Comparative effectiveness research with randomized trials or observational studies frequently addresses a time-to-event outcome and can require unique considerations in the presence of treatment noncompliance. Motivated by the challenges in addressing noncompliance in the ADAPTABLE pragmatic trial, we develop a multiply robust estimator to estimate the principal survival causal effects under the principal ignorability and monotonicity assumption. The multiply robust estimator involves several working models including that for the treatment assignment, the compliance strata, censoring, and time to event of interest. We demonstrate that the proposed estimator is consistent even if one, and sometimes two, of the working models are incorrectly specified. We further contribute sensitivity analysis strategies for investigating the robustness of the multiply robust estimator under violation of two identification assumptions specific to noncompliance. We implement the multiply robust method in the ADAPTABLE trial to evaluate the effect of low- versus high-dose aspirin assignment on patients' death and hospitalization from cardiovascular diseases, and further obtain the causal effect estimates when the identification assumptions fail to hold. We find that, comparing to low-dose assignment, assignment to the high-dose leads to differential effects among always high-dose takers, compliers, and always low-dose takers. Such treatment effect heterogeneity contributes to the null intention-to-treatment effect, and suggests that policy makers should design personalized strategies based on potential compliance patterns to maximize treatment benefits to the entire study population.

翻译：随机试验或观察性研究的比较效果分析常涉及时间-事件结局，并在存在治疗非依从性时需要特殊考量。受ADAPTABLE实效性试验中非依从性问题的启发，我们提出一种重加权稳健估计量，在主要不可忽略性和单调性假设下估计主要生存因果效应。该重加权稳健估计量包含多个工作模型，包括治疗分配模型、依从分层模型、删失模型以及事件时间模型。我们证明即使其中一个（有时两个）工作模型被错误设定，所提估计量仍具一致性。我们进一步提出敏感性分析策略，用于检验当违背非依从性特定两个识别假设时重加权稳健估计量的稳健性。我们将该重加权稳健方法应用于ADAPTABLE试验，评估低剂量与高剂量阿司匹林分配对患者心血管疾病死亡及住院的影响，并在识别假设不成立时获得因果效应估计值。研究发现，与低剂量分配相比，高剂量分配对持续高剂量服用者、依从者和持续低剂量服用者产生差异化效应。这种治疗效应异质性导致了意向治疗效应的零结果，表明政策制定者应根据潜在依从模式制定个性化策略，以最大化整个研究人群的治疗获益。