Published in:
01-05-2018 | Original Paper
Time-to-first-event versus recurrent-event analysis: points to consider for selecting a meaningful analysis strategy in clinical trials with composite endpoints
Published in: Clinical Research in Cardiology | Issue 5/2018
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Background
Composite endpoints combining several event types of clinical interest often define the primary efficacy outcome in cardiologic trials. They are commonly evaluated as time-to-first-event, thereby following the recommendations of regulatory agencies. However, to assess the patient’s full disease burden and to identify preventive factors or interventions, subsequent events following the first one should be considered as well. This is especially important in cohort studies and RCTs with a long follow-up leading to a higher number of observed events per patients. So far, there exist no recommendations which approach should be preferred.
Design
Recently, the Cardiovascular Round Table of the European Society of Cardiology indicated the need to investigate “how to interpret results if recurrent-event analysis results differ […] from time-to-first-event analysis” (Anker et al., Eur J Heart Fail 18:482–489, 2016). This work addresses this topic by means of a systematic simulation study.
Methods
This paper compares two common analysis strategies for composite endpoints differing with respect to the incorporation of recurrent events for typical data scenarios motivated by a clinical trial.
Results
We show that the treatment effects estimated from a time-to-first-event analysis (Cox model) and a recurrent-event analysis (Andersen–Gill model) can systematically differ, particularly in cardiovascular trials. Moreover, we provide guidance on how to interpret these results and recommend points to consider for the choice of a meaningful analysis strategy.
Conclusions
When planning trials with a composite endpoint, researchers, and regulatory agencies should be aware that the model choice affects the estimated treatment effect and its interpretation.