Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
JAMA. 2010 Mar 24;303(12):1180-7. doi: 10.1001/jama.2010.310.
Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping.
To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect.
Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008.
Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs.
Reviewers with methodological expertise conducted data extraction independently.
The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit.
Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.
理论和模拟研究表明，因疗效显著而提前终止的随机对照试验（RCT）会系统地高估其治疗效果。
比较因疗效显著而提前终止的 RCT（截断 RCT）与未提前终止的 RCT 荟萃分析（非截断 RCT）的治疗效果，并探讨与高估疗效相关的因素。
检索 MEDLINE、EMBASE、Current Contents 和全文期刊数据库，以确定截止到 2007 年 1 月的截断 RCT；检索 MEDLINE、Cochrane 系统评价数据库和效应评价数据库，以确定截止到 2008 年 1 月提取出单个 RCT 的系统评价。
选择的研究为提前终止因疗效显著而终止的 RCT，并与系统评价中的非截断 RCT 相匹配。具有医学内容专业知识的独立评审员，在不了解试验结果的情况下，根据与截断 RCT 的相似性，判断非截断 RCT 的资格。
具有方法学专业知识的评审员独立进行资料提取。
分析包括 91 项提前终止因疗效显著而终止的 RCT，提出了 63 个不同的问题，并与 424 项匹配的非截断 RCT 进行了比较。截断 RCT 与匹配的非截断 RCT 相比，相对危险度的汇总比值为 0.71（95%置信区间，0.65-0.77）。这种差异独立于存在统计学停止规则以及研究的方法学质量，如分配隐藏和盲法。在截断 RCT 中，当事件数少于 500 个时，截断 RCT 和非截断 RCT 之间的治疗效果大小差异较大（相对危险度比<0.75）。在 63 个问题中的 39 个问题（62%）中，非截断 RCT 的汇总效应未能显示出显著的益处。
因疗效显著而提前终止的 RCT 与未提前终止的 RCT 相比，其治疗效果更大。这种差异独立于统计学停止规则的存在，在较小的研究中更为明显。
