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Time-to-first-event versus recurrent-event analysis: points to consider for selecting a meaningful analysis strategy in clinical trials with composite endpoints

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Abstract

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.

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Acknowledgements

This work was supported by the German Research Foundation (Grant Numbers RA 237/1–2 and JA 1821/4-1).

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Authors and Affiliations

  1. Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany

    Geraldine Rauch

  2. Institute of Medical Biometry and Informatics, University of Heidelberg, Berlin, Germany

    Geraldine Rauch & Meinhard Kieser

  3. Institute of Medical Biostatistics, Epidemiology and Informatics, University of Mainz, Mainz, Germany

    Harald Binder & Antje Jahn-Eimermacher

  4. Institute of Medical Biometry and Statistics, University of Freiburg, Freiburg im Breisgau, Germany

    Harald Binder

  5. Heart Failure Clinic, Department of Medicine, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain

    Antoni Bayes-Genis

  6. University of Applied Sciences Darmstadt, Darmstadt, Germany

    Antje Jahn-Eimermacher

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  1. Geraldine Rauch
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  2. Meinhard Kieser
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Corresponding author

Correspondence to Geraldine Rauch.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Rauch, G., Kieser, M., Binder, H. et al. Time-to-first-event versus recurrent-event analysis: points to consider for selecting a meaningful analysis strategy in clinical trials with composite endpoints. Clin Res Cardiol 107, 437–443 (2018). https://doi.org/10.1007/s00392-018-1205-7

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  • DOI: https://doi.org/10.1007/s00392-018-1205-7

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