Rivastigmine for Alzheimer's disease

 

Abstract

Background

Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.

Objectives

To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.

Search methods

The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 27 March 2008 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713"  . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources.

Selection criteria

All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients.

Data collection and analysis

One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data.

Main results

Nine trials, involving 4775 participants, were included in the analyses. Use of rivastigmine in high doses was associated with statistically significant benefits on several measures. High-dose rivastigmine (6 to 12 mg daily) was associated with a two-point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -1.99, 95% confidence interval -2.49 to -1.50, on an intention-to-treat basis) and a 2.2 point improvement in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks. At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function. There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo. There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine. The 2008 update includes a new study testing two types of rivastigmine transdermal patch, one delivering a higher dose than previously tested (17.4 mg/day) and a smaller patch delivering 9.6 mg/day. The efficacy of the smaller patch was not significantly different compared with the capsules of similar daily dose, but was associated with significantly fewer adverse events of nausea, vomiting, dizziness and asthenia. The efficacy of the larger patch was not significantly different compared with the smaller patch, but the smaller patch was associated with significantly fewer adverse events of nausea, vomiting, weight loss and dizziness. There appears to be advantages associated with the smaller patch compared with both the higher dose patch and the 6-12 mg/day capsules.

Authors' conclusions

Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in the rate of decline of cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both. This review has not examined economic data.

 

Plain language summary

Rivastigmine is beneficial for people with Alzheimer's disease

Alzheimer's disease (AD) is the commonest cause of dementia affecting older people, and is associated with loss of cholinergic neurons in parts of the brain subserving aspects of memory. Acetylcholinesterase inhibitors, such as rivastigmine, delay the breakdown of acetylcholine released into synaptic clefts and may enhance cholinergic neurotransmission. There is evidence that rivastigmine is beneficial for people with Alzheimer's disease, in being associated with small improvements in the rate of decline of cognitive function and activities of daily living. Adverse effects were consistent with the cholinergic actions of the drug.

 

摘要

背景

Rivastigmine在阿茲海默氏症的使用

阿茲海默症是老年人最常見的失智症，治療策略上是增加大腦各部分乙醯膽鹼的傳遞，使用乙醯膽鹼?的抑制劑可以減緩乙醯膽鹼在突觸的分解。Tacrine是第一個經完整臨床試驗而使用在這一方面用途的藥物，但是它有顯著的副作用例如肝毒性。其他的乙醯膽鹼抑制劑，包括Rivastigmine，在特定的作用上有較好的優勢，而且有較少的副作用。Rivastigmine已經被包括歐盟以及美國的六十個國家允許使用。

目標

確認Rivastigmine在阿茲海默氏症病患使用的安全性與效度。

搜尋策略

CDCIG以下面的關鍵字在2008年3月27號搜尋資料庫：Rivastigmine或 exelon 或 ENA 或 "SDZ ENA 713" 。CDCIG的資料庫包含所有主要的衛生照護的檔案庫(The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) 以及許多的臨床試驗登記。

選擇標準

所有使用Rivastigmine治療阿茲海默症病人超過兩周的雙盲隨機試驗的效果，都與安慰組做平行比較。

資料收集與分析

一個審查者(JSB)使用以上篩選規範去評估研究的品質與選錄的資料。

主要結論

有九個試驗，內含4775個參與試驗者被選入這個分析。使用高劑量的Rivastigmine在許多測量上呈現顯著性的好處。以二十六周的觀察，高劑量的Rivastigmine(每天六到十二毫克)與 ADASCog的進步呈現相關(和對照組兩分的差異)(weighted mean difference −1.99, 95% confidence interval −2.49 to −1.50)；在日常生活的評量上也有2.2分的進步(weighted mean difference −2.15, 95% confidence interval −3.16 to −1.13, on an intentiontotreat basis)。 在低劑量(每天小於等於四毫克)與對照組的差異也達到統計上的意義，但僅限於智能評估上。在副作用方面高劑量的Rivastigmine和對照組相比有較高比率的噁心，嘔吐，下痢，食慾不振，頭痛，暈厥，腹痛，頭暈。有一些證據顯示這樣的副作用在較低劑量可能比較少見。 2008年最新的研究資料顯示有兩種新型的Rivastigmine經皮貼片(一種是可傳遞較高劑量的，17.4毫克 −一天；一種是較低劑量的，9.8毫克 −一天)。與高劑量的貼片相比，低劑量的貼片在效用上相差不多，但在噁心嘔吐與頭暈的副作用明顯減少。很明顯的，低劑量貼片與高劑量貼片，或高劑量口服劑型相比，有較佳的優勢。

作者結論

Rivastigmine對中到重度的阿茲海默氏症是有益的。與對照組相比，使用rivastigmine 612mg的病人在智能、日常生活活動度、失智程度方面均有進步。副作用的產生與乙醯膽鹼的作用相關。經皮貼片被使用在一個臨床試驗，有證據顯示低劑量的貼片，有較少的副作用，不管是和口服劑型相比，或和高劑量的貼片相比。這個回顧並沒有檢視經濟學方面的資料。

翻譯人

本摘要由高雄長庚醫院張瓊之翻譯。

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

總結

阿茲海默氏症是造成老人失智最常見的原因，疾病和乙醯膽鹼退化相關，也會影響記憶力。乙醯膽鹼?抑制劑，例如Rivastigmine，可以減緩乙醯膽鹼的分解，進而加速神經傳導物質的傳遞。證據顯示Rivastigmine對阿茲海默症是有益的，不管是在智能退化的速度上或是日常生活照顧上。副作用與乙醯膽鹼的作用相關。