Erythropoietin, Iron, or Both in Heart Failure: FAIR-HF in Perspective

Despite recent advances in heart failure (HF) treatment morbidity and mortality remain high; the 1-year mortality is ∼20%.1 Suboptimal treatment and the presence of comorbidities are major factors responsible for the poor prognosis. Anaemia and renal failure are the most prevalent comorbidities in the HF population.2 The prevalence of anaemia increases with the severity of HF and is reportedly over 40% for patients with advanced HF.3 Anaemia in HF is associated with diabetes, low body mass index, higher systolic and lower diastolic blood pressure, recent HF hospitalization, and renal failure. In a recent meta-analysis, it has been shown that the prevalence of anaemia is similar in patients with systolic and diastolic HF and in both conditions it is a powerful predictor of mortality.4 There is still ongoing discussion about whether anaemia is a mediator or merely a marker of worse outcome. Most probably, to an extent both are true. It is tempting to suggest that the treatment of anaemia positively influences the survival of HF patients. Moreover, it is one of the few reversible conditions in chronic HF patients. Logically, treatment based on the aetiology and pathophysiology of anaemia should be most effective and beneficial. However, the aetiology of anaemia in patients with chronic HF is complex and multifactorial, including renal failure, haemodilution, ACE-inhibitor use, and anaemia of chronic disease.5 Erythropoietin (EPO) levels are generally increased in patients with chronic HF. Even when corrected for the severity of anaemia, one-third of the patients with severe chronic HF still had plasma EPO concentrations well above the expected levels for the severity of anaemia, indicating a reduced bone marrow response to endogenous EPO.6 On the other hand, iron deficiency is also commonly observed in chronic HF patients. The cause of this deficiency may be related to poor nutrition, malabsorption, and cardiac cachexia.7 Furthermore, the use of aspirin and oral anticoagulation may lead to microscopic amounts of gastrointestinal blood loss, which contributes to the iron deficiency. In a recent study using bone marrow biopsies, it was noted that in patients with severe chronic HF, iron deficiency was observed in more than half of the patients.8 Moreover, defective mobilization of iron stores due to cytokine activation may also play an important role. Accordingly, treatment strategies have been focused on iron therapy and administration of EPO. The first studies of the use of EPO in chronic HF patients were published almost 10 years ago and showed a beneficial effect on surrogate cardiovascular endpoints, including cardiac performance, exercise time, and renal function.9 Recently, the effects of darbepoetin-alfa (a longer acting EPO analogue) have been investigated in several larger trials in patients with chronic HF. These studies showed that treatment with darbepoetin-alfa was safe and effectively raised haemoglobin levels, and that exercise capacity and quality-of-life improved.10–12 Interestingly, a pre-specified pooled analysis of the two largest studies showed a decreased risk of the composite clinical endpoint (death and hospitalization for HF) in the darbepoetin-treated patients.13 All of the EPO studies have been included a meta-analysis, which included a total of 650 patients from seven studies. Erythropoietin treatment was associated with a significant 41% lower risk of HF hospitalization.14 No significant difference in the mortality risk between the two groups was observed. Besides effects on the bone marrow, EPO also has direct effects on the heart. Experimental studies have shown an improvement in cardiac function through inhibition of apoptosis and induction of neovascularization.15,16 Parallel to EPO treatment, another approach to anaemia correction has been proposed.17 This includes administration of intravenous iron, since relative iron deficiency, as noted above, is a major factor implicated in the aetiology of anaemia in HF. The FAIR-HF trial investigated the role of intravenous iron in chronic HF patients. The design of the study has been published previously.18 The authors enrolled 459 patients with chronic HF, NYHA Class II or III, and iron deficiency with anaemia (haemoglobin 9.5–12.0 g/dL = 5.9–7.8 mmol/L) and without anaemia (haemoglobin 12.0–13.5 g/dL = 7.8–8.4 mmol/L). The mean left ventricular ejection fraction was 32%. Weekly ferric carboxymaltose therapy rapidly increased iron levels; a modest increase in haemoglobin levels was observed in the subgroup of patients with anaemia, but not in patients without anaemia.19 The administration of iron significantly improved symptoms, NYHA class, quality-of-life, and exercise capacity (Figure 1). Interestingly enough, the same results were obtained in the anaemic and non-anaemic groups. A trend towards fewer hospitalizations was seen in the actively treated group. As with EPO, there are concerns about intravenous iron therapy. In addition to allergic reactions, iron may accelerate free radical formation, increase oxidative stress, and cause endothelial dysfunction.20 In conclusion, relatively small-scale studies have shown promising results for anaemia correction with EPO. Clearly, the final verdict on efficacy of EPO and thus its future clinical use in HF patients with anaemia should be defined by the result of the RED-HF study.21 In RED-HF, 2600 patients will be randomized to treatment with darbepoetin or placebo, with a primary combined endpoint of death and first hospital admission for worsening HF. The estimated completion of the study is December 2011. As to therapy with iron, more larger-scale studies are needed to establish the safety and efficacy profile of intravenous iron in HF patients. Furthermore, studies designed to unravel the pathophysiology of anaemia are important. These studies will help to identify patients who will benefit most from iron, EPO, or both. Conflict of interest: none declared.