The significance of anemia in heart failure (HF) has received attention recently as evidenced by state-of-the art papers published over the last few years. The prevalence has varied widely from 7% to 70%, depending both on the severity of HF and diagnostic criteria used to define it.1 The World Health Organization (WHO) has arbitrarily defined anemia in the general population as hemoglobin (Hb) concentration < 13g/dL in men and < 12g/dL in women. The National Kidney Foundation (NKF) has defined anemia as Hb ≤ 12.5 in men and postmenopausal women with chronic kidney disease (CKD).2,3
Although several studies have documented higher mortality rates in anemic HF patients, other studies reported the absence of an adverse effect of anemia on mortality in HF. In the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial, anemia remained a significant, independent predictor of death or hospitalization for HF.4
There are multiple potential mechanisms by which HF could contribute to the development of anemia. These may include renal dysfunction, hemodilution, proinflammatory, hematinic deficiency (iron deficiency, in particular), decreased perfusion to the bone marrow, or drug therapy (such as angiotensin-converting enzyme [ACE] inhibitors). Several of these mechanisms are active, simultaneously resulting in anemia in HF patients.5
The consistent association of anemia with adverse clinical outcomes in HF has led to substantial interest in anemia as a potential therapeutic target. Therapeutic options available to increase Hb include the use of iron alone or in combination with erythropoietic stimulating agents (ESAs). In an open-label study of 16 anemic HF patients, iron treatment significantly increased Hb and improved New York Heart Association (NYHA) functional class, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, and 6-min walk distance (6MWD).6
Another recent study included 40 anemic HF patients randomized to either saline or iron; Hb increased by a mean of 1.4 g/dL (p ≤ 0.01), and there was an improvement in creatinine clearance, MLHFQ score, and the 6MWD in the iron but not placebo group.7 In addition, the Ferric iron sucrose in Heart Failure (FERRIC-HF) trial evaluated exercise capacity in iron-deficient anemic and non-anemic HF patients. It was a randomized, open-label, observer-blinded treatment with placebo or iron. Iron therapy increased serum ferritin and improved NYHA functional class.8 Large randomized placebo-controlled trials are required to confirm these intriguing findings. One such trial, Iron Supplementation in Heart Failure Patients With Anemia (IRON-HF) trial, is in progress.9
Moreover, the use of ESAs is considered another rational strategy as several small studies showed an increase in Hb with the use of such agents. Three studies investigated epoetin alfa, one study used epoetin beta, and three examined the effects of darbepoetin alfa.
Silverberg and his colleagues reported the effect of epoetin alfa and iron in two different studies. Both showed an increase in Hb, which was associated with improvements in NYHA functional class and Left Ventricular (LV) ejection fraction and a decrease in diuretic dose and hospitalizations.10,11 Furthermore, Mancini and his group conducted a patient-blind randomized study in 26 anemic HF patients. They randomized patients to epoetin alfa plus oral iron and folate or to placebo. After 3 months, ...