Intravenous iron therapy in patients with heart failure. A double-edged sword

Abstract

We read with interest the article of Beck-da-Silva et al., who recently concluded that intravenous (IV) iron seems to be superior over oral supplementation for improving functional capacity of heart failure patients [1]. Irrespective of the study design, involving comparison of functional outcomes between two different means of iron supplementation, we raise some clinical issues about the rationale underlying this investigation. According to the data published by Beck-da-Silva et al., the modest number of patients (n = 23) enrolled in this multicenter investigation had moderate anemia (i.e., hemoglobin concentration comprised between 90 and 120 g/L) but no evidence of iron deficiency, which would be the only plausible reason supporting whatever form of iron administration in thesepatients [1]. Themean ferritin value of the entire cohort of patients (132 ± 138 μg/L) was comprised within the current reference range of the healthy population for this parameter (i.e., 30– 300 μg/L for males and 15–200 μg/L for females, respectively). In particular, recent evidence shows that ferritin can effectively exclude iron deficiency anemia at a diagnostic threshold comprised between 40 and 70 μg/L [2]. No data were also provided about the values of mean corpuscular volume (MCV),mean cell hemoglobin (MCH)and redblood cell distributionwidth (RDW), which are all widely used parameters for establishing a diagnosis of iron deficiency [3,4]. It is well known, however, that anemia in up to two-third of patients with chronic heart failure is directly attributable to increased plasma volume and erythrocyte dilution rather than to a real reduction of red blood cell mass, thus generating a misleading impression of anemia [5]. Due to these drawbacks, there are several reasons that argue against the conclusion that IV iron should be considered a viable option in patients with heart failure and no evidence of iron deficiency. The leading targets of treating irondeficiencyanemia include restoring hemoglobin concentrations and red cell indices to normal, along with replenishing otherwise depleted iron stores [4]. Serum ferritin levels higher than 15 μg/L completely rule out iron deficiency anemia in the general adult population, and thereby preclude the need for iron supplementation [6]. On the other hand, it is noteworthy that the amount of physiological excretion of iron is negligible. Therefore, iron overload, especially when normal storage sites are full, is associated with large accumulation of this compound in body tissues and organs, thus causing a variety of adverse biological consequences. Iron is a vital compound for bacteria and other microorganisms, and it is generally assumed that iron supplementation predisposes to a greater risk of bacterial infections and infectious disease morbidity. Several bodies of evidence also suggest that iron triggers the generation of free radicals, which are involved in a kaleidoscope of chronic and severe disorders, including coronary atherosclerosis [7]. There is also a particular concern that iron supplementation in patients with heart failure may turn to be as a doubleedged sword, wherein it may induce transient functional improvement, but it may then chronically worsen cardiac perfusion, and even cause iron-overload cardiomyopathy and relatedmortality [8]. Additional undesirable effects that may be occasionally encountered in patients undergoing IV iron therapy include allergic or anaphylactic reactions [9]. Although the etiology is multifaceted and imperfectly understood, anemia is indeed frequent in patients with chronic heart failure [10], and has detrimental consequences on physical functioning and general health [11]. However, the convincing evidences gathered so far suggest that major caution should be used before recommending IV iron therapy in heart failure patients with no evidence of iron deficiency, wherein the potential benefits on functional capacity may be largely offset by serious side effects caused by iron overload.