Qizilbash N, Birks J, Lopez Arrieta J, Lewington S, Szeto S
SmithKline Beecham, New Frontiers Science Park (South), Third Avenue, Harlow, Essex, UK, CM19 5AW.
Cochrane Database Syst Rev. 2007 Jul 18(3):CD000202. doi: 10.1002/14651858.CD000202.
Tacrine is one of the first drugs to be widely marketed for the loss of memory and intellectual decline in Alzheimer's disease, often accompanied by abnormal behaviour and physical decline. The alleged success of tacrine in the treatment of these symptoms has been heralded as confirmation of the cholinergic theory of Alzheimer's disease. The efficacy of tacrine for symptoms of dementia remains controversial. This is reflected by the low rate of prescription of tacrine in countries where it is approved and the lack of approval by several regulatory authorities in Europe and elsewhere. The uncertainty about the efficacy of tacrine is due to the difficulties in interpretation of the results from the clinical trials. The reasons for this are the small effects of tacrine compared to placebo for all outcomes; the high incidence of adverse events; the lack of benefit observed in several trials; the use of cross-over designs and their associated methodological problems in a disease like dementia; the use of different measurement scales to assess outcome in different trials; and the problem of high dropout rates.
To determine the clinical efficacy of tacrine for the symptoms of Alzheimer's disease.
The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'tacrine', 'tetrahydroaminoacridine' and 'THA' (see the Group's search strategy for full details).
All unconfounded, double-blind, randomized trials in which treatment with tacrine was administered for more than a day and compared to placebo in patients with dementia of the Alzheimer's type.
Data were extracted independently by two reviewers, pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used.
This review produced no clear results. The results were compatible with tacrine producing improvement, no change or even harm for those with Alzheimer's disease. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analyses failed to detect any difference between tacrine and placebo (OR 0.87; 95%CI 0.61 - 1.23). Behavioural disturbance, as measured by the Alzheimer's Disease Assessment Scale-noncognitive, failed to detect any difference between tacrine and placebo (SMD -0.04; 95%CI -0.52 - 0.43). For cognition function, the effect of tacrine was not statistically significantly different from placebo for the MiniMental State Examination score (0-30; high =good) (SMD 0.14; 95%CI -0.02 - 0.30) and was barely statistically significantly in favour of treatment for the Alzheimer's Disease Assessment Scale-cognitive scale (SMD -0.22; 95%CI -0.32 - -0.13). Adverse events were not reported in a systematic way in the different trials, making formal comparison difficult. Raised serum liver enzymes was the major reason for withdrawal. The odds ratio for withdrawal due to an adverse event was significantly different from one, the control group experienced fewer events (OR 5.7; 95%CI 4.1-7.9). Gastrointestinal side effects (diarrhoea, anorexia, dyspepsia and abdominal pain) were the other major cause of adverse events and for withdrawal, and the odds ratio for withdrawal was also significantly different from one in favour of the control group (OR 3.8; 95%CI 2.8-5.1). No deaths were reported in any of the studies during the trial period, up to six months.
AUTHORS' CONCLUSIONS: This review provides no convincing evidence that tacrine is a useful treatment for the symptoms of Alzheimer's disease. However, as so few trials presented data in a format suitable for pooling, the results of this review may be modified when further data from all relevant trials are included. There is an urgent need for the independent evaluation of the data already existing in the trials but not accessible through published or grouped data. An independent meta-analysis of the individual-patient data is required. The results and conclusions of this update are unaltered by further searching as the additional studies do not add any further valid/eligible data.
他克林是最早广泛用于治疗阿尔茨海默病所致记忆丧失和智力衰退的药物之一，这些症状常伴有行为异常和身体机能衰退。他克林在治疗这些症状方面所谓的成功被视为对阿尔茨海默病胆碱能理论的证实。他克林对痴呆症状的疗效仍存在争议。这体现在该药在获批国家的低处方率以及欧洲和其他地区多个监管机构未予批准。他克林疗效的不确定性源于临床试验结果解读的困难。原因包括：与安慰剂相比，他克林对所有结局的影响较小；不良事件发生率高；在多项试验中未观察到益处；在痴呆这类疾病中使用交叉设计及其相关方法学问题；在不同试验中使用不同测量量表评估结局；以及高失访率问题。
确定他克林对阿尔茨海默病症状的临床疗效。
使用“他克林”“四氢氨基吖啶”和“THA”检索Cochrane痴呆症临床试验组注册库（完整细节见该组检索策略）。
所有无混杂因素、双盲、随机试验，其中对阿尔茨海默型痴呆患者给予他克林治疗超过一天并与安慰剂进行比较。
由两名审阅者独立提取数据，酌情且可能时进行汇总，并估计汇总比值比（95%可信区间）或平均差（95%可信区间）。尽可能使用意向性分析数据。
本综述未得出明确结果。结果表明他克林对阿尔茨海默病患者可能有改善、无变化甚至有害。许多已发表结果无法用于综合分析。对于总体临床改善的测量，意向性分析未发现他克林与安慰剂之间有任何差异（比值比0.87；95%可信区间0.61 - 1.23）。用阿尔茨海默病评估量表非认知部分测量的行为障碍，未发现他克林与安慰剂之间有任何差异（标准化均数差 -0.04；95%可信区间 -0.52 - 0.43）。对于认知功能，他克林对简易精神状态检查表评分（0 - 30分；高分 = 良好）的影响与安慰剂无统计学显著差异（标准化均数差0.14；95%可信区间 -0.02 - 0.30），对阿尔茨海默病评估量表认知部分的影响仅在统计学上勉强支持治疗（标准化均数差 -0.22；95%可信区间 -0.32 - -0.13）。不同试验未系统报告不良事件，难以进行正式比较。血清肝酶升高是停药的主要原因。因不良事件停药的比值比显著不同于1，对照组不良事件较少（比值比5.7；95%可信区间4.1 - 7.9）。胃肠道副作用（腹泻、厌食、消化不良和腹痛）是不良事件和停药的另一主要原因，停药比值比也显著不同于1，支持对照组（比值比3.8；95%可信区间2.8 - 5.1）。在长达6个月的试验期内，任何研究均未报告死亡病例。
本综述未提供令人信服的证据表明他克林对阿尔茨海默病症状是一种有用的治疗方法。然而，由于很少有试验以适合汇总的格式呈现数据，当纳入所有相关试验的更多数据时，本综述结果可能会改变。迫切需要对试验中已存在但无法通过已发表或分组数据获取的数据进行独立评估。需要对个体患者数据进行独立的荟萃分析。由于额外研究未增加任何进一步的有效/合格数据，进一步检索未改变本次更新的结果和结论。
