European Journal of Cardiovascular Medicine

Anemia of Chronic Disease (ACD), also referred to as anemia of inflammation, is a prevalent condition characterized by reduced erythropoiesis and impaired iron metabolism, commonly associated with chronic inflammatory disorders, infections, autoimmune diseases, and malignancies (1). Unlike iron-deficiency anemia, ACD is marked by adequate or elevated iron stores with diminished availability for erythropoiesis due to the inhibitory effects of inflammatory cytokines on iron mobilization and erythropoietin production (2,3).

The pathogenesis of ACD involves increased hepcidin levels, which inhibit iron release from macrophages and reduce intestinal iron absorption, contributing to functional iron deficiency despite adequate body iron stores (4). Additionally, inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) negatively impact erythropoietin response, further exacerbating anemia (5,6).

Management of ACD aims at correcting anemia, improving quality of life, and minimizing the need for blood transfusions. Traditional treatment approaches include iron supplementation (IS), either oral or intravenous, to replenish iron stores and enhance erythropoiesis (7). However, the efficacy of IS is often limited by impaired iron absorption and utilization due to persistent inflammation (8).

Erythropoiesis-Stimulating Agents (ESA), such as epoetin alfa and darbepoetin alfa, have emerged as effective alternatives for enhancing erythropoiesis by stimulating bone marrow activity and increasing hemoglobin levels (9). Despite their efficacy, the use of ESAs is associated with potential adverse effects, including thromboembolic events and increased cardiovascular risks (10).

Comparative studies evaluating the efficacy of IS and ESA in managing ACD have reported varying outcomes. Some studies suggest superior efficacy of ESA in achieving target hemoglobin levels, while others emphasize the importance of optimizing iron status for improved response (11,12). Nevertheless, there is a lack of consensus regarding the most effective treatment strategy, necessitating further investigation.

The present study aims to compare the efficacy of iron supplementation and erythropoiesis-stimulating agents in managing ACD, assessing their impact on hemoglobin levels, serum ferritin, and transferrin saturation over a 12-week period.

Study Design and Participants:

This randomized clinical trial was conducted to compare the efficacy of iron supplementation (IS) and erythropoiesis-stimulating agents (ESA) in managing Anemia of Chronic Disease (ACD). The study included a total of 120 patients aged 18 years and above diagnosed with ACD based on clinical evaluation and laboratory findings (Hemoglobin < 11 g/dL, Serum Ferritin > 100 ng/mL, and Transferrin Saturation < 20%). Patients with iron deficiency anemia, hematologic malignancies, active bleeding, or uncontrolled systemic diseases were excluded. The written informed consent was obtained from all participants before enrollment.

Randomization and Group Allocation:

Patients were randomly assigned to one of two intervention groups using a computer-generated randomization sequence:

• Group A (Iron Supplementation): Received oral iron supplementation with 100 mg of elemental iron daily for 12 weeks.
• Group B (Erythropoiesis-Stimulating Agents): Received subcutaneous administration of epoetin alfa at a dose of 40,000 IU weekly for 12 weeks.

Treatment Monitoring and Follow-Up:

Participants were assessed at baseline, 6 weeks, and 12 weeks. During each visit, clinical examination and laboratory investigations were performed to evaluate the efficacy and safety of the interventions.

Outcome Measures:

The primary outcome was the change in hemoglobin (Hb) levels from baseline to 12 weeks. Secondary outcomes included changes in serum ferritin and transferrin saturation (TSAT).

• Hemoglobin (Hb): Measured using an automated hematology analyzer.
• Serum Ferritin: Determined via enzyme-linked immunosorbent assay (ELISA).
• Transferrin Saturation (TSAT): Calculated as (Serum Iron / Total Iron-Binding Capacity) × 100

Safety Assessment:

Adverse events related to the interventions were monitored throughout the study period, and participants were advised to report any side effects.

Statistical Analysis:

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software, version 27.0. Descriptive statistics were presented as mean ± standard deviation (SD) for continuous variables. Comparisons between groups were performed using independent t-tests, while intra-group comparisons were assessed using paired t-tests. A one-way ANOVA was applied to compare more than two sets of data. Statistical significance was set at p < 0.05.

Baseline Characteristics

A total of 120 patients diagnosed with Anemia of Chronic Disease (ACD) were enrolled in the study and randomly assigned to either Group A (Iron Supplementation, n=60) or Group B (Erythropoiesis-Stimulating Agents, n=60). The baseline characteristics of the study population are summarized in Table 1. Both groups were comparable concerning age, gender, hemoglobin levels, serum ferritin, and transferrin saturation (TSAT).

Table 1: Baseline Characteristics of the Study Population

Comparison of Hematological Parameters

The improvement in hematological parameters was assessed at baseline, 6 weeks, and 12 weeks. Both interventions resulted in significant improvements in hemoglobin levels, serum ferritin, and transferrin saturation. However, the extent of improvement differed between groups (Table 2).

Table 2: Comparison of Hematological Parameters between Groups

Statistical Analysis

Statistical analysis revealed that Group B (ESA) demonstrated a significantly greater increase in hemoglobin levels at 6 weeks and 12 weeks compared to Group A (IS) (p < 0.01, Table 2). However, Group A showed a more pronounced improvement in transferrin saturation levels over the same period (p < 0.05, Table 2). Serum ferritin levels increased significantly in both groups, with Group A showing a higher final level at 12 weeks (p < 0.05, Table 2).

The present study compared the efficacy of Iron Supplementation (IS) and Erythropoiesis-Stimulating Agents (ESA) in managing Anemia of Chronic Disease (ACD). The results demonstrated that ESA therapy was significantly more effective in enhancing hemoglobin (Hb) levels compared to IS alone, which aligns with previous studies suggesting superior erythropoietic response with ESAs (1,2). However, the improvement in transferrin saturation (TSAT) was more prominent in the IS group, emphasizing the importance of iron availability for effective erythropoiesis (3).

ACD is primarily characterized by impaired iron utilization and reduced erythropoietin production due to the effects of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (4,5). This inflammatory milieu results in increased hepcidin synthesis, which restricts iron availability by inhibiting iron absorption from the gut and trapping iron within macrophages (6). As observed in the current study, the IS group experienced a significant improvement in TSAT and serum ferritin levels, suggesting partial correction of functional iron deficiency (7).

The significant rise in hemoglobin levels observed in the ESA group is consistent with findings from previous studies demonstrating that ESAs effectively stimulate erythropoiesis by enhancing erythroid precursor cell proliferation and differentiation (8,9). The improvement in Hb levels from 9.4 ± 0.7 g/dL to 12.3 ± 1.0 g/dL in the ESA group is in agreement with similar studies that reported substantial hematological responses with the use of epoetin alfa (10,11).

Nevertheless, iron supplementation remains an essential component of ACD management, particularly in patients with low TSAT. Oral iron administration has shown efficacy in improving iron parameters, but its effectiveness is often limited by inflammation-induced hepcidin elevation and poor gastrointestinal absorption (12,13). In the present study, the IS group exhibited a moderate increase in hemoglobin levels (9.5 ± 0.8 g/dL to 11.0 ± 0.9 g/dL), which may be attributed to improved iron bioavailability despite the underlying inflammatory state.

The discrepancy in ferritin levels between the two groups at the end of the study period is noteworthy. Ferritin, an acute-phase reactant, tends to be elevated in inflammatory conditions, making it a less reliable indicator of iron status in patients with ACD (14,15). Despite this limitation, the improvement in ferritin levels observed in the IS group suggests enhanced iron storage and availability for erythropoiesis.

Limitations of this study include the relatively short duration of follow-up and the absence of intravenous iron therapy, which may offer improved efficacy over oral iron in the setting of ACD (19). Additionally, the study did not assess long-term safety outcomes associated with ESA use, warranting further investigation.

Future studies should explore the combination of iron supplementation and ESA therapy, as well as the use of novel agents such as hepcidin antagonists and hypoxia-inducible factor (HIF) stabilizers, which have shown promise in enhancing iron availability and promoting erythropoiesis (20).

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