S2 Appendix -

<div> Introduction High-Flow Nasal Therapy (HFNT) is an innovative non-invasive form of respiratory support. Compared to standard oxygen therapy (SOT), there is an equipoise regarding the effect of HFNT on patient-centred outcomes among those at high risk of developing postoperative pulmonary complications after undergoing cardiac surgery. The NOTACS trial aims to determine the clinical and cost-effectiveness of HFNT compared to SOT within 90 days of surgery in the United Kingdom, Australia, and New Zealand. This protocol describes the methods and analyses planned for economic evaluation embedded within the ongoing NOTACS trial. Methods and analysis The economic evaluation will identify, measure and value resources and health outcomes in both trial arms and compare changes in costs with ‘days alive and at home’ and EQ-5D-5L quality adjusted life years (QALYs) from the perspective most relevant to the decision-making country. Results from pooling data across the trial will use health and social care sector perspective. All patient-specific data including hospital/community care and health outcomes will be collected prospectively. Unit costs will be sourced from national, published or local data. Missing data will be assessed, with values replaced depending on assumed mechanism of missingness, and impact of replacement on cost-effectiveness assessed. Costs and outcomes by trial arm will be presented as components and totals per patient using a range of descriptive statistics. Regression models for costs and effects will account for patient characteristics, quality of life and health service utilization at baseline. Uncertainty in parameters, sampling and heterogeneity will be addressed through deterministic, probabilistic and subgroup analyses to assess the impact of varying methods and assumptions for costs, outcomes and approaches used in base-case analysis. Results will be interpreted using recommended national cost-effectiveness thresholds. Registration details The study is registered with ISRCTN (ISRCTN14092678) on 13/05/2020. ISRCTN is a primary registry of the WHO ICTRP network and includes all items from the WHO Trial Registration data set. </div>