Donepezil for mild cognitive impairment

 

Abstract

Background

Problems with memory which do not meet the diagnostic criteria for dementia, usually called mild cognitive impairment (MCI), can be the first sign of an impending dementia, particularly Alzheimer's disease (AD). There is no consensus on a definition or diagnostic criteria for MCI, and MCI remains a vague term and those so described are a heterogeneous population, consisting of people who may rapidly progress to dementia but also of people with stable cognitive deficits and some who may actually improve.

Treatment in the very earliest stages of AD may delay progression to AD. Donepezil (Aricept, E2020), a cholinesterase inhibitor, has been shown to benefit all severities of AD including mild and it would be reasonable to investigate its efficacy for those with MCI.

Objectives

To assess the effects of donepezil in people with mild cognitive impairment but no diagnosis of dementia.

Search methods

We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 20 May 2010 using the term: donepezil and in combination with those studies in which the participants had mild cognitive impairment.

Selection criteria

All double blind, randomized trials in which treatment with donepezil was compared with placebo for patients with mild cognitive impairment.

Data collection and analysis

Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated.

Main results

The three included studies, with a total of 782 patients, all with a MMSE greater than 23 points, identified similar patients for inclusion, but were quite different with respect to design and objective. Pooling results in a meta-analysis was not possible.
In the first study the 13-item ADAS-Cog showed benefit associated with 10 mg/day donepezil compared with placebo at 24 weeks (MD 1.90, 95% CI 0.51 to 3.29, p=0.007), but four other measures of cognitive function did not. The analysis of withdrawals before the end of treatment at 24 weeks, withdrawals due to an adverse event, and numbers experiencing an adverse event, showed a significant difference between the donepezil group and the placebo group in favour of placebo, (43/133 donepezil 23/137 placebo, OR 2.37, 95% CI 1.33 to 4.22, p=0.003), (29/133 donepezil 10/137 placebo, OR 3.54, 95% CI 1.65 to 7.60, p=0.001), (116/133 donepezil, 100/137 placebo, OR 2.52 95% CI 1.34 to 4.76, p=0.004). Various adverse effects were recorded, and several types of event, diarrhoea, nausea, vomiting, leg cramps and abnormal dreams, were reported more frequently in the donepezil group compared with the placebo.

In the second study there was a significant difference between the number of patients diagnosed with AD or another dementia between the donepezil group and the placebo group in favour of donepezil after one year of treatment (16/253 donepezil 38/259 placebo) (OR 0.39, 95% CI 0.21 to 0.72, p=0.003), but no difference after 3 years of treatment (63/253 donepezil 73/259 placebo) (OR 0.84, 95% CI 0.57 to 1.25, p=0.4).

The third study assessed cognitive function but did not report the results.

Authors' conclusions

There are two included studies which reported results for cognitive function. One study demonstrated a modest treatment effect in cognitive function as assessed by ADAS-Cog13 but not for other outcomes assessing different domains of cognitive function. Donepezil was associated with significantly more adverse effects compared with placebo, mostly gastrointestinal. From the second study, there is no evidence that donepezil delays the onset of AD. There is no evidence to support the use of donepezil for patients with MCI. The putative benefits are minor, short lived and associated with significant side effects.

 

Plain language summary

There is no evidence to support the use of donepezil for patients with mild cognitive impairment (MCI). The putative benefits are minor, short lived and associated with significant side effects

Problems with memory which do not meet the diagnostic criteria for dementia, usually called mild cognitive impairment (MCI), can be the first sign of an impending dementia, particularly Alzheimer's disease, but are not necessarily so. Some memory problems are temporary and some do not worsen. Treatment in the very earliest stages of AD may delay progression to AD. Donepezil (Aricept, E2020), a cholinesterase inhibitor, has been shown to benefit all severities of AD including mild and it is reasonable to investigate its efficacy for those with MCI. There is little evidence that donepezil improved cognitive function, and no evidence that donepezil delays progression to AD, but it was associated with significant side effects. There is no evidence to support the use of donepezil for patients with MCI.

 

摘要

背景

使用Donepezil治療輕度認知能力受損

記憶力的問題未達到失智症診斷標準時，通常稱為輕度認知能力受損(MCI)，而這可能是失智症的早期徵兆，尤其是阿茲海默症。MCI沒有一致性的定義和診斷標準，所以MCI還是一個模糊的名詞而且被稱做MCI可能包含不同的類型的患者，其中包括可能快速進展為失智症的一群，還有另一群認知缺損維持穩定或甚至於有進步。若早期治療AD有可能會延緩AD的發展，Donepezil (Aricept, E2020)是一種膽鹼?抑制劑，對所有嚴重程度的AD包含輕度是有療效的，所以研究Donepezil使用在MCI患者上的療效是合理的。

目標

本研究的目的在於評估使用donepezil對輕度認知能力受損但沒達到失智症診斷標準的患者的影響。

搜尋策略

在2006年1月6日針對Specialized Register of the Cochrane Dementia and Cognitive Improvement Group資料庫搜尋符合的試驗，這個登錄包含主要健康照護資料庫如CENTRAL、MEDLINE、EMBASE、CINAHL 和PsycINFO以及許多進行中且定期更新的試驗資料庫。

選擇標準

所有比較donepezil和安慰劑使用在治療MCI的雙盲，隨機性試驗都被納入研究中。

資料收集與分析

資料從已發表的報告中擷取出來，並適當的整合治療的效果或評估風險及效益。

主要結論

2個納入的研究總共收了782位病人，所有患者的MMSE(簡易智能量表)分數都高於23分，而且納入試驗的患者都十分相似，但是在研究的設計及目的上確有很大的不同，所以無法整合結果來進行metaanalysis。在第一個研究中，每日使用10毫克donepezil的組別比起安慰劑組，在第24週有較好ADASCog(包含13個子項)的表現 (MD 1.90, 95% 信心區間 0.51 to 3.29, p = 0.007)，但在其他四種認知功能評量方法並未顯示出不同。在治療24週結束前因副作用而中止試驗以及經歷副作用數目顯示在donepezil和安慰劑組之間具有顯著差異，且安慰劑組有較少的副作用(43/133 donepezil 23/137 安慰劑, OR 2.37, 95% 信心區間 1.33 to 4.22, p = 0.003), (29/133 donepezil 10/137 安慰劑, OR 3.54, 95%信心區間1.65 to 7.60, p = 0.001), (116/133 donepezil, 100/137 安慰劑, OR 2.52 95%信心區間1.34 to 4.76, p = 0.004)。數種副作用被記錄，而其中許多症狀包括腹瀉，噁心，嘔吐，腿部抽筋和不正常的夢較常出現在使用donepezil的組別中。在第二個試驗中，經過一年的治療後，donepezil組比起安慰劑組，患者有較少比例發展成AD或是其他類型的失智症 (16/253 donepezil 38/259 安慰劑) (OR 0.39, 95% 信心區間 0.21 to 0.72, p = 0.003)，但在經過三年的治療之後卻沒有差異性(63/253 donepezil 73/259 安慰劑) (OR 0.84, 95% 信心區間 0.57 to 1.25, p = 0.4)

作者結論

有兩個試驗被納入，其中一個試驗顯示利用ADASCog13進行認知功能評估，donepezil是有療效的，但在其他的認知功能評估上並無顯著效果。使用Donepezil比起安慰劑明顯的有較多的副作用，其中大多是胃腸的副作用。從另一個試驗發現沒有證據支持donepezil會減緩AD的發生，也沒有證據支持使用donepezil來治療MCI的患者，因為其效果有限，只有短期作用而且有明顯副作用。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

沒有證據支持使用donepezil對輕度認知能力受損(MCI)的病人有所幫助，預定的益處十分少，短效且有明顯的副作用。當記憶力的問題不能符合失智症診斷的標準時，通常稱為輕度認知能力受損(MCI)，這可以是失智症尤其阿茲海默症是的前兆，但並非絕對如此。有些記憶問題是暫時性的而有些並不會惡化。在AD早期階段開始進行治療有可能會延緩發展成AD。Donepezil (Aricept, E2020)是一種膽鹼?的抑制劑，對所有嚴重程度的AD包含輕度是有療效的，所以研究Donepezil使用在MCI患者上的療效是合理的。這裡只有少數的證據說明donepezil可以改善認知功能而且沒有證據顯示donepezil會延緩患者發展成AD但他確有較多的副作用。這裡沒有證據支持使用donepezil來治療MCI患者。