A DAG-based comparison of interventional effect underestimation between composite endpoint and multi-state analysis in cardiovascular trials
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Le résumé fourni par la source
BACKGROUND: Composite endpoints comprising hospital admissions and death are the primary outcome in many cardiovascular clinical trials. For statistical analysis, a Cox proportional hazards model for the time to first event is commonly applied. There is an ongoing debate on whether multiple episodes per individual should be incorporated into the primary analysis. While the advantages in terms of power are readily apparent, potential biases have been mostly overlooked so far. METHODS: Motivated by a randomized controlled clinical trial in heart failure patients, we use directed acyclic graphs (DAG) to investigate potential sources of bias in treatment effect estimates, depending on whether only the first or multiple episodes are considered. The biases first are explained in simplified examples and then more thoroughly investigated in simulation studies that mimic realistic patterns. RESULTS: Particularly the Cox model is prone to potentially severe selection bias and direct effect bias, resulting in underestimation when restricting the analysis to first events. We find that both kinds of bias can simultaneously be reduced by adequately incorporating recurrent events into the analysis model. Correspondingly, we point out appropriate proportional hazards-based multi-state models for decreasing bias and increasing power when analyzing multiple-episode composite endpoints in randomized clinical trials. CONCLUSIONS: Incorporating multiple episodes per individual into the primary analysis can reduce the bias of a treatment's total effect estimate. Our findings will help to move beyond the paradigm of considering first events only for approaches that use more information from the trial and augment interpretability, as has been called for in cardiovascular research.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- A DAG-based comparison of interventional effect underestimation between composite endpoint and multi-state analysis in cardiovascular trials
- Date Crossref
- 04/07/2017
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Johannes Gutenberg University Mainz Institute of Medical Biostatistics pays non établi dans la noticeUniversité ou école supérieure
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University Medical Center of the Johannes Gutenberg University Mainz pays non établi dans la noticeÉtablissement de santé
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Universitat Autònoma de Barcelona pays non établi dans la noticeUniversité ou école supérieure
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Hospital Universitari Germans Trias i Pujol pays non établi dans la noticeÉtablissement de santé
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University of Freiburg Institute for Medical Biometry and Statistics pays non établi dans la noticeUniversité ou école supérieure
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Heart Failure Clinic pays non établi dans la noticeÉtablissement de santé
Institute of Medical Biostatistics — Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz et Universitat Autònoma de Barcelona, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.