Clinical Trials Center, Cardiovascular Research Foundation, New York, New York.
NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York.
JAMA Cardiol. 2022 Mar 1;7(3):320-327. doi: 10.1001/jamacardio.2021.5724.
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.
To assess the consequence of imprecise event rate estimations on interpretation of peer-reviewed randomized clinical trials.
PubMed/MEDLINE was searched for articles published between January 1, 2015, and April 30, 2021.
Noninferiority randomized clinical trials of coronary stents published in selected journals with clinical events as the primary end point.
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.
Overestimation or underestimation, assumed and observed corresponding relative margins, and relative reanalysis of the primary end points of trials with absolute margins.
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.
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.
非劣效性试验的结果和解释取决于非劣效性边界的大小，以及使用的是相对还是绝对非劣效性边界，并且可能受到事件发生率估计不精确的影响。
评估事件发生率估计不精确对同行评议的随机临床试验解释的影响。
2015 年 1 月 1 日至 2021 年 4 月 30 日期间，在 PubMed/MEDLINE 上搜索了发表的文章。
在选定的期刊上发表的冠状动脉支架非劣效性随机临床试验，以临床事件为主要终点。
两名审查员（M.S.和 F.V.）独立提取了试验特征、非劣效性假设、主要终点临床结果和研究结论的数据。通过将假定的对照事件率除以观察到的对照事件率来评估对照事件率的高估或低估。对于具有绝对边界的非劣效性终点，假定的相应相对边界定义为绝对边界与假定事件率的比值，观察到的相应相对边界定义为对照臂中绝对边界与观察到的事件率的比值。使用假定的相应相对边界和 Farrington-Manning 比值风险检验对具有绝对边界的非劣效性终点进行了重新分析。
试验中对照臂的高估或低估、假定的和观察到的相应相对边界，以及具有绝对边界的主要终点的相对重新分析。
来自 58 项试验的 106989 名患者被纳入研究。对照臂的事件发生率被高估了中位数（IQR）28%（2%-74%）。大多数非劣效性试验使用绝对而不是相对边界（58 项试验中的 55 项[94.8%]）。由于高估，绝对非劣效性边界变得比最初假设的更宽松（观察到的相对非劣效性边界的中位数[IQR]为 1.62[1.50-1.80]，而假定的相对非劣效性边界为 1.47[1.39-1.55]；P<.001）。在符合绝对非劣效性边界的试验比较中，50 项试验中有 17 项（34.0%）不符合相应假定的相对非劣效性边界。
在这项系统评价和荟萃分析中，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。由于这些试验大多使用绝对边界来定义非劣效性，因此这种高估导致相对非劣效性边界过于宽松。
