Event-specific win ratios and testing with terminal and non-terminal events

Abstract

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.

Methods: 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 ${\chi }^2$ test.

Results: 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 ${\chi }^2$ 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 p-values.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00094302.

Keywords: Multiple endpoints; U-statistics; non-parametric; survival data; test of treatment effect; win ratios.