Erythropoietin, which is produced in the kidneys in response to hypoxia, acts on the bone marrow to promote the survival and proliferation of erythroid precursor cells, increasing the production of red blood cells. Recombinant human erythropoietin (rHuEPO) and a more recent erythropoietin analog with a longer half‐life, darbepoetin alfa, have been used in various trials to treat anemia associated with HF. The rationale for using ESAs is that although anemia in HF is multifactorial, it may represent an absolute or a relative deficiency or resistance to endogenous erythropoietin.

Silverberg et al. were the first to use ESAs in patients with anemia and HF, in an open randomized trial of 32 patients with moderate to severe HF and Hb 10–11.5 g/dl.24 Treatment with rHuEPO and intravenous (IV) iron was followed by improvement in NYHA class, increased left ventricular ejection fraction and reductions in hospitalizations and need for diuretics. Several small‐scale studies with rHuEPO or darbepoetin alfa have shown improvements in oxygen uptake and functional capacity, reduced BNP levels and improved quality of life.25–27 However, the results have been inconsistent. In a study by van Veldhuisen et al. of 165 patients with HF and Hb between 9.1 and 12.5 g/dl,28 administration of darbepoetin alfa for a target value of 14 g/dl raised Hb levels and improved some quality of life indices as assessed by the Kansas City Cardiomyopathy Questionnaire, but no improvements were seen in the 6‐minute walk test, NYHA functional class, or Minnesota Living with Heart Failure score.

A meta‐analysis published in 2011 of 11 randomized clinical trials, nine placebo‐controlled and five double‐blinded, of a total of 794 patients with HF and anemia treated with ESAs showed improvements in symptoms and functional capacity and a reduction in clinical events.29 It should be noted that in many of the small published trials iron supplementation was used in association with ESAs.

However, the latest evidence does not support the use of ESAs to treat anemia in HF. The lack of demonstrated benefit, and indeed the associated risks, were demonstrated in the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED‐HF) trial, which randomized 2278 patients with systolic HF and anemia to receive darbepoetin alfa or placebo, with a target Hb level of 13.0 g/dl.30 Oral or IV iron was administered as tolerated if TSAT fell to less than 20% at any time. No significant differences were seen in the composite primary outcome of death from any cause or hospitalization for worsening heart failure in a mean follow‐up of 28 months (50.7% in the darbepoetin alfa group and 49.5% in the placebo group (hazard ratio 1.01; 95% confidence interval [CI] 0.90–1.13) or in the incidence of stroke, although the latter was slightly higher in the darbepoetin alfa group (3.7% vs. 2.7%). However, thromboembolic events were more frequent in the darbepoetin alfa group (13.5% vs. 10%).

These results are similar to those of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which compared darbepoetin alfa with placebo in 4028 patients with diabetes, chronic kidney disease, and anemia, a third of whom had HF.31 Higher rates of stroke and thromboembolic events were seen in the darbepoetin alfa group.

Possible reasons for the adverse events seen with the use of ESAs include worsening of hypertension, elevated thromboembolic risk and increased release of endothelin.

The disappointing results reported for ESAs contrast with those described for IV iron supplementation alone in patients with HF and iron deficiency, even without manifest anemia.

The use of IV iron in the form of ferric carboxymaltose for the treatment of anemia of various causes was reviewed in a 2011 meta‐analysis of 11 randomized trials and three cohort studies.32 A total of 2348 patients were treated with IV ferric carboxymaltose in randomized trials and 348 in cohort studies, 832 receiving oral iron, 762 receiving placebo and 384 receiving IV iron sucrose. Compared to oral iron (the most common comparator), IV ferric carboxymaltose increased mean Hb by 4.8 g/dl, ferritin by 163 μg/l and TSAT by 5.3%, and was significantly better than comparator in achieving the target Hb level (number needed to treat: 5.9). The incidence of serious adverse events was similar with IV ferric carboxymaltose and comparator, but gastrointestinal adverse events were significantly more frequent in patients treated with oral iron.

Six studies have been published on iron supplementation in HF, including two open non‐controlled trials,33,34 one open controlled trial,35 and three randomized placebo‐controlled, double‐blind trials36–38 (Table 2).

Improvements in symptoms, exercise capacity and quality of life were seen in parallel with rises in Hb levels in all these studies. In the Ferric Iron Sucrose in Heart Failure (FERRIC‐H) trial, symptoms and exercise capacity also improved, although to a lesser extent, in non‐anemic patients.36 Improved oxygen consumption did not relate to absolute increases in Hb but to increased TSAT.

The multicenter randomized double‐blind placebo‐controlled Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR‐HF) trial was the largest.38 Treatment with ferric carboxymaltose significantly improved the two main outcomes: 50% of patients randomized to ferric carboxymaltose reported at least moderate improvement on the Patient Global Assessment questionnaire, compared to 28% of the placebo group (odds ratio [OR] for improvement 2.51, 95% CI 1.75–3.61), and 47% of the treatment group achieved NYHA class I or II, compared to 30% in the placebo group (OR 2.40, 95% CI 1.55–3.71). Improvements were also seen in the 6‐minute walk test and in quality of life scores, but prognosis was not affected (despite a tendency for fewer hospitalizations in the treatment group); the trial was not designed to assess the effect of iron supplementation on prognosis. The benefits of iron supplementation were seen in patients without as well as with anemia; this is slightly puzzling, but may be explained by the fact that only low‐intensity exercise was tested, which correlates with iron levels in tissues. If maximum aerobic capacity had been tested, the non‐anemic group would probably not have shown improvement, since this parameter depends on Hb concentrations rather than muscle oxidative capacity.39

The question arises as to whether similar results could be obtained with oral iron. Absorption of oral iron(II) is blocked by hepcidin; moreover, gastrointestinal tolerance of oral iron drugs is generally poor, and they interact with various other medications, including proton pump inhibitors.40 Furthermore, even if the iron is absorbed, its transport to the bone marrow is blocked by hepcidin, as in cases of anemia of chronic disease, which do not respond to oral iron. In IV formulations, iron in the form of iron(III) is bound to carbohydrate complexes, which are taken up from the bloodstream into the reticuloendothelial system within hours of administration. Most is incorporated into iron stores, but some binds to transferrin and reaches the bone marrow, thus overcoming blockade by hepcidin and resulting in underuse of this iron in tissue storage sites, formation of free radicals and increased risk of infection due to reduced cellular immunity and bacterial growth enhancement.41 However, the FAIR‐HF trial did not show higher rates of infection or cardiovascular events. Unlike the iron dextran previously used, current IV iron preparations such as iron sucrose, ferric gluconate and ferric carboxymaltose are well tolerated, rarely causing hypersensitive reactions, and thus do not require a test dose.42

A recent study shows improvements in previously low health‐related quality of life after four weeks of treatment with ferric carboxymaltose irrespective of previous anemia status.43

A health economic analysis of ferric carboxymaltose for HF patients with or without anemia in the UK showed the treatment to be cost‐effective, below the threshold of 22 200–33 300 euros per quality‐adjusted life year gained typically used by the UK National Institute for Health and Clinical Excellence, and robust in sensitivity.44

Three clinical trials are currently underway comparing ferric carboxymaltose with placebo in patients with HF and iron deficiency: CONFIRM‐HF (NCT01453608), with 300 patients, and iCHF (NCT01837082), with 100 patients, both ending in December 2013; and EFFECT‐HF (NCT01394562), with 160 patients, due to end in January 2014. These trials are intended to determine the efficacy of ferric carboxymaltose in terms of improving functional capacity, and its safety. A combined analysis of the results of FAIR‐HF and these trials will also show whether ferric carboxymaltose reduces clinical events such as death and hospitalization for HF.

Although not considered relevant at the initial assessment, the patient's Hb level of 11 g/dl will reduce her functional capacity and contribute to risk of morbidity and mortality. According to the European guidelines on HF, a diagnostic work‐up of her anemia should have been performed, as well as medical therapy and echocardiographic assessment. Serum ferritin <100 ng/ml or 100–299 ng/ml associated with TSAT <20% indicates inflammation or chronic disease as the cause and should be corrected by iron supplementation, preferably parenterally.

The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that no patient data appear in this article.

The authors declare that no patient data appear in this article.