Nonproportional Hazards for Time-to-Event Outcomes in Clinical Trials: JACC Review Topic of the Week.

Most major clinical trials in cardiology report time-to-event outcomes using the Cox proportional hazards model so that a treatment effect is estimated as the hazard ratio between groups, accompanied by its 95% confidence interval and a log-rank p value. But nonproportionality of hazards (non-PH) over time occurs quite often, making alternative analysis strategies appropriate. This review presents real examples of cardiology trials with different types of non-PH: an early treatment effect, a late treatment effect, and a diminishing treatment effect. In such scenarios, the relative merits of a Cox model, an accelerated failure time model, a milestone analysis, and restricted mean survival time are examined. Some post hoc analyses for exploring any specific pattern of non-PH are also presented. Recommendations are made, particularly regarding how to handle non-PH in pre-defined Statistical Analysis Plans, trial publications, and regulatory submissions.