Birks Jacqueline S, Chong Lee Yee, Grimley Evans John
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, UK, OX3 7LD.
Cochrane Database Syst Rev. 2015 Sep 22;9(9):CD001191. doi: 10.1002/14651858.CD001191.pub4.
Alzheimer's disease 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 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 lower risk of adverse effects have since been introduced. Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA.
To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources.
We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared.
One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data.
A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies).
AUTHORS' CONCLUSIONS: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.
阿尔茨海默病是影响老年人的最常见痴呆病因。旨在改善阿尔茨海默病临床表现的治疗策略之一是通过使用胆碱酯酶抑制剂来增强大脑中的胆碱能神经传递，以延缓释放到突触间隙中的乙酰胆碱的分解。他克林是为此目的进行广泛试验的首个胆碱酯酶抑制剂，与包括肝毒性在内的显著不良反应相关。此后引入了其他胆碱酯酶抑制剂，包括卡巴拉汀，其在作用特异性和较低不良反应风险方面具有更优特性。卡巴拉汀已在包括欧盟所有成员国和美国在内的60个国家获得使用批准。
确定卡巴拉汀对阿尔茨海默型痴呆患者的临床疗效和安全性。
我们于2015年3月2日在ALOIS（Cochrane痴呆与认知改善小组专业注册库）中进行检索，检索词为：Rivastigmine 或 exelon 或 ENA 或 “SDZ ENA 713”。ALOIS包含从多个主要医疗保健数据库（Cochrane图书馆、MEDLINE、EMBASE、PsycINFO、CINAHL、LILACS）的月度检索、众多试验注册库和灰色文献来源中识别出的临床试验记录。
我们纳入了所有无混杂因素、双盲、随机对照试验，其中对阿尔茨海默型痴呆患者给予卡巴拉汀治疗12周或更长时间，并将其效果与平行组安慰剂组患者的效果进行比较，或比较两种卡巴拉汀制剂。
一位综述作者（JSB）应用研究选择标准，评估研究质量并提取数据。
共有13项试验符合该综述的纳入标准。试验持续时间为12至52周。较早的试验测试了胶囊剂型，剂量高达12毫克/天。2007年以来的试验测试了持续剂量的透皮贴剂剂型，剂量分别为4.6、9.5和17.7毫克/天。我们的主要分析比较了口服6至12毫克/天或透皮9.5毫克/天的卡巴拉汀与安慰剂的安全性和疗效。7项试验为该分析贡献了3450例患者的数据。另外两项研究的数据未被纳入，原因是缺乏信息和方法学问题。所有纳入试验均为多中心试验，招募了轻度至中度阿尔茨海默病患者，平均年龄约75岁。所有试验在随机化和分配方面的偏倚风险较低，但在四项研究中，因失访导致的偏倚风险尚不清楚，一项研究中为低，两项研究中为高。治疗26周后，与安慰剂相比，卡巴拉汀在使用阿尔茨海默病评估量表 - 认知部分（ADAS - Cog）评分（平均差（MD） - 1.79；95%置信区间（CI） - 2.21至 - 1.37，n = 3232，6项研究）和简易精神状态检查表（MMSE）评分（MD 0.74；95% CI 0.52至0.97，n = 3205，6项研究）评估的认知功能方面有更好的结果，在日常生活活动方面（标准化均数差（SMD）0.20；95% CI 0.13至0.27，n = 3230，6项研究）以及临床医生评定的总体变化印象方面也是如此，接受卡巴拉汀治疗的患者中无变化或病情恶化的比例较小（比值比（OR）0.68；95% CI 0.58至0.80，n = 3338，7项研究）。三项研究报告了行为变化，与安慰剂相比无差异（标准化均数差（SMD） - 0.04；95% CI - 0.14至0.06，n = 1529，3项研究）。只有一项研究使用神经精神科问卷 - 照料者困扰（NPI - D）量表测量了对照料者的影响，发现两组之间无差异（MD 0.10；95% CI - 0.91至1.11，n = 529，1项研究）。总体而言，接受卡巴拉汀治疗的参与者退出试验（比值比（OR）2.01，95% CI 1.71至2.37，n = 3569，7项研究）或在试验期间发生不良事件（OR 2.16，95% CI 1.82至;2.57，n = 3587，7项研究）的可能性约为两倍。
卡巴拉汀（口服每日6至12毫克或透皮每日9.5毫克）似乎对轻度至中度阿尔茨海默病患者有益。与安慰剂相比，在认知功能下降率和日常生活活动方面观察到了更好的结果，尽管效果较小且临床重要性不确定。卡巴拉汀在临床医生总体评估结果方面也有获益。在行为变化或对照料者的影响方面，卡巴拉汀组与安慰剂组之间无差异。在这些剂量下，透皮贴剂的副作用可能比胶囊少，但疗效相当。由于失访导致偏倚的风险存在，所有综述结果的证据质量仅为中等。所有有可用数据的研究均由行业资助或赞助。本综述未审查经济数据。
