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Authors: Toenges, Gerrit
Mütze, Tobias
Jahn-Eimermacher, Antje
Title: A comparison of semiparametric approaches to evaluate composite endpoints in heart failure trials
Online publication date: 7-Sep-2022
Year of first publication: 2021
Language: english
Abstract: In heart failure (HF) trials efficacy is usually assessed by a composite endpoint including cardiovascular death (CVD) and heart failure hospitalizations (HFHs), which has traditionally been evaluated with a time-to-first-event analysis based on a Cox model. As a considerable fraction of events is ignored that way, methods for recurrent events were suggested, among others the semiparametric proportional rates models by Lin, Wei, Yang, and Ying (LWYY model) and Mao and Lin (Mao-Lin model). In our work we apply least false parameter theory to explain the behavior of the composite treatment effect estimates resulting from the Cox model, the LWYY model, and the Mao-Lin model in clinically relevant scenarios parameterized through joint frailty models. These account for both different treatment effects on the two outcomes (CVD, HFHs) and the positive correlation between their risk rates. For the important setting of beneficial outcome-specific treatment effects we show that the correlation results in composite treatment effect estimates, which are decreasing with trial duration. The estimate from the Cox model is affected more by the attenuation than the estimates from the recurrent event models, which both demonstrate very similar behavior. Since the Mao-Lin model turns out to be less sensitive to harmful effects on mortality, we conclude that, among the three investigated approaches, the LWYY model is the most appropriate one for the composite endpoint in HF trials. Our investigations are motivated and compared with empirical results from the PARADIGM-HF trial ( identifier: NCT01035255), a large multicenter trial including 8399 chronic HF patients.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Statistics in medicine
Pages or article number: 5702
Publisher: Wiley
Publisher place: Chichester u.a.
Issue date: 2021
ISSN: 1097-0258
Publisher DOI: 10.1002/sim.9149
Appears in collections:JGU-Publikationen

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