title: Analysis of recurrent events with an associated informative dropout time: Application of the joint frailty model.
abstract: This paper considers the analysis of a repeat event outcome in clinical trials of chronic diseases in the context of dependent censoring (e.g. mortality). It has particular application in the context of recurrent heart failure hospitalisations in trials of heart failure. Semi-parametric joint frailty models (JFMs) simultaneously analyse recurrent heart failure hospitalisations and time to cardiovascular death, estimating distinct hazard ratios whilst individual-specific latent variables induce associations between the two processes. A simulation study was carried out to assess the suitability of the JFM versus marginal analyses of recurrent events and cardiovascular death using standard methods. Hazard ratios were consistently overestimated when marginal models were used, whilst the JFM produced good, well-estimated results. An application to the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity programme was considered. The JFM gave unbiased estimates of treatment effects in the presence of dependent censoring. We advocate the use of the JFM for future trials that consider recurrent events as the primary outcome. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
authors.affiliation: University of Oxford, Oxford, U.K.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Rogers
authors.affiliation: Vital Systems, Inc, Rolling Meadows, U.S.A.
authors.forename: Alex
authors.initials: A
authors.lastname: Yaroshinsky
authors.affiliation: London School of Hygiene and Tropical Medicine, London, U.K.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Pocock
authors.affiliation: Mesoblast, New York, U.S.A.
authors.forename: David
authors.initials: D
authors.lastname: Stokar
authors.affiliation: Celladon, San Diego, U.S.A.
authors.forename: Janice
authors.initials: J
authors.lastname: Pogoda
mesh_terms: D003627:Data Interpretation, Statistical; D006333:Heart Failure / Q000401:mortality* / Q000628:therapy; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D015233:Models, Statistical; D012008:Recurrence; D016896:Treatment Outcome
keywords: dependent censoring; heart failure; joint frailty models; recurrent events