The prevalence of anemia in patients with New York Heart Association (NYHA) functional class IV heart failure (HF) approaches 80% (1). Iron deficiency (ID) has been reported as the cause of anemia in more than 70% of advanced HF patients (2). The underlying mechanisms of ID in advanced HF are multiple and complex. In the majority of these patients, a clear cause of ID such as gastrointestinal blood loss is not identified. In anemia of chronic disease, there is abnormal iron bioavailability due to decreased duodenal absorption, entrapment in the reticuloendothelial system, and block of iron's release from iron stores, resulting in less iron for erythropoiesis. Therefore, although ID represents the cause of anemia development in HF, chronic disease seems to be the underlying pathophysiological mechanism.

Thus, it is not known whether severely ill patients are likely to respond to iron alone, or addition of erythropoiesis-stimulating agents (ESA) is also necessary. The present study was designed to assess the magnitude and time course of the hematologic response to treatment with the combination of erythropoietin and intravenous iron versus intravenous iron alone, in iron-deficient anemic patients with advanced-stage HF. Forty-three consecutive anemic patients with advanced HF due to ischemic or dilated cardiomyopathy, recently hospitalized for HF decompensation, were screened. Anemia was defined as serum hemoglobin (Hgb) <12 g/dl in men and <11.5 g/dl in women. All patients underwent the standard diagnostic workup, including bone marrow aspiration, to determine the cause of their anemia. Thirty patients identified with ID (mean age: 57.3 ± 11.7 years, NYHA functional class: 3.3 ± 0.8, Vo₂ at peak exercise: 13.5 ± 4.9 ml/kg/min, left ventricular ejection fraction: 24 ± 6.9%, left ventricular end-diastolic diameter: 71.8 ± 8.0 mm, pulmonary capillary wedge pressure: 25.4 ± 9.2 mm Hg, and cardiac index: 1.8 ± 0.3 l/min/m²) were enrolled in this study.

Iron-deficient anemic patients were randomized to receive either the combination of subcutaneous darbepoetin alfa (DA) (50 μg) with intravenous iron sucrose (300 mg) once weekly (group A, n = 14), or intravenous iron alone (300 mg) once weekly (group B, n = 16). A total amount of 1,800 mg of iron was administered. Duration of treatment was pre-specified to 6 weeks for both groups. Iron sucrose was diluted in 100 ml of normal saline and was administered slowly over 3 h through a peripheral vein. A test dose of 25 mg of iron sucrose diluted in saline was infused before the first full dose, to assess tolerance.

Values are reported as mean ± SD. Differences in the baseline characteristics and Hgb values between the 2 groups were examined using the Student t test for unpaired observations (or Mann-Whitney test when the assumption of distribution normality was violated). Differences in Hgb within each group, as well as between groups at different time points, were examined with repeated measures 2-way analysis of variance (Bonferroni test for within-treatment group comparisons at the different time points). Mean values of systolic arterial pressure, serum creatinine, Hgb, mean corpuscular volume, and ferritin were 97.2 ± 10.6 mm Hg versus 98.4 ± 9.2 mm Hg, p = 0.762; 1.3 ± 0.5 mg/dl versus 1.4 ± 0.5 mg/dl, p = 0.697; 10.6 ± 0.9 g/dl versus 10.9 ± 1.1 g/dl, p = 0.420; 83 ± 7.4 fl versus 86.7 ± 7.7 fl, p = 0.203; and 121.1 ± 114.2 ng/ml versus 139.8 ± 163.9 ng/ml, p = 0.523, for groups A and B, respectively.

A significant increase in Hgb was observed from baseline to the sixth week of treatment and persisted to 3 months of follow-up (Group A: from 10.6 ± 0.9 g/dl to 12.8 ± 1.4 g/dl, p < 0.05, and to 12.9 ± 0.6 g/dl, p < 0.05, respectively, and in Group B: from 10.9 ± 1.1 g/dl to 12.6 ± 0.8 g/dl, p < 0.01, and 13.2 ± 0.5 g/dl, p < 0.001, respectively. There was no difference in Hgb values between the 2 groups at any time point (p = 0.71), suggesting that the combination of DA with intravenous iron does not correct anemia faster or achieve higher Hgb levels compared with intravenous iron alone. Hgb values remained corrected and within the optimal range of 12 to 14 g/dl at the end of the 3-month period of follow-up (Figure 65_gr1). No maintenance dose of either agent was administered after the end of the active treatment period.

The main finding of this study is that intravenous iron alone is as efficient as its combination with DA for the correction of anemia secondary to ID in patients with advanced HF.

It is well established that iron improves patients' clinical condition in HF (3). However, our study is the first, to our knowledge, to compare iron alone to erythropoietin plus iron in advanced HF patients, with ID documented by bone marrow aspiration. The rationale for combining ESA with iron, despite the fact that ID was unequivocally demonstrated, was based on the unique pathophysiological mechanisms of anemia in HF that could have blunted response to iron alone and the need for rapid anemia correction in severely ill patients. Our data document that at advanced stages of HF, when ID is the underlying cause of anemia, intravenous iron alone is adequate treatment. Simple blood sample indices that could accurately diagnose ID in HF and negate the need for bone marrow aspiration would be of profound value in everyday clinical practice.

The present study was not adequately powered to detect small differences between groups or to compare the effect of anemia correction with each 1 of these 2 therapeutic regimens on patients' symptoms or prognosis. Larger studies with clinical outcome as the primary endpoint are still needed. Only if anemia correction with ESA is proven to favorably affect prognosis in this group of patients would the additional cost and risks of these agents be justified (4). In addition, although we did not observe serious adverse effects of any regimen, the study was not adequately powered to confirm equivalence in safety of these treatment approaches.

In conclusion, monotherapy with intravenous iron should be regarded as an efficient treatment option for ID in advanced stages of HF.