CA-125 concentrations are associated with renal function decline but not congestion or prognosis in patients with chronic heart failure: results from EMPEROR-POOLED
Authors: Januzzi J , Mohebi R , On Behalf Of Emperor Committees And Investigators  
Published: November 2023

Abstract

Background
Carbohydrate antigen 125 (CA-125, also described as cancer antigen 125), has emerged as a candidate biomarker of congestion in heart failure (HF). Effects of sodium/glucose cotransporter-2 inhibitor therapy on CA-125 and its role as a prognostic measure in HF remains uncertain.

Purpose
In study participants from the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction (EF) and renal function, we sought to investigate associations between CA-125 and congestion, the effect of empagliflozin on CA-125 concentrations, and the ability of the biomarker to predict cardio-renal outcomes.

Methods
1111 patients with HF and available biomarker data were included into this analysis. Serum CA-125 was measured at baseline, 12 and 52 weeks using an Electroluminescence assay. The measurements were performed within a biomarker research agreement of Boehringer Ingelheim, the sponsor of these trials and Roche Diagnostics International Ltd. Congestion signs or symptoms were evaluated across CA-125 tertiles. A mixed model for repeated measurements was used to compare the treatment effects on CA-125. Multivariable analyses adjusted for the prespecified EMPEROR baseline variables plus N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were used to examine the association of CA-125 with HF hospitalization or cardiovascular (CV) death and estimated glomerular filtration rate (eGFR) slope.

Results
Across CA-125 tertiles at baseline, no significant association was present with HF symptom severity, jugular vein distention, pulmonary rales, S3 gallop or peripheral oedema (all p-values &gt;0.10). Treatment with empagliflozin was associated with 7% greater reduction of CA-125 level versus placebo to week 12 (adjusted geometric mean ratio: 0.93; 95% confidence interval [CI], 0.87-0.99, p = 0.03) but not to week 52 (adjusted geometric mean ratio: 0.97, 95% CI 0.90-1.06; p = 0.50). No significant association was found for tertiles of CA-125 at baseline with the risk of CV death/HF hospitalization; with a hazard ratio (HR) for higher vs lower CA-125 tertiles of 1.34 (95% CI 0.91–1.96). In the same model NT-proBNP and hs-cTnT were strongly prognostic (both p-values &lt;0.0001). Compared to lower tertiles, study participants in the third CA-125 tertile had higher rate of kidney function decline with a more negative eGFR slope (p for trend = 0.03).

Conclusion
In chronic HF, across a wide range of EF and of renal function, CA-125 levels were not strongly associated with clinical signs or symptoms of congestion. Empagliflozin lowered CA-125 levels more than placebo at week 12 but not at week 52. Among individuals with HF, CA-125 concentrations did not provide additional prognostic information for CV death/HF hospitalization beyond conventional cardiac biomarkers but may predict subsequent kidney function decline.