The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model
The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model
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DOI：
10.3310/hta16210
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发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Hyde, C.
中科院分区：
文献类型：
--
作者：
Bond, M.;Rogers, G.;Hyde, C.
背景：阿尔茨海默病（AD）是最常见的痴呆形式。它主要是一种老年疾病，在英国65岁以上的人中有5%受到影响。目的：审查并更新英格兰和威尔士NHS关于多奈哌齐、加兰他敏、卡巴拉汀[乙酰胆碱酯酶抑制剂（AChEI）]和美金刚在其许可适应症中治疗AD的临床有效性和成本效益的指南，2006年11月，（2007年9月和2009年8月修订）。数据来源：2009年11月检索了电子数据库中的系统综述和/或荟萃分析、随机对照试验（RCT）和正在进行的研究，并于2010年3月更新;本次更新检索未发现新的可纳入研究。检索的数据库包括The科克伦图书馆（2009年第4期，科克伦系统评价数据库和科克伦对照试验中心注册库）、MEDLINE、MEDLINE过程中和其他非索引引文、EMBASE、PsycINFO、EconLit、ISI Web of Science数据库-科学引文索引、会议论文引文索引和BIOSIS;评价和传播中心（CAD）数据库- NHS经济评价数据库、卫生技术评估和效果评价摘要数据库。评价方法：临床有效性系统评价按照NHS CRD发布的原则进行。我们纳入了随机对照试验，其人群为AD患者。干预和对照药物取决于疾病的严重程度，通过简易精神状态检查（MMSE）进行测量。干预措施：轻度AD（MMSE 21-26）-多奈哌齐、加兰他敏和卡巴拉汀;中度AD（MMSE 10-20）-多奈哌齐、加兰他敏、卡巴拉汀和美金刚;重度AD（MMSE < 10）-美金刚。对照品：轻度AD（MMSE 21-26）-安慰剂或最佳支持治疗（BSC）;中度AD（MMSE 10-20）-多奈哌齐、加兰他敏、利斯的明、美金刚、安慰剂或BSC;重度AD（MMSE < 10）-安慰剂或BSC。结果包括临床、总体、功能、行为、生活质量、不良事件、成本和成本效益。在适当的情况下，使用成对荟萃分析、多重结局指标、荟萃回归和混合治疗比较汇总数据。该决策模型主要基于上一份技术评估报告中所述的三态马尔可夫模型的结构，以制度化的时间为基础，以最新的有效性、成本和效用估计为参数。尽管我们的结果存在不确定性，但我们在基本案例中发现，AChEI在支付意愿（WTP）为30时可能会节省成本，000每质量调整生命年（QALY）的人与轻度至中度AD。对于这类药物，AChEI比BSC更具成本效益的可能性> 99%。这些分析假设乙酰胆碱酯酶抑制剂对生存没有影响。对于AChEI，在轻度至中度AD患者中，概率敏感性分析表明多奈哌齐是最具成本效益的，在WTP为30，000磅/QALY时，有28%的概率成为最具成本效益的选择（WTP为20，000磅/QALY时，有27%）。在确定性结果中，多奈哌齐优于其他药物和BSC，后者与卡巴拉汀贴剂一起沿着，与更高的成本和更少的QT相关。因此，尽管加兰他敏的总成本略低于多奈哌齐（69，592磅vs 69，624英镑），但多奈哌齐的QALY收益略高（1.616 vs 1.617）足以让多奈哌齐主导加兰他敏。在WTP为30，000磅/QALY时，美金刚在中度至重度队列中与BSC相比具有成本效益的概率为38%（WTP为20，000磅/QALY时为28%）。美金刚的确定性ICER为32，100磅/QALY.Limitations的概率ICER为36，700磅/QALY. Trials最长随访6个月，缺乏关键结果的报告，没有提供亚组分析，并使用不敏感的措施。该模型不包括行为症状，并有不确定性的模型结构和parameters.Conclusions：额外的临床有效性的证据表明，继续从AChEI在缓解AD症状的临床效益，虽然有争议的影响的大小。虽然也有关于美金刚有效性的新证据，但它仍然不如AChEI的证据支持这种药物的使用。关于成本效益的结论与以前的评估大不相同。这是因为作为ICER基础的药物使用和非药物使用之间的有效性和成本变化非常小。这导致了高度不确定的结果，这是非常敏感的变化。研究重点：随机对照试验，包括死亡率，时间机构化和生活质量，动力亚组分析。资金：国家卫生研究所卫生技术评估计划。
Background: Alzheimer's disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK.Objectives: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009).Data sources: Electronic databases were searched for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases - Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CAD) databases - NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects.Review methods: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). Interventions: mild AD (MMSE 21-26) - donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20) - donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10) - memantine. Comparators: mild AD (MMSE 21-26) - placebo or best supportive care (BSC); moderate AD (MMSE 10-20) - donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10) - placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixed-treatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities.Results: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of 30,000 per quality-adjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of 30,000 pound per QALY (27% at a WTP of 20,000 pound per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (69,592 pound vs 69,624) pound, the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine. The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of 30,000 pound per QALY is 38% (and 28% at a WTP of 20,000 pound per QALY). The deterministic ICER for memantine is 32,100 pound per/QALY and the probabilistic ICER is 36,700 pound per/QALY.Limitations: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters.Conclusions: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug's use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change.Research priorities: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis.Funding: The National Institute for Health Research Health Technology Assessment programme.