Yang Song, Troendle James
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Clin Trials. 2021 Apr;18(2):180-187. doi: 10.1177/1740774520972408. Epub 2020 Nov 24.
BACKGROUND/AIMS: In clinical trials, the primary outcome is often a composite endpoint defined as time to the first occurrence of either death or certain non-fatal events. Thus, a portion of available data would be omitted. In the win ratio approach, priorities are given to the clinically more important events, and more data are used. However, its power may be low if the treatment effect is predominantly on the non-terminal event.
We propose event-specific win ratios obtained separately on the terminal and non-terminal events. They can then be used to form global tests such as a linear combination test, the maximum test, or a test.
In simulations, these tests often improve the power of the original win ratio test. Furthermore, when the terminal and non-terminal events experience differential treatment effects, the new tests are often more powerful than the log-rank test for the composite outcome. Whether the treatment effect is primarily on the terminal events or not, the new tests based on the event-specific win ratios can be useful when different types of events are present. The new tests can reject the null hypothesis of no difference in the event distributions in the two treatment arms with the terminal event showing detrimental effect and the non-terminal event showing beneficial effect. The maximum test and the test do not have test-estimation coherency, but the maximum test has the coherency that the global null is rejected if and only if the null for one of the event types is rejected. When applied to data from the trial Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT), the new tests all reject the null hypothesis of no treatment effect while both the log-rank test used in TOPCAT and the original win ratio approach show non-significant -values.
Whether the treatment effect is primarily on the terminal events or the non-terminal events, the maximum test based on the event-specific win ratios can be a useful alternative for testing treatment effect in clinical trials with time-to-event outcomes when different types of events are present.
背景/目的：在临床试验中，主要结局通常是一个复合终点，定义为首次出现死亡或某些非致命事件的时间。因此，一部分可用数据会被遗漏。在胜率法中，更重视临床上更重要的事件，并使用了更多数据。然而，如果治疗效果主要体现在非终点事件上，其检验效能可能较低。
我们提出分别在终点事件和非终点事件上获得的特定事件胜率。然后可以用它们来构建全局检验，如线性组合检验、最大检验或检验。
在模拟中，这些检验通常能提高原始胜率检验的效能。此外，当终点事件和非终点事件经历不同的治疗效果时，对于复合结局，新检验通常比对数秩检验更具效能。无论治疗效果是否主要体现在终点事件上，当存在不同类型的事件时，基于特定事件胜率的新检验可能会很有用。新检验可以拒绝两个治疗组事件分布无差异的原假设，其中终点事件显示有害作用，非终点事件显示有益作用。最大检验和检验不具有检验-估计一致性，但最大检验具有这样的一致性：当且仅当其中一种事件类型的原假设被拒绝时，全局原假设才被拒绝。当应用于成人射血分数保留的心力衰竭患者醛固酮拮抗剂治疗试验（TOPCAT）的数据时，新检验均拒绝了无治疗效果的原假设，而TOPCAT中使用的对数秩检验和原始胜率法均显示P值无统计学意义。
无论治疗效果主要体现在终点事件还是非终点事件上，基于特定事件胜率的最大检验都可以作为在存在事件发生时间结局的临床试验中检验治疗效果的一种有用替代方法，尤其是当存在不同类型的事件时。
