IMPORTANCE The outcome and interpretation of noninferiority trials depend on the magnitude of the noninferiority margin and whether a relative or absolute noninferiority margin is used and may be affected by imprecision in event rate estimation. OBJECTIVE To assess the consequence of imprecise event rate estimations on interpretation of peer-reviewed randomized clinical trials. DATA SOURCES PubMed/MEDLINE was searched for articles published between January 1, 2015, and April 30, 2021. STUDY SELECTION Noninferiority randomized clinical trials of coronary stents published in selected journals with clinical events as the primary end point. DATA EXTRACTION AND SYNTHESIS Two reviewers (M.S. and F.V.) independently extracted data on trial characteristics, noninferiority assumptions, primary end point clinical outcomes, and study conclusions. Overestimation or underestimation of the control event rate was evaluated by dividing the assumed control event rate by the observed control event rate. For noninferiority end points with absolute margins, the assumed corresponding relative margin was defined as the ratio of the absolute margin and the assumed event rate, and the observed corresponding relative margin as the ratio between the absolute margin and the observed event rate in the control arm. Noninferiority comparisons with absolute margins were reanalyzed using the assumed corresponding relative margin and the Farrington-Manning score test for relative risk. MAIN OUTCOMES AND MEASURES Overestimation or underestimation, assumed and observed corresponding relative margins, and relative reanalysis of the primary end points of trials with absolute margins. RESULTS A total of 106 989 patients from 58 trials were included. The event rate in the control arms was overestimated by a median (IQR) of 28% (2%-74%). Most noninferiority trials used absolute rather than relative margins (55 of 58 trials [94.8%]). Owing to overestimation, absolute noninferiority margins became more permissive than originally assumed (median [IQR] of observed relative noninferiority margin, 1.62 [1.50-1.80] vs assumed relative noninferiority margin, 1.47 [1.39-1.55]; P < .001). Among trial comparisons that met noninferiority with an absolute noninferiority margin, 17 of 50 trials (34.0%) would not have met noninferiority with a corresponding assumed relative noninferiority margin. CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, assumed event rates were often overestimated in noninferiority coronary stent trials. Because most of these trials use absolute margins to define noninferiority, such overestimation results in excessively permissive relative noninferiority margins.

中文翻译：

---

冠状动脉支架非劣效性试验中不准确假设的后果：系统评价和荟萃分析。

重要性 非劣效性试验的结果和解释取决于非劣效性界值的大小以及是否使用相对或绝对非劣效性界值，并且可能受到事件发生率估计不精确的影响。目的 评估不精确的事件发生率估计对同行评审随机临床试验解释的影响。数据来源 PubMed/MEDLINE 搜索了 2015 年 1 月 1 日至 2021 年 4 月 30 日期间发表的文章。 研究选择 发表在选定期刊上的冠状动脉支架的非劣效性随机临床试验，以临床事件为主要终点。数据提取和综合 两名评价者（MS 和 FV）独立提取试验特征、非劣效性假设、主要终点临床结果和研究结论的数据。通过将假设的控制事件率除以观察到的控制事件率来评估控制事件率的高估或低估。对于具有绝对界值的非劣效性终点，假定的相应相对界值定义为绝对界值与假定的事件发生率之比，观察到的相应相对界值定义为绝对界值与对照组中观察到的事件发生率之间的比值. 使用假定的相应相对边缘和相对风险的 Farrington-Manning 评分测试重新分析与绝对边缘的非劣效性比较。主要结果和测量 高估或低估，假设和观察到的相应相对边际，以及对具有绝对边际的试验主要终点的相对再分析。结果 共纳入 58 项试验的 106 989 名患者。对照组的事件发生率被高估了 28% (2%-74%) 的中位数 (IQR)。大多数非劣效性试验使用绝对边缘而不是相对边缘（58 项试验中的 55 项 [94.8%]）。由于高估，绝对非劣效性界值变得比最初假设的更为宽容（观察到的相对非劣效性界值的中位数 [IQR]，1.62 [1.50-1.80] 对比假定的相对非劣效性界值，1.47 [1.39-1.55]；P < .001）。在满足非劣效性且具有绝对非劣效性界值的试验比较中，50 项试验中有 17 项 (34.0%) 不会满足具有相应假定相对非劣效性界值的非劣效性。结论和相关性 在本系统评价和荟萃分析中，在非劣效性冠状动脉支架试验中，假定的事件发生率经常被高估。因为这些试验中的大多数都使用绝对界值来定义非劣效性，所以这种高估会导致过度宽容的相对非劣效性界值。