Cholinesterase inhibitors for Parkinson's disease dementia

  • Review
  • Intervention

Authors


Abstract

Background

The loss of cholinergic, dopaminergic and noradrenergic innervations seen in Parkinson's Disease Dementia (PDD) suggest a potential role for cholinesterase inhibitors. Concerns have been expressed about a theoretical worsening of Parkinson's disease related symptoms, particularly movement symptoms.

Objectives

To assess the efficacy, safety, tolerability and health economic data relating to the use of cholinesterase inhibitors in PDD.

Search methods

The trials were identified from the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 19 April 2005 using the search term parkinson*. This register contains records from major health care databases and many ongoing trial databases and is updated regularly.

Comprehensive searches of abstracts from major scientific meetings were performed. Pharmaceutical companies were approached for information regarding additional and ongoing studies.

Selection criteria

Randomized, double-blind, placebo-controlled studies assessing the effectiveness of cholinesterase inhibitors in PDD. Inclusion and exclusion criteria were stated to limit bias.

Data collection and analysis

Two reviewers (IM, CF) independently reviewed the quality of the studies utilizing criteria from the Cochrane Collaboration Handbook. Medications were examined separately and as a group. The outcome measures assessed were in the following domains: neuropsychiatric features, cognition, global impression, daily living activities, quality of life, burden on caregiver, Parkinsonian related symptoms, treatment acceptability as determined by withdrawal from trials, safety as determined by the frequency of adverse events, institutionalisation, death and health economic factors.

Main results

A detailed and systematic search of relevant databases identified one published randomized, double-blind, placebo-controlled study (Emre 2004) involving 541 patients that compared rivastigmine with placebo. Rivastigmine produced statistically significant improvements in several outcome measures. On the primary cognitive measure, the ADAS-Cog, rivastigmine was associated with a 2.80 point ADAS-Cog improvement [WMD -2.80, 95% Cl -4.26 to -1.34, P = 0.0002] and a 2.50 point ADCS-ADL improvement [95% Cl 0.43 to 4.57, P = 0.02] relative to placebo. Clinically meaningful (moderate or marked) improvement occurred in 5.3% more patients on rivastigmine, and meaningful worsening occurred in 10.1% more patients on placebo.

Tolerability appeared to be a significant issue. Significantly more patients on rivastigmine dropped out of the study due to adverse events [62/362 versus 14/179, OR 2.44, 95% Cl 1.32 to 4.48, P = 0.004]. Nausea [20/179 versus 105/362, OR 3.25, 95% Cl 1.94 to 5.45, P < 0.00001], tremor [7/179 versus 37/362, OR 2.80, 95% Cl 1.22 to 6.41, P = 0.01] and in particular vomiting [3/179 versus 60/362, OR 11.66, 95% Cl 3.60 to 37.72, P < 0.0001] were significantly more common with rivastigmine. However, significantly fewer patients died on rivastigmine than placebo [4/362 versus 7/179, OR 0.27, 95% CI 0.08 to 0.95, P = 0.04]

Authors' conclusions

Rivastigmine appears to improve cognition and activities of daily living in patients with PDD. This results in clinically meaningful benefit in about 15% of cases. There is a need for more studies utilising pragmatic measures such as time to residential care facility and both patient and carer quality of life assessments. Future trials should involve other cholinesterase inhibitors, utilise tools to analyse the data that limit any bias and measure health economic factors. It is unlikely that relying solely on the last observation carried forward (LOCF) is sufficient. Publication of the observed case data in the largest trial would assist (Emre 2004). Adverse events were associated with the cholinergic activity of rivastigmine, but may limit patient acceptability as evidenced by the high drop out rate in the active arm.

摘要

背景

使用乙醯膽鹼酯酉每抑制劑來治療帕金森氏症的失智症

帕金森氏症失智症(PDD)患者腦中膽鹼、多巴胺和正腎上腺素(noradrenergic)含量的減少可以推測乙醯膽鹼酯酉每抑制劑在治療PDD的潛在性角色。目前有許多研究關注於帕金森氏症相關症狀的惡化特別是運動症狀。

目標

本研究的主要目的在於評估使用乙醯膽鹼酯酉每抑制劑治療PDD患者的有效性、安全性、耐受性和健康經濟效益。

搜尋策略

在2005年4月19日利用「parkinson*」為關鍵字針對Specialized Register of the Cochrane Dementia and Cognitive Improvement Group資料庫進行檢索以取得試驗資料,這個資料庫中含有主要健康照護資料庫和許多正在進行試驗資料庫的資料,並且會進行定期的更新,另外也會針對專業會議論文的摘要進行綜合式檢索,並接觸製藥公司以取得其他或正在進行中的試驗資料。

選擇標準

評估使用乙醯膽鹼酯酉每抑制劑對PDD患者療效的隨機、雙盲安慰劑對照試驗都可能被納入研究中。並使用納入以及排出準則來減少偏差。

資料收集與分析

有2位審查者(IM、CF)分別根據Cochrane Collaboration Handbook所記載的規範審閱試驗的品質,藥物會被個別或是集中進行試驗,主要進行評量的試驗結果包括有:神經精神特徵、認知功能、整體評量、生活品質、對照護者的影響、與帕金森氏症有關的症狀、利用移出試驗的情形來判斷對於治療的接受度、利用不良事件發生頻率來決定試驗的安全性,住院狀況,死亡和健康經濟因素。

主要結論

針對相關資料庫進行詳細且整體性的搜尋後,確認有一個已公開的隨機雙盲安慰劑對照試驗(Emre 2004)係以541名患者為受試對象,並且比較使用rivastigmine與安慰劑進行治療的影響,在許多治療成果上,使用rivastigmine的組別都出現了明顯的改善現象,主要的認知功能測量(使用ADASCog量表)結果中,rivastigmine治療組在ADASCog得分上有28分的進步(WMD值為 −2.80,95%的信心區間介於 −4.25至 −1.34之間,p = 0.0002),在ADASADL的得分有2.50分的進步(95%的信心區間介於0.43至4.57之間,p = 0.02)。使用rivastigmine進行治療的患者,在臨床有意義(中度或明顯)的改善上有5.3%的提升,而接受安慰劑治療的患者,有意義的惡化發生率則多了10.1%,使用rivastigmine 的患者因為不良事件而被移出試驗的比例也明顯較高(62/362和14/179,OR值為0.44,95%的信心區間介於1.32至4.48之間,p = 0.004),此外,使用rivastigmine的患者也較為普遍出現噁心(20/179和105/362,OR值為3.25,95%的信心區間介於1.94至5.45之間,p<0.00001)、顫抖(7/1792和37/362,OR值為2.80,95%的信心區間介於1.22至6.41之間,p = 0.01)和嘔吐(3/179和60/361,OR值為11.66,95%的信心區間介於3.60至37.72之間,<0.0001)的情形,但是,使用rivastigmine治療的組別中患者死亡率卻明顯低於使用安慰劑的組別(4/362和1179,OR值為.27,95%的信心區間介於0.08至0.95之間,p = 0.04)。

作者結論

使用rivastigmine顯然可以提升PDD患者的認知和每日活動能力,這樣的結果在臨床重要效益上大約有15%,需要更多的試驗利用系統化的測量,例如評估入住照護中心時間以及患者和照護者的生活品質。後續的試驗應該著重在其他的乙醯膽鹼酯酉每抑制劑的療效並利用數據分析工具來減少試驗偏差,並且針對健康經濟因素進行檢視。不能單純依賴 last observation carried forward (LOCF),已發表的大型個案觀察資料可能有幫助(Emre 2004)。不良事件與rivastigmin的乙醯膽鹼活性有關,這可能會限制患者的接受度,因為在rivastigmin治療組中有許多患者被移出試驗之外。

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

Rivastigmin似乎可以中度的改善PDD患者的認知和日常生活功能。失智症通常和帕金森氏症有關,當一定數量的神經傳導物質受到影響,尤其乙醯膽鹼活性降低可能與PDD有關,這可以推測乙醯膽鹼酉每抑制劑可能有療效。Rivastigmin似乎可以中度的改善PDD患者的認知和日常生活功能,臨床上大約有15%的患者可以獲得改善。Rivastigmin的其他症狀的療效仍有待確認,患者對於噁心、嘔吐和顫抖的耐受性也是一個問題。

Plain language summary

Rivastigmine appears to moderately improve cognition and to a lesser extent activities of daily living in patients with PDD

Dementia is frequently associated with Parkinson's Disease. While a number of neurotransmitters appear to be involved, loss of cholinergic functioning is particularly associated with Parkinson's Disease Dementia (PDD) suggesting a potential utility for cholinesterase inhibitors. Rivastigmine appears to moderately improve cognition and to a lesser extent activities of daily living in patients with PDD. There was a clinically meaningful benefit in 15% of patients. Efficacy in other domains requires confirmation. Tolerability in particular nausea, vomiting and tremor appear problematic.

Laički sažetak

Rivastigmin umjereno poboljšava kogniciju i, u manjoj mjeri aktivnosti svakodnevnog života kod oboljelih od demencije kod Parkinsonove bolesti.

Demencija je često povezana s Parkinsonovom bolešću. Dok se čini se da su uključeni brojni neurotransmiteri, gubitak kolinergičkog djelovanja posebno je povezan s demencijom kod Parkinsonove bolesti što ukazuje na potencijalnu korist od liječenja inhibitorima kolinesteraze. Čini se da lijek rivastigmin umjereno poboljšava stanje kognicije u pacijenata, te u manjoj mjeri aktivnosti svakodnevnog života kod bolesnika s demencijom i Parkinsonovom bolešću. Klinički značajna korist zabilježena je u 15% pacijenata. Učinkovitost u drugim područjima se treba potvrditi. Podnošenje lijeka čini se problematično jer su opisane nuspojave kao što su mučnine, povraćanje i tremor.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Diana Rubić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Ancillary