95 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RATIONALE AND DESIGN to the definition of the ISTH), 4) composite of major or CRNM bleeding complications and thromboembolic events (where thromboembolic events are defined as ischaemic stroke, TIA and peripheral arterial thromboembolism), 5) thromboembolic events, 6) composite of ischaemic and haemorrhagic stroke, 7) health-related quality of life (measured after six and twelve months from baseline), 8) cost-effectiveness, and 9) identification of risk factors for bleeding. Cost-effectiveness will be calculated on the basis of the EQ-5D-5L questionnaire (to calculate quality-adjusted life years (QALYs)), and on details of healthcare utilisation (hospitalisation (e.g. duration and intensive care admission), doctor visits and other additional care). An independent committee, consisting of several different physicians and blinded for the randomisation allocation, will first adjudicate all fatal outcomes, both in the intervention and in the control (and observational) arm, using all available patient data. Further adjudication of other outcomes may be warranted following observations made in the trial. Data analysis The primary analysis of this randomised controlled trial will be based on the intentionto-treat principle in a Cox proportional hazards model, after checking for the proportional hazards assumption. Model estimates are used to calculate the hazard of the occurrence of a major or CRNM bleeding complication, whichever comes first. Treatment-specific Kaplan-Meier survival curves will be plotted to graphically illustrate the results. For total incidence of events, where recurrent events within the same patient are accounted for, Poisson regression and/or negative binomial regression will be applied, accounting for overdispersion as appropriate. For some bleeding complications, it may not be possible to obtain the exact occurrence dates, resulting in interval censoring. We expect that ignoring interval censoring, and using midpoint imputation, will not have a substantial impact on the results as telephone assessors are instructed to reduce the length of the time interval as much as possible. However, to assess the robustness of the results, we will perform additional sensitivity analyses that formally address the issue of interval censoring. Analyses of the secondary outcomes will follow the primary analysis, where appropriate. Cost-effectiveness will be assessed by means of the incremental costeffectiveness ratio, that is, the difference in average costs between the intervention and the control arm, divided by the difference in QALYs between both arms. Unit prices will be based on Dutch standard prices for economic evaluations in healthcare in order to facilitate comparisons with other economic evaluations.28 A Cox regression model will be used for the identification of risk factors for bleeding in frail elderly patients with AF treated with either a VKA or a NOAC. For this, also data in the observational arm (i.e. subjects with an eGFR <30 mL/min/1.73 m2) will be used. 6
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