Why Does the Intravenous Iron Supplementation Not Work in Heart Failure Patients on Hemodialysis?

The cardiovascular disease continuum begins with risk factors, progresses to ischemic heart disease and heart failure (HF), ends with the death of the patient.1 With ageing of the society along with increasing prevalence of risk factors, the prevalence of HF has been steadily increasing in Korea.2 Although HF is a disease with high morbidity and mortality, the development of effective pharmacologic and non-pharmacologic treatment has improved the prognosis of HF patients. Consequently, most cardiology societies strongly advocate the guideline-directed medical therapy emphasizing the four pillars of HF drugs, i.e., angiotensin-receptor neprilysin-inhibitor, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2-inhibitors, so the prescription of these life-saving drugs has been dramatically increased.3 However, due to great emphasis on these 4 drugs and the complexity of HF management, many physicians forget or ignore the importance of comorbidities in HF. Among those, iron deficiency is common and its treatment with intravenous iron supplementation proved to be effective in acute4 and chronic HF.5 Since iron deficiency is closely related to (iron-deficiency) anemia, many physicians do not differentiate both. Treating anemia with erythropoietin-stimulating hormones did not lead to improved outcomes in HF patients.6 This is an intrigue question why treatment of iron deficiency improves the outcomes, but not anemia correction. Iron is a key component of hemoglobin, myoglobin, cytochromes, and proteins responsible for oxygen storage, transport, and utilization.7, 8 Therefore, iron deficiency itself can lead to generalized energy depletion and aggravate the course of HF.9 Therefore, intravenous iron supplementation with ferric carboxymaltose improved outcomes in HF patients with iron deficiency. It is of note that these studies excluded patients with end-stage renal disease (ESRD), so the value of intravenous iron supplementation in HF with ESRD is unknown.

In this issue, Kim and colleagues10 investigated an important question regarding the effect of intravenous iron supplementation for HF and red blood cell transfusion in 101 HF patients with ESRD on hemodialysis. Approximately two thirds of the patients received intravenous iron supplementation and they did not show lower hospitalization for HF compared with those without intravenous iron supplementation. This neutral study result may be disappointing, but not unexpected. Before generalization to all HF patients on hemodialysis, there are some issues that need some consideration. First, previous studies with intravenous iron supplementation included only HF patients with confirmed iron deficiency. However, the prevalence of iron deficiency is unknown in this study population. The effect of intravenous iron supplementation may be attenuated in patients without iron deficiency. Second, previous studies included patients with HF with reduced ejection fraction (EF), whereas here the mean left ventricular EF was 61% suggesting many patients with HF with preserved EF were included. Third, different iron supplementations are investigated. Previous studies used intravenous ferric carboxymaltose whereas in this study patients received intravenous iron sucrose. Forth, the sample size is too small to exclude type 2 error, i.e., false negative finding. To have a definite answer on the effect of intravenous iron supplementation for HF patients on hemodialysis, a dedicated, randomized, placebo-controlled clinical study is necessary. Such study may include patients with HF and reduced EF and confirmed iron deficiency who are on hemodialysis. The sample size should be adequate and intravenous ferric carboxymaltose supplementations should be used. Until then, the effect of intravenous iron supplementation in patients with HF on hemodialysis should be cautiously interpreted.