Comparison of the restricted mean survival time with the hazard ratio in superiority trials with a time-to-event end point
Comparison of the restricted mean survival time with the hazard ratio in superiority trials with a time-to-event end point
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DOI：
10.1002/pst.1846
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发表时间：
2018-05-01
影响因子：
1.5
通讯作者：
Kuan, Pei-Fen
中科院分区：
文献类型：
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作者：
Huang, Bo;Kuan, Pei-Fen
随着新型疗法的出现，与传统治疗相比，其作用机制不同，临床试验中偏离比例风险（PH）假设的事件发生时间终点越来越常见。在这些情况下，风险比可能不是治疗效果的有效统计测量，对数秩检验可能不再是最有效的统计检验。限制平均生存时间（RMST）是一种替代的稳健且临床可解释的总结性指标，不依赖于PH假设。我们进行了广泛的模拟，以评估性能和操作特性的RBST为基础的推理和对基于风险比的推理，在各种情况下和设计参数设置。当Kaplan-Meier生存曲线上的大多数时间点存在有利于1个治疗组的明显分离时，对数秩检验通常是一种有效检验，但RMST检验的性能相似。在观察到生存曲线晚期分离的非PH情景下，当截断时间合理地接近观察到的曲线的尾部时，基于RRST的检验具有比对数秩检验更好的性能。此外，当预期实验组中存在平坦生存尾部（或低事件率）时，不建议选择最大观察事件时间的最小值作为RMST的截断时间点。此外，我们建议在临床环境中纳入基于截断时间内RMST曲线的分析，其中怀疑存在实质性偏离PH假设。
With the emergence of novel therapies exhibiting distinct mechanisms of action compared to traditional treatments, departure from the proportional hazard (PH) assumption in clinical trials with a time-to-event end point is increasingly common. In these situations, the hazard ratio may not be a valid statistical measurement of treatment effect, and the log-rank test may no longer be the most powerful statistical test. The restricted mean survival time (RMST) is an alternative robust and clinically interpretable summary measure that does not rely on the PH assumption. We conduct extensive simulations to evaluate the performance and operating characteristics of the RMST-based inference and against the hazard ratio-based inference, under various scenarios and design parameter setups. The log-rank test is generally a powerful test when there is evident separation favoring 1 treatment arm at most of the time points across the Kaplan-Meier survival curves, but the performance of the RMST test is similar. Under non-PH scenarios where late separation of survival curves is observed, the RMST-based test has better performance than the log-rank test when the truncation time is reasonably close to the tail of the observed curves. Furthermore, when flat survival tail (or low event rate) in the experimental arm is expected, selecting the minimum of the maximum observed event time as the truncation timepoint for the RMST is not recommended. In addition, we recommend the inclusion of analysis based on the RMST curve over the truncation time in clinical settings where there is suspicion of substantial departure from the PH assumption.