Tissue-predominant congestion in acute heart failure: prognostic value of CA125 and modifying effect of SGLT2 inhibitors

Background

Carbohydrate antigen 125 (CA125) is a validated biomarker of tissue-predominant congestion in acute heart failure (AHF) and is strongly linked to early adverse outcomes. Sodium glucose cotransporter-2 (SGLT2) inhibitors preferentially mobilize interstitial fluid and may therefore be particularly effective in patients with tissue congestion. The aim of this study was to evaluate the prognostic impact of CA125 and determine whether SGLT2 inhibitor therapy modifies this risk in patients hospitalized for AHF.

Methods

We analyzed 1.403 consecutive patients admitted for AHF. CA125 was measured on admission, and patients were categorized according to the established 35 U/mL cutoff and SGLT2 inhibitor prescription at discharge: C1 (CA125 <35 without SGLT2i), C2 (CA125 ≥35 without SGLT2i), C3 (CA125 <35 with SGLT2i), and C4 (CA125 ≥35 with SGLT2i). The primary outcome was a 1-year all-cause mortality. Survival was assessed using Kaplan–Meier curves and log-rank tests. The differential prognostic effect of CA125 according to SGLT2i use was evaluated with Cox proportional hazards models including an interaction term, and results were expressed as hazard ratios (HRs) with 95% confidence intervals (CI).

Results

Mean age was 87±7 years, and 298 (65.7%) were women. Median (IQR) CA125 and BNP levels were 55.6 (26.3–119.8) U/mL and 568.7 (315–1,036.9) pg/mL, respectively. The proportions of patients treated with SGLT2i and with CA125 ≥35 U/mL were 51% and 72%, respectively. Patients with CA125 ≥35 U/mL without SGLT2i exhibited a more severe baseline risk profile.

During a median follow-up of 356 (120–601) days, 633 patients (45.4%) died. Event rates differed significantly across categories (C1: 44.8%, C2: 59.8%, C3: 27.2%, C4: 38.7%; p<0.001). Kaplan–Meier curves demonstrated clearly divergent trajectories, with the highest risk observed in patients with elevated CA125 not treated with SGLT2i. (Figure 1)

The interaction between CA125 and SGLT2i remained significant after multivariable adjustment (p-value for interaction = 0.048). Compared with the lower-risk reference group (CA125 <35 U/mL with SGLT2i), patients with CA125 ≥35 U/mL without SGLT2i showed the highest risk of adverse events (HR 1.71, 95% CI 1.25–2.35; p<0.001). Conversely, patients with CA125 ≥35 U/mL who received SGLT2i did not show increased risk. When CA125 was analyzed as a continuous variable, its association with adverse outcomes differed according to SGLT2i use, with a trend toward increasing risk among patients not treated with SGLT2i (p for interaction = 0.090). (Figure 2).

Conclusion

In patients with acute heart failure, the prognostic impact of CA125 is influenced by SGLT2. High CA125 levels was associated with higher risk of death only when coexisted without SGLT2. On the contrary, when patients received SGLT2 at discharge, high CA125 lacked prognostic effect. Further studies are needed to confirm these findings and to understand their pathophysiological significance.Kaplan Meier curvesFor image description, please refer to the figure legend and surrounding text.Interaction Between CA125 and SGLT2iFor image description, please refer to the figure legend and surrounding text.