OBJECTIVES This study sought to evaluate the prognostic effect of carbohydrate antigen-125 (CA125)–guided therapy(CA125 strategy) versus standard of care (SOC) after a hospitalization for acute heart failure (AHF).BACKGROUND CA125 has emerged as a surrogate of fluid overload and inflammatory status in AHF. After an episode ofAHF admission, elevated values of this marker at baseline as well as its longitudinal profile relate to adverse outcomes,making it a potential tool for treatment guiding.METHODS In a prospective multicenter randomized trial, 380 patients discharged for AHF and high CA125 wererandomly assigned to the CA125 strategy (n ¼ 187) or SOC (n ¼ 193). The aim in the CA125 strategy was to reduce CA125to #35 U/ml by up or down diuretic dose, enforcing the use of statins, and tightening patient monitoring. The primaryendpoint was 1-year composite of death or AHF readmission. Treatment strategies were compared as a time to first eventand longitudinally.RESULTS Patients allocated to the CA125 strategy were more frequently visited, and treated with ambulatory intra-venous loop diuretics and statins. Likewise, doses of oral loop diuretics and aldosterone receptor blockers were morefrequently modified. The CA125 strategy resulted in a significant reduction of the primary endpoint, whether evaluated astime to first event (66 events vs. 84 events; p ¼ 0.017) or as recurrent events (85 events vs. 165 events; incidence rateratio: 0.49; 95% confidence interval: 0.28 to 0.82; p ¼ 0.008). The effect was driven by significantly reducing reho-spitalizations but not mortality.CONCLUSIONS The CA125 strategy was superior to the SOC in terms of reducing the risk of the composite of1-year death or AHF readmission. This effect was mainly driven by significantly reducing the rate of rehospitalizations.(Carbohydrate Antigen-125-guided Therapy in Heart Failure [CHANCE-HF)