Edinburgh Clinical Trials Unit, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom.
British Heart Foundation/University Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom.
PLoS One. 2022 Jul 1;17(7):e0271027. doi: 10.1371/journal.pone.0271027. eCollection 2022.
The high-sensitivity cardiac troponin on presentation to rule out myocardial infarction (HiSTORIC) study was a stepped-wedge cluster randomised trial with long before-and-after periods, involving seven hospitals across Scotland. Results were divergent for the binary safety endpoint (type 1 or type 4b myocardial infarction or cardiac death) across certain pre-specified analyses, which warranted further investigation. In particular, the calendar-matched analysis produced an odds ratio in the opposite direction to the primary logistic mixed-effects model analysis.
Several post-hoc statistical models were fitted to each of the co-primary outcomes of length of hospital stay and safety events, which included adjusting for exposure time, incorporating splines, and fitting a random time effect. We improved control of patient characteristics over time by adjusting for multiple additional covariates using different methods: direct inclusion, regression adjustment for propensity score, and weighting. A data augmentation approach was also conducted aiming to reduce the effect of sparse data bias. Finally, the raw data was examined.
The new statistical models confirmed the results of the pre-specified trial analysis. In particular, the observed divergence between the calendar-matched and other analyses remained, even after performing the covariate adjustment methods, and after using data augmentation. Divergence was particularly acute for the safety endpoint, which had an event rate of 0.36% overall. Examining the raw data was particularly helpful to assess the sensitivity of the results to small changes in event rates and identify patterns in the data.
Our experience reveals the importance of conducting multiple pre-specified sensitivity analyses and examining the raw data, particularly for stepped wedge trials with low event rates or with a small number of sites. Before-and-after analytical approaches that adjust for differences in patient populations but avoid direct modelling of the time trend should be considered in future stepped wedge trials with similar designs.
高敏肌钙蛋白用于排除心肌梗死的首发检测（HiSTORIC）研究是一项采用阶梯式楔形集群随机试验设计，在苏格兰的七家医院进行，该试验具有较长的前后对照期。在某些特定分析中，二分类安全性终点（1 型或 4b 型心肌梗死或心源性死亡）的结果存在差异，这需要进一步调查。特别是，日历匹配分析产生的比值比与主要逻辑混合效应模型分析的方向相反。
对住院时间和安全性事件这两个主要共同结局的每个次要结局，拟合了几种事后统计模型，包括调整暴露时间、纳入样条、拟合随机时间效应。我们通过使用不同的方法调整多个额外的协变量，从而更好地控制随时间变化的患者特征：直接纳入、倾向评分回归调整和加权。还采用了数据扩充方法，旨在减少稀疏数据偏差的影响。最后，我们还检查了原始数据。
新的统计模型证实了预先指定的试验分析结果。特别是，即使在进行协变量调整方法后，并且在使用数据扩充后，日历匹配分析与其他分析之间的观察到的差异仍然存在。安全性终点的差异尤为明显，总体事件发生率为 0.36%。检查原始数据对于评估结果对事件率微小变化的敏感性以及识别数据中的模式特别有帮助。
我们的经验表明，对于低事件率或少数站点的阶梯式楔形试验，进行多次预先指定的敏感性分析和检查原始数据非常重要。在未来具有类似设计的阶梯式楔形试验中，应该考虑采用调整患者人群差异但避免直接对时间趋势建模的前后分析方法。
