Running title: CA125 in Worsening Heart Failure Funding BIOSTAT-CHF was funded by the European Commission [FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29] and CIBER Cardiovascular (16/11/00420 and 16/11/00403). Address for correspondence Prof. Dr. Adriaan A. Voors

Objectives. This work aims to evaluate the association between antigen carbohydrate 125 (CA125) and the risk of 1-year clinical outcomes in patients with worsening heart failure (HF). Background. CA125 is a widely available biomarker that is up-regulated in patients with acute HF and has been postulated as a useful marker of congestion and risk stratification. Methods. In a large multicenter cohort of patients with worsening HF, either in-hospital or in the outpatient setting, the independent associations between CA125 and 1-year death and the composite of death/HF-readmission (adjusted for BIOSTAT risk score) were determined with the Royston-Parmar method (n=2356). In a sensitivity analysis, the prognostic implications of CA125 were also adjusted for a clinical congestion score (CCS). Data were validated in the BIOSTAT-CHF validation cohort (n=1630). Results. Surrogates of congestion, such as NT-proBNP and a CCS, emerged as independent predictors of CA125. In multivariable survival analyses, higher CA125 was associated with an increased risk of mortality and the composite of death/HF-readmission (p<0.001 for both comparisons), even after adjustment for the CCS (p<0.010 for both comparisons). The addition of CA125 to the BIOSTAT score led to a significant risk reclassification for both outcomes (category-free net reclassification improvement=0.137, p<0.001 and 0.104, p=0.003, respectively). All outcomes were confirmed in an independent validation cohort. Conclusions. In patients with worsening HF, higher levels of CA125 were positively associated with parameters of congestion. Furthermore, CA125 remained independently associated with a higher risk of clinical outcomes, even beyond a predefined risk model and clinical surrogates of congestion.