Provincial Research Data Services, Alberta Health Services, Edmonton, Alberta, Canada.
Canadian VIGOUR Centre, University of Alberta, Alberta, Canada.
BMC Med Res Methodol. 2023 Feb 6;23(1):35. doi: 10.1186/s12874-023-01857-0.
Composite endpoints for estimating treatment efficacy are routinely used in several therapeutic areas and have become complex in the number and types of component outcomes included. It is assumed that its components are of similar asperity and chronology between both treatment arms as well as uniform in magnitude of the treatment effect. However, these assumptions are rarely satisfied. Understanding this heterogeneity is important in developing a meaningful assessment of the treatment effect.
We developed the Weighted Composite Endpoint (WCE) method which uses weights derived from stakeholder values for each event type in the composite endpoint. The derivation for the product limit estimator and the variance of the estimate are presented. The method was then tested using data simulated from parameters based on a large cardiovascular trial. Variances from the estimated and traditional approach are compared through increasing sample size.
The WCE method used all of the events through follow-up and generated a multiple recurrent event survival. The treatment effect was measured as the difference in mean survivals between two treatment arms and corresponding 95% confidence interval, providing a less conservative estimate of survival and variance, giving a higher survival with a narrower confidence interval compared to the traditional time-to-first-event analysis.
The WCE method embraces the clinical texture of events types by incorporating stakeholder values as well as all events during follow-up. While the effective number of events is lower in the WCE analysis, the reduction in variance enhances the ability to detect a treatment effect in clinical trials.
在多个治疗领域，复合终点通常被用于估计治疗效果，其包含的组成结局数量和类型已经变得非常复杂。人们假设治疗组之间的组成部分具有相似的严重程度和时间进程，并且治疗效果的幅度也是一致的。然而，这些假设很少得到满足。了解这种异质性对于对治疗效果进行有意义的评估非常重要。
我们开发了加权复合终点（WCE）方法，该方法使用复合终点中每种事件类型的利益相关者价值来计算权重。我们给出了乘积限估计量和估计量方差的推导。然后，我们使用基于大型心血管试验参数模拟的数据来测试该方法。通过增加样本量来比较估计值和传统方法的方差。
WCE 方法使用了随访期间的所有事件，并生成了多次复发性事件生存分析。治疗效果的测量方法是比较两个治疗组之间的平均生存差异及其相应的 95%置信区间，与传统的首次事件分析相比，这种方法提供了生存和方差的更保守估计，生存更高，置信区间更窄。
WCE 方法通过纳入利益相关者的价值以及随访期间的所有事件，接受了事件类型的临床特点。虽然 WCE 分析中的有效事件数量较少，但方差的减少增强了临床试验中检测治疗效果的能力。
