Alternatives to Hazard Ratios for Comparing the Efficacy or Safety of Therapies in Noninferiority Studies.
Alternatives to Hazard Ratios for Comparing the Efficacy or Safety of Therapies in Noninferiority Studies.
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DOI：
10.7326/m14-1741
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发表时间：
2015-07-21
影响因子：
39.2
通讯作者：
Wei LJ
中科院分区：
文献类型：
--
作者：
Uno H;Wittes J;Fu H;Solomon SD;Claggett B;Tian L;Cai T;Pfeffer MA;Evans SR;Wei LJ
关于临床事件发生的时间，非劣效性研究经常被用来调查与替代疗法相比，治疗的有效性或安全性是否可接受。此类研究的治疗差异的经验性量化通常基于危险比估计。风险比不是一个相对风险，在临床上可能很难解释，特别是当基本的比例风险假设被违反时。危险比估计的精确度主要取决于观察到的事件的数量，而不是直接取决于暴露时间或研究人群的样本量。如果事故率低，研究可能需要不切实际的大量事件，以确保可以达到预先指定的风险比率的非劣性标准。这篇文章讨论了当前设计和分析非劣势研究方法的不足。然后，我们提供不依赖于任何模型假设的替代程序来比较两种治疗方法。对于一项非劣性安全性研究，患者的暴露时间比观察到的事件数量更具有临床重要性。如果研究患者的暴露时间足够长，可以可靠地评估安全性，这些替代程序可以有效地提供临床上可解释的安全性证据，即使观察到的事件相对较少。我们用两项研究的数据来说明这些步骤。一种是探讨止痛药的心血管安全性；另一种是研究糖尿病新疗法的心血管安全性。这些评估干预安全性或有效性的替代策略导致了比传统的通过危险比估计对分析结果更有意义的解释。
A noninferiority study is often used to investigate whether a treatment’s efficacy or safety profile is acceptable compared to an alternative therapy regarding the time to a clinical event. The empirical quantification of the treatment difference for such a study is routinely based on the hazard ratio estimate. The hazard ratio, which is not a relative risk, may be difficult to interpret clinically, especially when the underlying proportional hazards assumption is violated. The precision of the hazard ratio estimate depends primarily on the number of observed events, but not directly on either exposure times or sample size of the study population. If the event rate is low, the study may require an impractically large number of events to ensure that the prespecified noninferiority criterion for the hazard ratio is attainable. This article discusses deficiencies of the current approach for design and analysis of a noninferiority study. We then provide alternative procedures, which do not depend on any model assumption, to compare two treatments. For a noninferiority safety study, the patients’ exposure times are more clinically important than the observed number of events. If the study patients’ exposure times are long enough to evaluate safety reliably, these alternative procedures can effectively provide clinically interpretable evidence on safety, even with relatively few observed events. We illustrate these procedures with data from two studies. One explores the cardiovascular safety of a pain medicine; the second examines the cardiovascular safety of a new treatment for diabetes. These alternative strategies to evaluate safety or efficacy of an intervention lead to more meaningful interpretations of the analysis results than the conventional one via the hazard ratio estimate.