Schneider Lon S, Dagerman Karen S, Higgins Julian P T, McShane Rupert
University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Arch Neurol. 2011 Aug;68(8):991-8. doi: 10.1001/archneurol.2011.69. Epub 2011 Apr 11.
We directly assessed the clinical trials' evidence for memantine's efficacy in mild Alzheimer disease (AD). Memantine is indicated in the United States and Europe for moderate to severe AD, which is diagnosed if a patient has a Mini-Mental State Examination (MMSE) score of less than 15 or less than 20, respectively. Yet memantine is very frequently prescribed for mild AD and mild cognitive impairment, and a manufacturer-sponsored meta-analysis claimed its efficacy in mild AD.
DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Manufacturer-sponsored meta-analyses, registries, presentations, and publications were systematically searched for randomized placebo-controlled, parallel-group clinical trials of memantine in patients with mild to moderate AD. The trials' characteristics and outcomes were extracted by one reviewer and checked by another. Meta-analyses were performed as inverse variance-weighted averages of mean differences using fixed-effects models. Summary results for patients with mild AD were obtained by contrasting the summary results for patients with mild or moderate AD with the summary results for the subset of patients with moderate AD.
Three trials were identified that included 431 patients with mild AD (ie, with MMSE scores of 20-23) and 697 patients with moderate AD (ie, with MMSE scores of 10-19). There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined: mean differences (95% confidence intervals [CIs]) on the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC-plus), the Alzheimer Disease Cooperative Study-activities of daily living (ADCS-ADL) scale, and the Neuropsychiatric Inventory (NPI) were -0.17 (95% CI, -1.60 to 1.26), -0.09 (95% CI, -0.30 to 0.12), 0.62 (95% CI, -1.64 to 2.71), and 0.09 (95% CI, -2.11 to 2.29), respectively. For patients with moderate AD, there were small differences on the ADAS-cog and the CIBIC-plus, -1.33 (95% CI, -2.28 to -0.38) and -0.16 (95% CI, -0.32 to 0.00), respectively, but no differences on the ADCS-ADL scale (-0.57 [95% CI, -1.75 to 0.60]) or the NPI (0.25 [95% CI, -1.48 to 1.99]).
Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD. Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.
我们直接评估了美金刚治疗轻度阿尔茨海默病（AD）疗效的临床试验证据。在美国和欧洲，美金刚被用于治疗中度至重度AD，分别是指患者的简易精神状态检查表（MMSE）得分小于15分或小于20分的情况。然而，美金刚却常常被用于治疗轻度AD和轻度认知障碍，且一项由制造商发起的荟萃分析称其对轻度AD有效。
数据来源、研究选择与数据提取：系统检索了由制造商发起的荟萃分析、登记资料、报告及出版物，以查找美金刚治疗轻至中度AD患者的随机安慰剂对照平行组临床试验。由一名审阅者提取试验的特征及结果，并由另一名审阅者进行核对。采用固定效应模型，以均值差的逆方差加权平均值进行荟萃分析。通过对比轻度或中度AD患者的汇总结果与中度AD患者亚组的汇总结果，得出轻度AD患者的汇总结果。
共识别出三项试验，其中包括431例轻度AD患者（即MMSE得分为20 - 23分）和697例中度AD患者（即MMSE得分为10 - 19分）。在任何一项试验中或合并数据时，美金刚与安慰剂在轻度AD患者的任何结局指标上均无显著差异：阿尔茨海默病评估量表认知子量表（ADAS-cog）、基于临床医生访谈的变化印象加照顾者意见（CIBIC-plus）、阿尔茨海默病协作研究日常生活活动（ADCS-ADL）量表以及神经精神科问卷（NPI）的均值差（95%置信区间[CI]）分别为-0.17（95%CI，-1.60至1.26）、-0.09（95%CI，-0.30至0.12）、0.62（95%CI，-1.64至2.71）和0.09（95%CI，-2.11至2.29）。对于中度AD患者，在ADAS-cog和CIBIC-plus上有微小差异，分别为-1.33（95%CI，-2.28至-0.38）和-0.16（95%CI，-0.32至0.00），但在ADCS-ADL量表（-0.57[95%CI，-1.75至0.60]）或NPI（0.25[95%CI，-1.48至1.99]）上无差异。
尽管美金刚经常被超适应证使用，但缺乏其对轻度AD有益的证据，且其对中度AD疗效的证据也不足。需要进行前瞻性试验，以进一步评估美金刚单独使用或与胆碱酯酶抑制剂联合使用对轻度和中度AD的潜在疗效。
