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Introduction: In clinical trials, time-to-event analyses are essential for evaluating treatment efficacy and understanding patient outcomes. Traditional methods such as the Cox proportional hazards model or Kaplan-Meier estimation typically focus on time-to-first events. However, this approach may overlook recurrent and competing events, which are common in chronic disease settings and can provide critical insights into disease progression and treatment impact.

Methods: We present a systematic overview of statistical methods for multiple time-to-event outcomes, including recurrent and terminal events. These methods include the weighted hazard ratio by Rauch, Wei-Lachin approach, Andersen-Gill (AG) model, Wei-Lin-Weissfeld model, Prentice-Williams-Peterson (PWP) models, joint frailty models, Ghosh and Lin’s approach, and prioritized composite outcome analyses (e.g., win ratio, win odds). We applied these methods to data from a randomized, controlled cardiovascular trial.

Results: Each method yielded consistent but nuanced differences in estimating treatment effects. For instance, prioritized outcomes (e.g., win ratio) highlighted early benefits in non-fatal events, while joint models better captured long-term competing risks. The AG and PWP models offered different event-order interpretations. These findings demonstrate that model choice significantly influences interpretation, especially regarding the clinical prioritization of events.

Discussion: Our results underscore that no single model is universally optimal. Instead, each method answers a slightly different clinical question. We discuss practical implementation considerations, the interpretability of effect measures, and model assumptions in the context of RCTs.

Conclusion: Moving beyond the time-to-first-event paradigm allows for richer, more clinically relevant analyses. This work aims to support applied researchers in selecting and interpreting appropriate methods for multiple-event survival data in randomized trials.

The authors declare that they have no competing interests.

The authors declare that a positive ethics committee vote has been obtained.