Intravenous iron therapy in heart failure with reduced ejection fraction: tackling the deficiency

Introduction

Over the past decade, there has been significant interest in the treatment of iron deficiency (ID) in patients with heart failure with reduced ejection fraction (HFrEF). With the recent AFFIRM-AHF trial, there are now four randomized controlled trials that have demonstrated symptomatic benefit in treating iron-deficient HFrEF patients with intravenous ferric carboxymaltose (FCM). While systemic ID is an important comorbidity that can occur in patients with HFrEF and should be appropriately treated, excess iron is cardiotoxic and over-treatment of HFrEF patients with intravenous iron may have detrimental effects.

This Perspective discusses the major clinical trials of intravenous iron supplementation in HFrEF patients; addresses potential safety concerns of intravenous iron; provides new insights regarding oral iron repletion; and proposes future directions.

Trials of intravenous iron supplementation in heart failure

Iron is an essential nutrient that is necessary for oxygen delivery and metabolic homeostasis, and patients with HFrEF are at risk of developing absolute and functional ID. There are now four randomized clinical trials that have evaluated the effect of intravenous FCM in iron-deficient HFrEF patients. All four trials were relatively small and short-term, and the majority of patients were white and European. The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials collectively demonstrated that intravenous FCM in ambulatory HFrEF patients with ID improves symptoms, as measured by functional capacity (six-minute-walk-test), New York Heart Association (NYHA) classification, and subjective assessment. The most recent trial, AFFIRM-AHF, demonstrated that intravenous FCM modestly reduces total HF hospitalizations in a high-risk population of iron-deficient patients admitted for acute HF. No effect on cardiovascular death was seen in pre- or post-COVID19 analyses.

All four trials defined ID in HFrEF using the criteria of serum ferritin <100 ng/ml (absolute ID) or serum ferritin 100–300 ng/ml with serum transferrin saturation (Tsat) <20% (functional ID), regardless of the presence or absence of anemia. Interestingly, these criteria were not derived from HFrEF patients but rather adopted from ID patients with CKD. However, CKD is associated with uremia-mediated inflammation, increased levels of hepcidin, and decreased renal production of erythropoietin (EPO) requiring erythropoiesis-stimulating agents; none of which are not seen in HFrEF. Given the differences in ID pathophysiology between CKD and HFrEF, it is unclear if these serum markers accurately diagnose ID in HFrEF patients, particularly functional ID. Additionally, HFrEF patients with co-existing CKD have complex iron metabolism which requires additional study. Indeed, in FAIR-HF and CONFIRM-HF, the median ferritin levels were 39 ng/mL and 46 ng/mL respectively, both significantly lower than the ferritin cutoff of 100 ng/mL. In AFFIRM-AHF, the benefits of intravenous FCM were also more pronounced in patients with ferritin <100 ng/mL.

These trials demonstrate that ID is an important comorbidity in HFrEF, and that treatment of true ID in HFrEF improves symptoms and modestly reduces hospitalizations. While these are important endpoints, HFrEF therapies are most impactful when the therapy improves survival and significantly reduces non-fatal HF events. Additionally, it remains to be seen if intravenous iron improves myocardial function or alters the natural history of HFrEF.

Potential safety concerns with intravenous iron therapies

The symptomatic benefits of intravenous iron supplementation in HFrEF patients with true ID should be balanced with the potential safety concerns associated with iron excess. While oral iron absorption is tightly regulated by the effects of hepcidin and rarely leads to iron excess, intravenous iron introduces large amounts of non-transferrin bound iron which bypass regulatory mechanisms and can cause iron overload.

The accumulation of unbound iron can be detrimental to cells and tissues by catalyzing reactive oxygen species. In rodent models, intravenous iron infusions were associated with increased oxidative stress and progression of atherosclerosis.¹ In healthy human volunteers, intravenous iron resulted in transient endothelial dysfunction and biomarkers of oxidative stress.² The toxic effects of intravenous iron may be particularly important to consider in the setting of 1) infection, as many infectious agents thrive on iron, and 2) coronary artery disease patients with vulnerable or high-risk plaques, in whom the pro-oxidative effects of iron may theoretically promote plaque rupture.

It is also important to note that while certain HFrEF patients may be systemically iron deficient, they may simultaneously have increased myocardial iron. Reductions in myocardial iron reduce oxidative stress and cardiotoxicity in rodent models of cardiac injury, suggesting that targeted therapies which replete systemic iron yet specifically reduce myocardial iron may be beneficial.³ Questions also remain regarding the long-term safety of intravenous iron in HFrEF, particularly in patients who receive repeated intravenous iron infusions. The follow-up periods of the four trials mentioned above ranged from only 16 to 52 weeks, and data is lacking regarding the long-term effects of intravenous iron on ventricular remodeling, inflammation, and survival.

Alternative strategies - oral iron supplementation

An understudied alternative to intravenous iron is oral iron supplementation. Oral iron is inexpensive, widely available, and newer agents like oral sucrosomial iron are better absorbed with fewer gastrointestinal side effects. In fact, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommend a trial of oral iron prior to the use of intravenous FCM (except in CKD).

The only study to compare intravenous versus oral iron in HFrEF patients with ID was terminated prematurely due to insufficient funding, but preliminary results showed increases in serum ferritin and Tsat in both iron groups.⁴ Additionally, the IRONOUT-HF trial suggested that a subset of HFrEF patients with ID defined by low hepcidin (<6.6 ng/mL) may benefit from oral iron polysaccharide through improvement in iron indices.

Most recently, a prospective pilot study showed that three-month therapy with low-dose oral sucrosomial iron in iron-deficient HFrEF patients was associated with higher iron indices and improved exercise capacity and quality of life at three months which persisted at six months. There was also a trend towards reduced B-type natriuretic peptide with oral sucrosomial iron compared to control.⁵ These encouraging results are being further investigated in the IVOFER-HF trial (2017-005053-37), which is comparing the effect of intravenous FCM versus oral sucrosomial iron on functional capacity in iron-deficient HFrEF patients.

Conclusions and future directions

Intravenous FCM provides systemic metabolic benefits in iron-deficient HFrEF patients through improvement in symptoms and reduction in hospitalizations. However, important questions remain about the effect of intravenous iron on myocardial and endothelial function, mortality, and long-term safety, especially in the setting of infection and inflammation. These questions will hopefully be answered in ongoing well-powered trials: HEART-FID (NCT03037931), FAIR-HF2 (NCT03036462), and IRON-MAN (NCT02642562).

Additional research is also needed in several key aspects of the field. First, more accurate criteria for defining true systemic ID in HFrEF are needed using novel biomarkers like hepcidin and soluble transferrin receptor, including validation with bone marrow iron stores. Second, large randomized trials in diverse populations should assess the head-to-head efficacy of intravenous iron versus novel low-dose oral iron formulations. Third, novel targeted iron agents that replete systemic iron stores yet prevent myocardial iron overload may hold promise in the treatment of HFrEF. Finally, mechanistic studies are required to assess the effects of intravenous iron on biological outcomes, including oxidative stress, endothelial function, and plaque stability, particularly in high-risk settings such as infection.