Molnar Frank J, Man-Son-Hing Malcolm, Hutton Brian, Fergusson Dean A
Open Med. 2009 Mar 24;3(2):e31-50.
Intention-to-treat analysis is used in the analysis of randomized controlled trials to preserve trial power in the presence of missing subject data as well as to control for both known and unknown confounding factors. One form of intention-to-treat analysis is last-observation-carried-forward (LOCF). Concerns exist regarding whether it is appropriate to use LOCF in analyses involving progressive conditions or in situations where missing data are non-random (e.g., subjects drop out because of treatment side effects or differing disease severity).
To examine the use of intention-to-treat imputation of missing data techniques, and specifically LOCF, in randomized controlled trials of the use of cholinesterase inhibitors and memantine to treat Alzheimer's disease, vascular dementia, mixed dementia and mild cognitive impairment.
We conducted a systematic electronic search of MEDLINE and the Cochrane Central Register of Controlled Trials from 1984 to 2008 for double-blinded, randomized controlled trials of cholinesterase inhibitors or memantine that examined progressive symptoms in Alzheimer's disease, vascular dementia, mixed dementia and mild cognitive impairment. We collected data on the use of intention-to-treat and non-intention-to-treat analyses and on contraindications to the use of LOCF analysis and we performed quality assessments of included trials.
Of the 57 studies that met the inclusion criteria, 12 did not report intention-to-treat analyses. Of the 34 studies that employed LOCF as the only form of intention-to-treat analysis, 24 reported conditions that could produce biased LOCF analyses favouring the drug under study. The latter finding was more common in cholinesterase inhibitor trials than in memantine studies.
The published results of some randomized controlled trials of dementia drugs may be inaccurate (i.e., drug effectiveness may be exaggerated) or invalid (i.e., there may be false-positive results) because of bias introduced through the inappropriate use of LOCF analyses. This bias favours cholinesterase inhibitors, potentially preventing funding of and patient access to less toxic treatment options such as memantine. Licensing agencies should consider whether to accept LOCF analyses in research on dementias and other chronic progressive conditions.
意向性分析用于随机对照试验的分析，以在存在缺失受试者数据的情况下保持试验效能，并控制已知和未知的混杂因素。意向性分析的一种形式是末次观察结转（LOCF）。对于在涉及进行性疾病的分析中或在缺失数据非随机的情况下（例如，受试者因治疗副作用或不同的疾病严重程度而退出）使用LOCF是否合适，存在担忧。
探讨在使用胆碱酯酶抑制剂和美金刚治疗阿尔茨海默病、血管性痴呆、混合性痴呆和轻度认知障碍的随机对照试验中，缺失数据技术的意向性分析，特别是LOCF的使用情况。
我们对1984年至2008年的MEDLINE和Cochrane对照试验中央注册库进行了系统的电子检索，以查找关于胆碱酯酶抑制剂或美金刚的双盲随机对照试验，这些试验研究了阿尔茨海默病、血管性痴呆、混合性痴呆和轻度认知障碍的进行性症状。我们收集了关于意向性分析和非意向性分析的使用情况以及LOCF分析使用的禁忌证的数据，并对纳入试验进行了质量评估。
在符合纳入标准的57项研究中，12项未报告意向性分析。在34项将LOCF作为意向性分析的唯一形式的研究中，24项报告了可能产生有利于所研究药物的有偏LOCF分析的情况。后一发现在胆碱酯酶抑制剂试验中比在美金刚研究中更常见。
由于不恰当地使用LOCF分析引入的偏差，一些痴呆药物随机对照试验的已发表结果可能不准确（即药物有效性可能被夸大）或无效（即可能存在假阳性结果）。这种偏差有利于胆碱酯酶抑制剂，可能会阻止对毒性较小的治疗选择（如美金刚）的资助和患者使用。许可机构应考虑是否接受痴呆症和其他慢性进行性疾病研究中的LOCF分析。
