Introduction and objectives: The early postdischarge period after acute heart failure (AHF) hospitalization is marked by high rates of rehospitalization and death, largely driven by residual congestion. Carbohydrate antigen 125 (CA125) is a congestion-sensitive biomarker, yet the prognostic value of its longitudinal trajectory after AHF remains poorly characterized. We aimed to determine whether serial CA125 measurements during the first 6 months postdischarge predict heart failure (HF) rehospitalization and all-cause mortality.

Methods: This single-center cohort study included 3980 consecutive AHF patients (October 2008-February 2023) with 6975 serial CA125 measurements (median follow-up, 161.5 days). Log-transformed CA125 trajectories were modeled using spline-fitted joint models linking longitudinal biomarker evolution with recurrent HF rehospitalizations (joint frailty model) and all-cause mortality (Weibull hazard), with adjustment for established clinical covariates.

Results: During follow-up, 814 rehospitalizations occurred in 549 patients (20.5%) and there were 604 deaths (15.2%). CA125 displayed a biphasic trajectory: an early postdischarge peak around day 10, a steep decline within the first month, and a gradual reduction thereafter (P < .001). In joint modeling, each log-unit increase in CA125 was associated with a 27% higher risk of recurrent HF rehospitalization (HR, 1.27; 95%CI, 1.17-1.37; P < .001), an association that remained constant over time. The association with mortality was time-dependent (P for interaction < .001), strongest within the first 60 days (HR, ∼1.70), and nonsignificant thereafter.

Conclusions: In patients with AHF, serial CA125 measurements display a distinct postdischarge trajectory and independently predict recurrent HF rehospitalizations and early mortality. These findings support the integration of CA125 monitoring into postdischarge management to guide risk stratification and decongestive therapy.