Greco Antonio, Spagnolo Marco, Laudani Claudio, Occhipinti Giovanni, Mauro Maria Sara, Agnello Federica, Faro Denise Cristiana, Legnazzi Marco, Rochira Carla, Scalia Lorenzo, Capodanno Davide
Division of Cardiology, Azienda Ospedaliero-Universitaria Policlinico "G. Rodolico-San Marco", University of Catania, Catania, Italy.
JACC Adv. 2024 Jun 5;3(7):101021. doi: 10.1016/j.jacadv.2024.101021. eCollection 2024 Jul.
Noninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin.
This study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials.
We reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included.
We analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; < 0.001).
Recalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.
非劣效性试验在心血管医学中越来越常见，但其报告和解读具有挑战性，尤其是当使用绝对风险差异作为非劣效性界值时。
本研究旨在探讨在心血管试验中使用绝对而非相对非劣效性界值的影响。
我们回顾了2015年至2022年在主要心血管会议上展示并在同一时期发表的非劣效性试验。根据对照组的实际与预期事件发生率，我们重新计算了绝对非劣效性界值并重新评估了试验结果。感兴趣的主要结局是重新计算后解读不同的试验比例。此外，我们分析了这些试验的结论陈述，以确定是否包含对研究结果解读的警示说明。
我们共分析了768项试验，其中88项采用非劣效性设计，66项使用绝对非劣效性界值。在符合分析条件的45项试验的48次比较中，基于观察到的而非预期的事件发生率重新计算绝对非劣效性界值后，11项（22.9%）结果出现分歧。最初声称非劣效的10项试验在界值重新计算后未达到非劣效性。所有这些试验在结论部分均未包含提示对研究结果进行谨慎解读的陈述。与其他试验相比，这些试验在预期和重新计算的非劣效性界值之间的中位数差异更大（44.7% [四分位间距：38.6% - 56.7%] 对15.3% [四分位间距：-1.5% 至28.9%]；< 0.001）。
根据实际事件发生率而非预期事件发生率重新计算非劣效性界值，导致约四分之一的心血管试验结果不同，大多数结果有分歧的试验缺乏谨慎解读。这些发现强调了使用或补充相对非劣效性界值的重要性，特别是在观察到的和预期的事件发生率之间存在显著差异的研究中。这突出了在非劣效性试验中，尤其是那些采用绝对界值的试验中，提高方法学和报告标准的迫切需求。
