Birks J
University of Oxford, Department of Clinical Geratology, Radcliffe Infirmary, Woodstock Road, Oxford, UK, OX2 6HE.
Cochrane Database Syst Rev. 2006 Jan 25;2006(1):CD005593. doi: 10.1002/14651858.CD005593.
Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues.
To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease.
The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases.
All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease.
Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated.
The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine.
AUTHORS' CONCLUSIONS: The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.
自1997年第一种胆碱酯酶抑制剂（ChEI）问世以来，大多数临床医生以及可能大多数患者会认为胆碱能药物多奈哌齐、加兰他敏和卡巴拉汀是轻度至中度阿尔茨海默病的一线药物治疗。这些药物具有略有不同的药理特性，但它们均通过抑制乙酰胆碱酯酶来抑制乙酰胆碱（一种与记忆相关的重要神经递质）的分解发挥作用。这些药物最多只能改善阿尔茨海默病的症状。Cochrane针对每种用于治疗阿尔茨海默病的ChEI的综述已经完成（Birks 2005、Birks 2005b和Loy 2005）。尽管有临床研究证据及其间的临床经验，但关于ChEIs是否有效仍存在争议。
评估多奈哌齐、加兰他敏和卡巴拉汀对阿尔茨海默病所致轻度、中度或重度痴呆患者的疗效。
2005年6月12日，使用检索词“多奈哌齐”、“E2020”、“安理申”、“加兰他敏*”、“雷米诺林”、“卡巴拉汀”、“艾斯能”、“ENA 713”和“ENA - 713”检索Cochrane痴呆与认知改善小组专业注册库。该注册库包含所有主要医疗保健数据库及许多正在进行的试验数据库的最新记录。
所有将ChEI治疗与安慰剂或另一种ChEI用于阿尔茨海默病所致轻度、中度或重度痴呆患者进行比较的无混杂因素、设盲、随机试验。
由一名审阅者（JSB）提取数据，在适当且可行的情况下进行合并，并估计合并治疗效果或治疗的风险与益处。
13项随机、双盲、安慰剂对照试验结果表明，对于阿尔茨海默病所致轻度、中度或重度痴呆患者，使用多奈哌齐、加兰他敏或卡巴拉汀按推荐剂量治疗6个月和1年，在70分的阿尔茨海默病评定量表认知部分（ADAS - Cog）中，认知功能平均改善 - 2.7分（95%可信区间 - 3.0至 - 2.3）。对其他测量方法不知情的研究临床医生对接受治疗患者的整体临床状况评价更为积极。在日常生活活动和行为测量方面也可见治疗益处。这些治疗效果均不显著。没有证据表明重度痴呆或轻度痴呆患者的效果较差，尽管除轻度至中度痴呆外几乎没有证据。因不良事件退出ChEI治疗组的患者约为29%，多于退出安慰剂组的患者（18%）。有证据表明接受ChEI治疗的患者总体不良事件多于接受安慰剂治疗的患者。尽管报告了多种不良事件类型，但ChEI组中恶心、呕吐、腹泻明显比安慰剂组更频繁。有四项研究均由一家制药公司资助，其中比较了两种ChEI，两项是多奈哌齐与加兰他敏的比较，两项是多奈哌齐与卡巴拉汀的比较。三项研究中患者对治疗未设盲，只有第四项研究（DON vs RIV/Bullock）是双盲的。两项研究提供的证据很少，它们为期12周，时间短得几乎不足以完成药物滴定。在52周时，对于认知、日常生活活动、在治疗结束前退出试验的人数、发生任何不良事件的人数或任何特定不良事件，DON vs GAL/Wilcock研究没有证据表明多奈哌齐与加兰他敏之间存在治疗差异。在两年时，DON vs RIV/Bullock研究没有证据表明多奈哌齐与卡巴拉汀在认知功能、日常生活活动和行为障碍方面存在差异。接受多奈哌齐治疗的患者发生不良事件的人数少于接受卡巴拉汀治疗的患者。
三种胆碱酯酶抑制剂对轻度至中度阿尔茨海默病有效。在治疗前无法确定哪些患者会对治疗有反应。没有证据表明ChEI治疗不具有成本效益。尽管三种胆碱酯酶抑制剂的作用方式略有不同，但在疗效方面没有证据表明它们之间存在任何差异。与卡巴拉汀相比，多奈哌齐似乎不良反应较少。如果采用超过三个月的仔细且逐步滴定方案，加兰他敏和卡巴拉汀在耐受性方面可能与多奈哌齐相当。多奈哌齐的滴定更直接，较低剂量可能值得考虑。
