This paper is motivated by evaluating the benefits of patients receiving mechanical circulatory support (MCS) devices in end-stage heart failure management inference, in which hypothesis testing for a treatment effect on the risk of recurrent events is challenged in the presence of terminal events. Existing methods based on cumulative frequency unreasonably disadvantage longer survivors as they tend to experience more recurrent events. The While-Alive-based (WA) test has provided a solution to address this survival-length-bias problem, and it performs well when the recurrent event rate holds constant over time. However, if such a constant-rate assumption is violated, the WA test can exhibit an inflated type I error and inaccurate estimation of treatment effects. To fill this methodological gap, we propose a Proportional Rate Marginal Structural Model-assisted Test (PR-MSMaT) in the causal inference framework of separable treatment effects for recurrent and terminal events. Using the simulation study, we demonstrate that our PR-MSMaT can properly control type I error while gaining power comparable to the WA test under time-varying recurrent event rates. We employ PR-MSMaT to compare different MCS devices with the postoperative risk of gastrointestinal bleeding among patients enrolled in the Interagency Registry of Mechanically Assisted Circulatory Support program.

翻译：本文的研究动机源于评估终末期心力衰竭管理中患者接受机械循环支持（MCS）装置的获益推断，其中，在存在终末事件的情况下，检验治疗对复发事件风险影响的假设面临挑战。基于累积频率的现有方法不合理地使生存期更长的患者处于劣势，因为他们倾向于经历更多的复发事件。基于存活期的（WA）检验为解决这一生存长度偏倚问题提供了一种方案，并且在复发事件发生率随时间保持恒定的情况下表现良好。然而，如果这种恒定发生率假设被违反，WA检验可能出现I类错误膨胀和治疗效应估计不准确的问题。为填补这一方法学空白，我们在复发事件与终末事件可分离治疗效应的因果推断框架下，提出了一种比例发生率边际结构模型辅助检验（PR-MSMaT）。通过模拟研究，我们证明在复发事件发生率随时间变化的情况下，我们的PR-MSMaT能够适当控制I类错误，同时获得与WA检验相当的检验效能。我们应用PR-MSMaT比较了机构间机械辅助循环支持计划中登记患者术后胃肠道出血风险的不同MCS装置。