Acute heart failure (AHF) is a condition associated with high morbidity and mortality and represents one of the leading causes of hospital admission in cardiology departments [1]. Systemic congestion, particularly hepatic congestion, plays a key role not only in the clinical presentation but also in preventing hospitalizations and disease progression [2]. Proper assessment of the congestion status is essential for therapeutic management and risk stratification in these patients [3].

The FIB-4 index, originally developed to estimate the degree of liver fibrosis in patients with viral hepatitis, has emerged as a prognostic tool in heart failure (HF) [4, 5]. This index, calculated from age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count, may reflect the impact of hepatic congestion in both chronic and acute HF scenarios. Recent studies have shown that elevated FIB-4 values are associated with higher mortality and rehospitalization in AHF patients, suggesting that congestion-induced liver dysfunction is an indirect marker of the severity of the congestive syndrome [6, 7].

On the other hand, carbohydrate antigen 125 (CA125), widely used in oncology as a marker for ovarian neoplasms, has shown utility as a biomarker of systemic volume overload in HF [8]. CA125 levels are known to rise in response to systemic inflammation and endothelial activation under hypervolemic conditions. Several studies have documented that elevated CA125 concentrations in HF patients correlate with greater clinical severity, poorer response to diuretic therapy, and increased risk of adverse events, including hospitalization and death [8, 9, 10, 11].

These distinct biological pathways suggest that each biomarker could provide complementary information and might enhance risk stratification in AHF. The primary objective of the study was to analyze the clinical characteristics associated with the combined blood levels of these biomarkers, compare short- and mid-term survival, determine their relationship with morbidity and mortality, and assess the correlation between both serum markers.

This was a retrospective study based on a database of patients consecutively admitted for AHF at the Department of Cardiology of a tertiary care hospital. Data collection was performed during hospitalization and was extracted and stored by a team of clinical cardiologists specialized in HF. Recruitment was conducted consecutively over 2 years (January 2023–December 2024), and 1088 patients were initially considered. Exclusion criteria included elective admissions (n = 403), inter-hospital transfers (n = 232), and low-output clinical syndromes (n = 51). The final sample comprised 402 patients.

FIB-4 was calculated using the formula: FIB-4 Index = [Age (years) $\times$ AST (U/L)] / [Platelet count (10⁹/L) $\times$ $\surd$ALT (U/L)] [4]. Four groups were formed based on biomarker combination, with low FIB-4 defined as 1.3 and normal CA125 as $\le$50 U/mL. The resulting groups were: Group 1: Low FIB-4 + Low CA125 (n = 43); Group 2: Low FIB-4 + High CA125 (n = 57); Group 3: High FIB-4 + Low CA125 (n = 117); Group 4: High FIB-4 + High CA125 (n = 185) (Fig. 1). Variables of interest included: Clinical: baseline characteristics, comorbidities and clinical profile; Echocardiographic: functional evaluation of both ventricles and inferior vena cava (IVC); Therapeutic: medications at the time of admission; Laboratory: standard parameters assessed with a specific panel for decompensated HF [12, 13].

Groups were compared, and follow-up analysis was performed for overall survival (all-cause mortality), morbidity (worsening—HF-related emergency visits and/or HF rehospitalizations), and correlation between both biomarkers. The study was conducted in accordance with the Declaration of Helsinki. The research protocol was approved by the Biomedical Research Ethics Committee of Hospital Universitari i Politècnic La Fe (reference code COMBICAR).

HF is a highly prevalent condition that shortens life expectancy and significantly impairs quality of life [1]. Throughout its natural course, patients frequently experience clinical worsening, including hospital emergency visits due to congestion and readmissions for decompensation [14]. Some biomarkers, such as CA125 and FIB-4, have been associated with worse clinical trajectories, although their role in the context of HF is still being clarified [9].

The combined use of FIB-4 and CA125 may provide complementary prognostic information in AHF. CA125 is a recognized marker of congestion in AHF; however, in some cases, it may remain at low levels even during decompensation [15]. FIB-4, serves as an indirect marker of hepatic congestion, chronic liver fibrosis, and systemic inflammation [4]. Even mild FIB-4 elevations ($\ge$1.3) have been associated with worse outcomes in HF, potentially identifying patients at risk before marked CA125 elevation occurs [16]. Although both markers are linked to systemic congestion, CA125 predominantly reflects interstitial and serosal fluid accumulation, whereas FIB-4 captures different pathophysiological domains [10, 17, 18, 19]. Their combination could therefore enhance risk stratification and help define distinct clinical phenotypes.

This shared pathophysiological link to congestion forms the basis for interpreting our findings. Prior studies have individually associated elevated CA125 or FIB-4 with adverse outcomes in HF, yet no previous work has explored their combined prognostic value in AHF. We recognize that these interpretations remain mechanistic hypotheses, as direct measurements of congestion were not performed, and further research is warranted to confirm these associations.

In this study, we observed that patients with both elevated FIB-4 and CA125 had poorer short- to medium-term outcomes, particularly in terms of clinical worsening (both HF readmissions and emergency visits for decompensation). However, no significant differences were found in survival within the two-year follow-up period.

The optimal thresholds for CA125 and FIB-4 in AHF are not well established. Most studies have adopted values from other clinical settings, such as CA125 $>$35 U/mL in oncology and FIB-4 thresholds of 1.3, 1.3–2.67, and $>$2.67 in hepatology [4, 20]. In AHF, only one study proposed a CA125 cut-off of 23 U/mL, but it was based on a retrospective cohort with heterogeneous measurement times [21]. We selected 50 U/mL to minimize variability and exclude minor, clinically irrelevant elevations, supported by our previous work linking CA125 $>$50 U/mL to worse outcomes [22]. For FIB-4, although various prognostic thresholds exist, Mohamed et al. [16] found that intermediate values (1.3–2.67) already predict higher mortality in reduced LVEF; thus, we adopted $\ge$1.3 to capture early signs of hepatic congestion.

In our cohort, patients with both biomarkers elevated more frequently presented systemic or mixed congestion. Prior studies report that CA125 has high sensitivity for systemic venous congestion, sometimes superior to NT-proBNP, whereas evidence for FIB-4 is more limited [23]. Our findings suggest an additive effect: in patients with CA125 $>$50 U/mL, a FIB-4 $\ge$1.3 nearly doubled the likelihood of systemic/mixed congestion (38.6% vs 59.5%; OR 2.33, 95% CI 1.27–4.29).

Consistent with prior AHF studies, our cohort had a high mean age ($>$70 years). Older patients often present with comorbidities, polypharmacy, and frailty, which can complicate management [24]. In this setting, combining FIB-4 and CA125 may add value for geriatric risk stratification, as congestion markers could be particularly informative for prognosis and treatment decisions.

Admission NT-proBNP levels, although less specific for systemic congestion than CA125, are well established as prognostic markers [25]. In our study, NT-proBNP was highest in the high FIB-4 + high CA125 group, supporting the hypothesis that these patients had greater congestion and worse outcomes. Conversely, those with both indices normal had the lowest NT-proBNP levels, consistent with a lower-risk profile.

Among echocardiographic findings, 28% of patients had preserved LVEF ($\ge$50%), with no significant differences across groups. Literature shows CA125’s prognostic value is independent of LVEF phenotype, whereas evidence on FIB-4 is more heterogeneous [16, 26]. Tseng et al. [27] found that FIB-4 was only associated with adverse outcomes in patients with preserved or mildly reduced LVEF. This has been attributed to the higher prevalence of hepatic steatosis and a pro-inflammatory state in these phenotypes, which may enhance the impact of hepatic congestion [28].

Regarding the right ventricle (RV), both CA125 and FIB-4 have been associated with RV dysfunction and systemic congestion [29]. In our cohort, severe RV dysfunction was more frequent in the high-risk group (11.8% vs 4.7%) but not statistically significant. However, other indirect indicators of central venous hypertension, such as reduced IVC collapsibility and higher prevalence of significant tricuspid regurgitation (TR), were significantly more common in this group. Some authors suggest that TR and reduced IVC collapsibility may be more sensitive indicators of central venous hypertension than RV dysfunction as estimated by tricuspid annular plane systolic excursion (TAPSE) [23, 30, 31]. Thus, the selected FIB-4 cutoff ($\ge$1.3) may have favored detection of subtle degrees of congestion, manifested earlier through signs like IVC dilation and TR rather than overt RV dysfunction. Overall, our findings reinforce the predictive value of the clinical-echocardiographic pattern of systemic congestion captured by CA125 and FIB-4, which appear to offer complementary information.

One-year survival was 77%, with no significant differences at two years. However, curves began diverging at around six months, and there was a trend toward a positive correlation between CA125 and mortality (p 0.1). In literature, higher values of both markers have been associated with worse prognosis. FIB-4, for instance, was evaluated in a registry of 1854 AHF patients and higher values were associated with increased 5-year all-cause mortality (HR: 1.009, 95% CI: 1.010–1.015) [27]. Thresholds similar to ours showed that FIB-4 $>$1.3 correlates with a 5-year mortality of 36%, compared to 23% for values 1.3 (HR: 1.33, 95% CI: 1.16–1.52). This risk rises further with FIB-4 $>$2.67 (mortality: 46%, HR: 2.14, 95% CI: 1.67–2.74) [16]. A multivariate analysis indicated that the prognostic value lies in the FIB-4 score itself, rather than in the individual components [32]. Furthermore, a meta-analysis of 16 studies involving 8401 AHF patients found that elevated CA125 was associated with increased risk of all-cause mortality (HR: 1.44, 95% CI: 1.21–1.72; p 0.001) [33]. Interestingly, the association between CA125 $>$50 U/mL and mortality only becomes statistically significant beyond two years of follow-up [22]. One advantage of FIB-4 compared to CA125 is its ability to be reassessed over short intervals, as CA125 may require up to 10 days to reflect changes after an intervention [34]. Maeda et al. [35] studied 877 hospitalized AHF patients and showed that a reduction in FIB-4 of less than 1% during admission doubled the risk of mortality or rehospitalization, compared to reductions greater than 27% (HR: 2.16, 95% CI: 1.41–3.32; p 0.001), regardless of baseline values.

Therefore, the absence of survival differences in our cohort may be influenced by the relatively short follow-up period, lack of post-discharge FIB-4 reassessment, and the low cutoff point (1.3 instead of 2.67).

In this study, the combination of CA125 and FIB-4 showed statistically significant differences regarding worsening events, identifying a very high-risk subgroup and a low-risk subgroup (51% vs 33% at two years; p 0.001). For example, extrapolating results from the STRONG-HF trial to a two-year horizon assuming a linear progression, the rehospitalization rate in the best-prognosis arm (intensified therapy) would be comparable to that of our low-risk group (38% vs 33%) [36]. These findings suggest that identifying patients with low CA125 and FIB-4 could enable more accurate risk stratification, and, in resource-limited settings, help prioritize interventions for those at greatest risk.

From our perspective, both CA125, and especially FIB-4, are still under investigation, and further research is needed to define their real clinical utility, both individually and in combination.

This study has several limitations, mainly related to its retrospective design. Selection bias was minimized by the small baseline differences between groups, recall bias by prospective data entry at discharge by experienced cardiologists, and missing data bias by consecutive patient inclusion with predefined exclusion criteria. All relevant variables were included to reduce confounding. Another limitation is the imbalance in subgroup sizes, which may have reduced statistical power, particularly in survival analyses; however, this reflects the real-world distribution of biomarker profiles in AHF, and non-significant results in small subgroups were interpreted with caution. In addition, recurrent-event models were not applied; survival was analyzed as time to first event and other outcomes were reported descriptively, which may not fully address intra-patient clustering but was considered appropriate for this exploratory design. Furthermore, we did not perform multivariable Cox regression as neither FIB-4 nor CA-125 showed a significant association with the primary endpoint in univariate analysis. Including non-significant variables could lead to an overfitted and non-informative model. Finally, although few studies have evaluated the prognostic role of FIB-4 and none its relationship with CA125, we believe our findings are of scientific interest and provide a basis for future prospective research in larger cohorts with longer follow-up.

FIB-4 is a simple and useful indicator that may have prognostic implications in patients with decompensated AHF, helping to predict post-discharge outcomes. Values above 1.3, when combined with serum CA125 levels greater than 50 U/mL, identify a subgroup of patients who, although they do not show increased short- to mid-term (2-year) mortality, do present a significantly higher probability of clinical worsening, including HF readmissions and emergency department visits due to decompensation. Longer prospective studies with larger patient cohorts are needed to confirm the results of this analysis.

The datasets generated for this study contain sensitive clinical information and cannot be made publicly available due to patient confidentiality and institutional restrictions. Data may be made available from the corresponding author upon reasonable request, subject to ethics committee approval.

Conceptualization: FA, RLV, LAB, LM; Methodology: FA, RLV, LAB; Data curation: VD, JMS, VS, SH, SB, AEA, MC, BG; Formal analysis & statistics: FA, LAB, VS; Investigation: All authors; Visualization: FA, LAB, VD; Writing – original draft: FA; Writing – review & editing: All authors, with lead contributions from RLV and LAB; Supervision: RLV, LM, LAB; Project administration: RLV; Guarantor of the work: RLV. All authors have read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted in accordance with the Declaration of Helsinki. The research protocol was approved by the Biomedical Research Ethics Committee of Hospital Universitari i Politècnic La Fe (reference code COMBICAR). Because the study is retrospective, the committee did not require informed-consent signatures.

We thank the clinical and administrative teams who assisted with data retrieval and patient follow-up, and we are grateful to the patients whose participation made this study possible.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM42797.