Abstract

Objective

Hematologic and nutritional abnormalities are common in patients hospitalized with acute heart failure and may be associated with adverse outcomes. This study aimed to evaluate the clinical characteristics and in-hospital mortality of patients classified according to combined anemia and hypoalbuminemia phenotypes.

Method

This retrospective study included 220 consecutive patients hospitalized with acute heart failure. Anemia was defined according to World Health Organization sex-specific hemoglobin thresholds, and hypoalbuminemia was defined as a serum albumin level <3.5 g/dL. Patients were classified into four phenotypes: Neither anemia nor hypoalbuminemia, anemia alone, hypoalbuminemia alone, and both anemia and hypoalbuminemia. Associations between phenotype groups and all-cause in-hospital mortality were evaluated using categorical comparisons and logistic regression. Given the limited number of mortality events, a parsimonious age-adjusted model and bootstrap sensitivity analysis were performed.

Results

Among 220 patients, 21 (9.5%) died during hospitalization. The four phenotype groups comprised 39 patients with neither abnormality, 34 with anemia alone, 45 with hypoalbuminemia alone, and 102 with both abnormalities. In-hospital mortality rates were 7.7%, 17.6%, 8.9%, and 7.8%, respectively, with no significant overall difference among groups (Fisher’s exact p=0.402). In the age-adjusted logistic regression model, phenotype group was not significantly associated with in-hospital mortality (overall p=0.391), and none of the individual phenotype comparisons reached statistical significance. Bootstrap sensitivity analysis yielded consistent findings. Receiver operating characteristic analysis showed limited discrimination for mortality for both albumin [area under the curve (AUC) 0.594, 95% confidence interval (CI) 0.477-0.711; p=0.157] and hemoglobin (AUC 0.474, 95% CI 0.344-0.603; p=0.694).

Conclusion

Combined anemia-hypoalbuminemia phenotypes were associated with distinct clinical and laboratory profiles but were not significantly associated with in-hospital mortality in this cohort. Neither admission albumin nor hemoglobin alone demonstrated significant discrimination for in-hospital mortality. These findings should be interpreted cautiously given the limited number of mortality events.

Introduction

Acute heart failure (AHF) is among the foremost precipitants of urgent hospital admission and is burdened by substantial early mortality and high rates of return hospitalization, even in the context of evolving treatment paradigms (1). The trajectory of illness among affected individuals is highly heterogeneous, mirroring the diverse pathophysiological substrates and varying degrees of cardiac decompensation that underlie this syndrome (2). As a result, the availability of practical and dependable markers for prognostic stratification is critical to enable individualized patient management and support timely therapeutic decision-making (3).

Anemia is a prevalent comorbid condition in the heart failure population, consistently linked to impaired exercise tolerance, increased readmission frequency, and worse long-term survival (4, 5). The mechanisms underlying anemia in this context are heterogeneous, encompassing contributions from renal dysfunction, iron deficiency states, chronic low-level systemic inflammation, hemodynamic fluid redistribution, and disruption of neurohumoral regulatory systems (6). In parallel, a decline in serum albumin concentration is a common biochemical accompaniment of acute cardiac decompensation, potentially reflecting malnutrition, hepatic congestion from venous hypertension, systemic inflammatory burden, and the cumulative severity of the patient’s condition (7, 8). A body of prior evidence has demonstrated that hypoalbuminemia confers elevated risk for adverse cardiovascular outcomes and mortality in populations with heart failure (9).

Although both abnormalities have individually demonstrated prognostic relevance, relatively little attention has been directed toward their simultaneous occurrence as an integrated clinical phenotype. Considering that anemia and hypoalbuminemia may reflect partially overlapping yet distinct aspects of systemic disease burden, evaluating their combined phenotypic patterns may provide additional insight into clinical heterogeneity and their potential relationship with short-term outcomes (10).

With this rationale, the present investigation was undertaken to evaluate the association between phenotypic combinations of anemia and hypoalbuminemia and all-cause in-hospital mortality in a cohort of patients hospitalized with AHF.

Materials and Methods

Study Design and Population

This was a single-center retrospective observational study carried out at at Mogadishu Somalia-Turkey Recep Tayyip Erdoğan Training and Research Hospital. Consecutive adult patients admitted with a confirmed diagnosis of AHF were screened for eligibility. A total of 220 patients with available clinical and laboratory data at admission formed the final study cohort.

AHF was diagnosed in accordance with established international guideline criteria, incorporating clinical features, relevant laboratory results, and echocardiographic findings consistent with acute decompensated heart failure (1). Demographic characteristics, comorbidities, laboratory parameters, and echocardiographic data were obtained from the institutional electronic medical records.

Definitions and Study Groups

Based on anemia and hypoalbuminemia status, patients were assigned to one of four phenotypic subgroups:

1. No anemia/no hypoalbuminemia

2. Anemia only

3. Hypoalbuminemia only

4. Combined anemia and hypoalbuminemia.

Classification was based on hemoglobin and serum albumin values obtained at hospital admission. Anemia was defined according to World Health Organization thresholds as a hemoglobin level below 13 g/dL in men and below 12 g/dL in women. Hypoalbuminemia was defined as a serum albumin concentration below 3.5 g/dL.

Data Collection

The following baseline variables were systematically recorded: Age, sex, diabetes mellitus, hypertension, chronic kidney disease, left ventricular ejection fraction, hemoglobin, serum albumin, C-reactive protein (CRP), pro-B-type natriuretic peptide, and neutrophil-to-lymphocyte ratio (NLR).

Study Outcome

The primary study endpoint was all-cause mortality occurring during the index hospitalization.

Statistical Analysis

All statistical analyses were performed using IBM SPSS Statistics (IBM Corp., Armonk, NY, USA). Continuous variables are presented as mean ± standard deviation, and categorical variables as numbers and percentages. Between-group comparisons of continuous variables were performed using one-way analysis of variance. Categorical variables were compared using the Pearson chi-square test or Fisher’s exact test, as appropriate according to expected cell counts.

Associations with in-hospital mortality were evaluated using binary logistic regression analysis. Univariable analyses were first performed for the anemia-hypoalbuminemia phenotype categories and selected clinically relevant variables. Because only 21 in-hospital deaths occurred, the multivariable analysis was intentionally restricted to a parsimonious model including age and the four-category anemia-hypoalbuminemia phenotype variable to reduce the risk of model overfitting. The group with neither anemia nor hypoalbuminemia served as the reference category. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). To assess the robustness of the regression findings in the setting of the limited number of events, a sensitivity analysis using 1,000 bootstrap samples with bias-corrected and accelerated 95% CIs was also performed.

Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of admission serum albumin and hemoglobin levels for in-hospital mortality. Death was defined as the positive outcome. Areas under the curve (AUCs) with 95% CIs were calculated. All tests were two-sided, and a p-value <0.05 was considered statistically significant.

Ethical Approval

Ethical approval was obtained from the Institutional Ethics Committee of Mogadishu Somalia-Turkey Recep Tayyip Erdoğan Training and Research Hospital (approval no: 1206, date: 02.05.2025). All procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki.

Results

A total of 220 patients were included in the analysis. Based on admission hemoglobin and serum albumin levels, 39 patients (17.7%) had neither anemia nor hypoalbuminemia, 34 (15.5%) had anemia alone, 45 (20.5%) had hypoalbuminemia alone, and 102 (46.4%) had both anemia and hypoalbuminemia. Significant between-group differences were observed for hemoglobin and serum albumin levels (p<0.001 for both), as expected from the phenotype definitions. Baseline demographic, clinical, and laboratory characteristics according to phenotype group are presented in Table 1. Overall, 21 of 220 patients (9.5%) died during the index hospitalization. In-hospital mortality occurred in 3 of 39 patients (7.7%) with neither anemia nor hypoalbuminemia, 6 of 34 (17.6%) with anemia alone, 4 of 45 (8.9%) with hypoalbuminemia alone, and 8 of 102 (7.8%) with both abnormalities. Although mortality was numerically highest in the anemia-only group, the overall difference among phenotype groups was not statistically significant (Fisher’s exact p=0.402). Therefore, no stepwise pattern of increasing mortality across the phenotype categories was observed.

Results of the logistic regression analyses for in-hospital mortality are presented in Table 2. In univariable analyses, none of the anemia-hypoalbuminemia phenotype categories was significantly associated with in-hospital mortality compared with patients with neither condition. Given the limited number of mortality events (n=21), the multivariable analysis was intentionally restricted to an age-adjusted parsimonious model to reduce the risk of overfitting.

In the age-adjusted model, the anemia-hypoalbuminemia phenotype variable was not significantly associated with in-hospital mortality overall (p=0.391). Compared with patients with neither abnormality, the adjusted OR was 2.431 (95% CI 0.552-10.706; p=0.240) for anemia alone, 1.211 (95% CI 0.252-5.820; p=0.811) for hypoalbuminemia alone, and 0.909 (95% CI 0.224-3.689; p=0.894) for combined anemia and hypoalbuminemia. Age was also not statistically significant in the adjusted model (OR 1.029, 95% CI 0.996-1.063; p=0.083). A sensitivity analysis based on 1,000 bootstrap samples yielded consistent findings, with no phenotype category reaching statistical significance; the wide bootstrap CIs further indicated substantial uncertainty associated with the limited number of mortality events.

ROC analysis demonstrated limited discriminatory performance of both admission serum albumin and hemoglobin for in-hospital mortality (Figure 1). The AUC was 0.594 (95% CI 0.477-0.711; p=0.157) for albumin and 0.474 (95% CI 0.344-0.603; p=0.694) for hemoglobin (n=220). Neither biomarker therefore demonstrated statistically significant discrimination for in-hospital mortality.

Discussion

This study evaluated the association between combined anemia-hypoalbuminemia phenotypes and in-hospital mortality among patients hospitalized with AHF. The principal finding was that, after reconstruction of the phenotype groups and reanalysis of the complete 220-patient cohort, in-hospital mortality did not differ significantly across the four phenotype categories. Although mortality was numerically highest among patients with anemia alone, none of the phenotype categories was significantly associated with mortality in either univariable or age-adjusted logistic regression analyses. In addition, neither admission serum albumin nor hemoglobin demonstrated statistically significant discriminatory ability for in-hospital mortality. These findings suggest that, in the present cohort, anemia-hypoalbuminemia phenotyping primarily characterized clinical and laboratory heterogeneity rather than providing independent short-term prognostic discrimination.

Anemia is widely recognized as a frequent and clinically meaningful accompaniment of heart failure and has been associated with reduced exercise capacity, increased rates of rehospitalization, and poorer long-term survival (4, 5). Its pathophysiology in heart failure is multifactorial and may involve iron deficiency, persistent systemic inflammation, impaired renal function, neurohormonal dysregulation, and hemodilution related to volume overload (6, 11, 12). In the present study, patients with anemia alone had the numerically highest in-hospital mortality rate; however, this difference was not statistically significant, and the association remained non-significant after adjustment for age. The wide CIs around the effect estimates indicate substantial uncertainty and preclude firm conclusions regarding the independent short-term prognostic contribution of anemia in this cohort.

Hypoalbuminemia is also frequently encountered in patients with heart failure and may reflect several interrelated processes, including systemic inflammation, hepatic congestion secondary to elevated venous pressure, nutritional impairment, and greater overall disease burden (7, 8). Previous studies have reported associations between lower serum albumin levels and adverse outcomes in both acute and chronic heart failure populations (9, 13). However, the present findings did not demonstrate a significant association between the isolated hypoalbuminemia phenotype and in-hospital mortality. Importantly, this should not be interpreted as contradicting the established biological and prognostic relevance of hypoalbuminemia in broader heart failure populations. Rather, it indicates that such an association could not be demonstrated in this particular cohort, in which the number of in-hospital deaths was limited.

The combined presence of anemia and hypoalbuminemia was likewise not associated with an increased risk of in-hospital mortality compared with the reference phenotype. Although anemia and hypoalbuminemia may arise through partially shared mechanisms, including inflammation, congestion, renal dysfunction, nutritional impairment, and neurohormonal activation (14), the present data do not support an additive prognostic effect of their coexistence. At the same time, the absence of a statistically significant association should not be interpreted as evidence that anemia adds no risk in patients with hypoalbuminemia. The relatively small number of mortality events and the resulting wide CIs limit the ability to distinguish between true absence of an association and insufficient statistical precision.

Inflammatory markers also varied numerically across the phenotype groups. CRP levels tended to be higher in groups characterized by hypoalbuminemia, whereas NLR values showed considerable variability. However, the between-group differences did not reach conventional statistical significance in the reanalysis. Therefore, although systemic inflammation remains a biologically plausible link among AHF, anemia, and hypoalbuminemia, the present findings do not establish a graded inflammatory pattern across the four phenotypes.

ROC analysis provided additional perspective on the prognostic performance of the individual biomarkers. Admission serum albumin yielded an AUC of 0.594, whereas hemoglobin yielded an AUC of 0.474; neither value was statistically significant. These findings indicate limited discriminatory performance of either biomarker alone for in-hospital mortality in this cohort. Importantly, the current analysis also does not demonstrate that the combined phenotype classification provides incremental prognostic value beyond albumin, hemoglobin, or established clinical assessment. Accordingly, the phenotype approach should be regarded as an exploratory method of characterizing clinical heterogeneity rather than as a validated risk-stratification tool.

Clinical Implications

Hemoglobin and serum albumin are routinely available laboratory measurements obtained at hospital admission and can readily identify clinically recognizable anemia-hypoalbuminemia phenotypes without additional testing or cost. Nevertheless, the present findings do not support using these phenotype categories as a stand-alone tool for short-term mortality prediction in patients with AHF. Their potential clinical relevance may instead lie in identifying different patterns of hematologic and nutritional abnormalities that warrant broader clinical assessment. Larger prospective studies with a greater number of outcome events are required to determine whether these phenotypes provide prognostic information beyond established clinical risk factors.

Study Limitations

Several limitations of this study should be acknowledged. First, its retrospective, single-center design limits the generalizability of the findings to broader patient populations and different healthcare settings. Second, although the overall cohort included 220 patients, only 21 in-hospital deaths occurred. This limited number of outcome events reduced statistical power, particularly for comparisons across the four phenotype groups, and resulted in wide CIs around several effect estimates. To reduce the risk of overfitting, the multivariable analysis was therefore intentionally restricted to a parsimonious age-adjusted model. Although a bootstrap sensitivity analysis using 1.000 samples yielded findings consistent with the primary regression analysis, the substantial uncertainty surrounding the estimates should be considered when interpreting the results. Accordingly, the absence of statistically significant associations should not be interpreted as evidence of equivalence or absence of clinically relevant effects.

Furthermore, potentially important confounding variables, including iron status parameters, formal nutritional assessment scores, and a broader range of inflammatory biomarkers, were not systematically available. Residual confounding therefore cannot be excluded. Finally, outcome assessment was restricted to all-cause mortality during the index hospitalization, and no post-discharge or long-term outcomes were evaluated. Larger, prospective, multicenter studies with a greater number of outcome events and longer follow-up are needed to determine whether anemia-hypoalbuminemia phenotypes have prognostic value beyond established clinical risk factors.

Conclusion

In patients hospitalized with AHF, combined anemia-hypoalbuminemia phenotypes were not significantly associated with in-hospital mortality. Neither isolated hypoalbuminemia nor the combined presence of anemia and hypoalbuminemia independently predicted in-hospital death, and admission serum albumin and hemoglobin demonstrated limited discriminatory performance when evaluated individually. Although these readily available laboratory parameters may help characterize hematologic and nutritional heterogeneity in AHF, the present findings do not support their use, either individually or as combined phenotypes, as stand-alone tools for short-term mortality risk stratification. Larger prospective studies with a greater number of outcome events are needed to clarify their potential prognostic value.