cognitive decline and functional dependence due to treatment reduced the time spent in institutional care and the burden on caregivers. Over a 3-year period, total net costs of caring for untreated patients with an initial Mini-Mental State Examination score ranging from 10 to 26 were EUR 53,206 compared with EUR 42,720 for a patient treated with donepezil--an annual cost saving of approximately EUR 3,500 per patient. Cost savings were mainly due to savings in unpaid caregiver time, which, apart from patient institutionalization, represented the most costly component of total care in this study but had no direct budgetary impact. Overall, these data suggest that donepezil is a cost-effective treatment for mild to moderately impaired AD patients living in France.     

Donepezil across the spectrum of Alzheimer's disease: dose optimization and clinical relevance

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population aging. The primary feature of AD is progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment can substantially improve quality of life. Donepezil is an acetylcholinesterase inhibitor approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once‐daily sustained‐release 23‐mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose–response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild‐to‐moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability. This review presents an overview of the evidence for donepezil across the spectrum of AD, with a focus on dose optimization for disease progression.     

Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's disease

Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. A number of studies show beneficial effects in the treatment of BPSD with acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the effect of donepezil (using the generic drug Memorit) as monotherapy for AD patients suffering from BPSD. Twenty-eight consecutive patients followed at the Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental Health Center were treated with donepezil for 6 months. Starting dose was 5 mg daily during the first 4 weeks and continuation with 10 mg daily thereafter. Treatment effects were evaluated using the Mini Mental State Examination (MMSE), the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the study. Of these, five patients needed additional rescue neuroleptic treatment due to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10 mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008). The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did not change significantly. When compared to the patients who completed the study, patients who discontinued had higher mean scores on the irritability and agitation subscales of the NPI, they were older, and they had longer disease duration and lower MMSE mean scores. Three adverse events were recorded: one syncope causing a toe phalanx fracture and gastrointestinal complaints that resolved over time in two additional patients. Acetylcholinesterase inhibitors should be considered for the treatment of BPSD before neuroleptic treatment is instituted in AD patients with low levels of irritability and agitation.     

Donepezil versus vitamin E in Alzheimer's disease: Part 2: mild versus moderate-severe Alzheimer's disease

SUMMARY: Early studies showed that the latency of P300 (P3) event related potential increases or diminishes when anticholinergic or cholinergic drugs are administered. We tested the hypothesis that new cholinesterase inhibitors like Donepezil (DPZ) may have an effect on the often abnormal P300 of patients with Alzheimer's Disease (AD), and therefore, that P300 recordings might simplify the evaluation of responses to cholinesterase inhibitor in patients with mild and moderate-severe AD. We evaluated 60 patients with AD: 30 patients with "mild" (Mini Mental State Examination 26-19) and 30 patients with "moderate-severe" (Mini Mental State Examination 18-10), according to the National Institute of Neurological and Communicative Disorders and Alzheimer's Disease and Related Disorders Association criteria in comparison with 40 age-matched controls. All subjects underwent P300 recordings and neuropsychologic examinations (Alzheimer's Disease Assessment Scale-Cognition and Wechsler Adult Intelligence Scale) during the 6-month follow-up. Patients were divided into four groups of 15 patients each: Group I DPZ (10 mg/day) and Group I Vitamin E (2000 IU/day) with "mild" AD; Group II DPZ and Group II Vitamin E with "moderate-severe" AD and same drug dosages. In patients treated with Vitamin E, we observed P3 latency increments (delta) by 11.8 +/- 1.8 ms in Group I and by 12.8 +/- 2.8 ms in Group II at 6 months; neuropsychologic test scores significantly worsened at 6 months (p < 0.001) in Group II patients. Donepezil induced significant P3 latency reductions (11.2 +/- 2.4 ms) in nine patients of Group I and all patients of Group II (16.1 +/- 4.0 ms), reaching a maximum at 3 months (23.2 +/- 2.7 ms). Alzheimer's Disease Assessment Scale-Cognition and Wechsler Adult Intelligence Scale scores improved during the same period, and the difference between Vitamin E and DPZ treated patients was highly significant for P3 (analysis of variance) and for P3-Alzheimer's Diseases Assessment Scale-Cognition (analysis of covariance) with p < 0.001 for pooled groups of patients with AD and Group II (DPZ) versus Group II (Vitamin E). Combined P3 event related potentials measurements, neuropsychologic test comparison evidences significant effects of DPZ in mild and in moderate-severe AD.     

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.     

Donepezil for Alzheimer's disease in clinical practice--The DONALD Study. A multicenter 24-week clinical trial in Germany

This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer's disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.     

Donepezil in Alzheimer's disease: eighteen month results from Southampton Memory Clinic

The objective of this study was to assess the efficacy of donepezil in patients with mild to moderate Alzheimer's disease (AD) in clinical practice. This was an open-label study in which patients were referred to an elderly mental health clinic in Southampton, UK. Eighty patients with mild to moderate AD received 5 mg/day donepezil for the first 4 weeks, after which, if tolerated, the dose was increased to 10 mg/day. Efficacy and safety assessments were carried out every 3 months. Efficacy was assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-carer Distress Scale (NPI-D). Mean improvements from baseline were observed at the 3-month assessment on all four efficacy measures. At 3 months, 39% of patients showed an improvement of at least 4 points on the ADAS-cog, and 37% of patients had improved by 4 points or more on the NPI. In those patients who showed improvement and were maintained on donepezil, improvements were sustained for 18 months on the MMSE and NPI, 15 months on the NPI-D, and for 6 months on the ADAS-cog. Six per cent of patients discontinued medication due to adverse events. In a typical clinical practice setting, patients with mild to moderate AD tolerated donepezil well. Clinically meaningful improvements in cognitive function and a reduction in neuropsychiatric symptoms were demonstrated in nearly 40% of patients with associated reduction in carer distress. Continued benefit was seen for up to 18 months in the selected group of patients who initially responded in treatment.     

Cost of Alzheimer's disease in a developing country setting

PURPOSE: To evaluate the economic impact of AD in Denizli, Turkey. DESIGN AND METHODS: This observational study was conducted with 42 AD patients and their primary caregivers. During the initial interview, demographic data and medical histories were collected with questionnaires. For an observational period of 15 days, data on time spent for patient care were collected using standard forms. Calculations on direct cost (e.g. per day medication, outpatient physician visits during the last 3 months), indirect cost (e.g. time spent for care by caregiver for daily living (ADL) and instrumental activity of daily living (IADL)) were made by summing up and taking averages of the appropriate items. ANOVA, and linear regressions were the methods for comparisons. RESULTS: The primary caregivers of the patients mainly were their children and/or spouses. The maximum mean time spent (h/week) was 21.0 (17.5) for severely damaged cognition. The average annual cost per case was between $1,766 [95% Confidence Intervals (CI); 1.300-2.231] and $4,930 (95% CI; 3.3714-6.147). The amount of caregiver cost was the most significant item in the overall cost and it showed an increase with the declining cognitive function of patients. Daily medication cost reflected the same pattern. In contrast, cost of outpatient physician was the lowest among the patients with the worst cognition. CONCLUSIONS: These results suggest that recently AD has become a significant cost for developing countries. This pilot study gives an idea of the cost of AD in developing countries where determining the actual cost can be difficult.     

A clinical perspective: anti tau's treatment in Alzheimer's disease

Alzheimer?s Disease (AD) physiopathology is not yet totally established. Nevertheless it is known that a metabolism dysfunction of the amyloid beta precursor protein (APP) and the abnormal tau protein phosphorylation lead to the formation of neuritic plaques and neurofibrillary tangles, respectively. These events finally drive to the clinical expression of dementia. Formally approved during the past decade, treatments for AD are lacking of an updating, being essentially symptomatic. Anticholinesterase agents have failed in providing a substantial improvement in the mental health condition of AD patients. On the other hand, antiamyloid strategies, have failed in their efficacy or security on their last development phases. In this context, tau represents a potential therapeutic target, by the action of drugs that diminish its aggregation, or acting by altering its phosphorylation or filaments formation. There is also anti-tau miscellaneous strategies such as normal microtubule-stabilizing agents. Thus, it might be possible that in a near future the neurodegenerative process could be stopped.     

Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer's disease: a meta-analysis of individual patient data from randomised controlled trials

BACKGROUND: The objective was to evaluate the efficacy and tolerability of donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations of mild to moderate Alzheimer's disease (AD). METHOD: A systematic review of individual patient data from Phase II and III double-blind, randomised, placebo-controlled studies of up to 24 weeks and completed by 20 December 1999. The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of adverse events. RESULTS: A total of 2376 patients from ten trials were randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or placebo (n = 893). Cognitive performance was better in patients receiving donepezil than in patients receiving placebo. At 12 weeks the differences in ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), - 2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001). The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001) and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10 mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to 2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6 to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were cholinergic in nature and generally of mild severity and brief in duration. CONCLUSION: Donepezil (5 and 10 mg/day) provides meaningful benefits in alleviating deficits in cognitive and clinician-rated global function in AD patients relative to placebo. Increased improvements in cognition were indicated for the higher dose.     

Use of donepezil for the treatment of mild-moderate Alzheimer's disease: an audit of the assessment and treatment of patients in routine clinical practice

There have been a number of randomised, placebo-controlled trials of donepezil in the treatment of mild-moderate Alzheimer's disease and these report significant benefits for a proportion of patients. Little is known about the use of donepezil in routine clinical practice. The aims of this study were to examine the use of donepezil in routine clinical practice and to identify some of the practical and resource implications associated with treatment. A number of areas were examined against published guidelines including assessment, diagnosis, initiation of treatment, monitoring and discontinuation of treatment. This was a retrospective case note study involving patients with mild - moderate Alzheimer's disease over a one-year period. One hundred and seventeen patients were commenced on donepezil and 93 successfully completed three months of treatment. Of these, 47% demonstrated an improvement in cognition, activities of daily living or carer observation (or a combination). Compliance with accepted guidelines with respect to assessment, diagnosis and monitoring requires a standardised approach that has both clinical and resource implications.