Treating iron deficiency in patients with heart failure: The role of ferric carboxymaltose

The burden of iron deficiency in heart failure
Iron deficiency (ID) is common among patients with heart failure (HF), affecting up to 55 percent of patients with stable chronic heart failure (HF) and up to 83 percent of patients with acute decompensated heart failure. [J Am Coll Cardiol 2018;71:782-793]

Iron plays an important role in oxygen transport, oxygen storage, the normal functioning of key oxidative enzymes and respiratory chain proteins. Iron is also involved in the synthesis and degradation of lipids, carbohydrates, DNA, and RNA. [Eur Heart J 2010;31:1872-1880]

The pathophysiological mechanisms of progressive HF are interconnected to increasing ID, resulting in a vicious cycle (Figure 1).

The presence of ID may have multifaceted clinical consequences. Regardless of anaemia, ID has been shown to be independently associated with reduced exercise capacity, increased cardiovascular (CV) and all-cause mortality, and recurrent HF hospitalizations. [Eur Heart J 2021;doi:10.1093/eurheartj/ehab368] Therefore, efficacious treatment of ID may improve HF symptoms and reduce hospitalizations.

Treatment of ID in HF
The 2021 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic HF recommend that all HF patients be periodically screened for anaemia and ID with a full blood count, serum ferritin concentration, and transferrin saturation (TSAT). Monitoring of iron status is recommended for prognostic assessment and treatment. In patients with HF, ID is defined as either a serum ferritin concentration of <100 ng/mL or 100–299 ng/mL with TSAT <20 percent.

The ESC also recommends intravenous ferric carboxymaltose in patients with heart failure with reduced ejection fraction (HFrEF) and ID (Table 1). In addition, in both pre-discharge and post-discharge management planning, iron status should be monitored, and ID should be treated as it has an impact on patient outcomes. [Eur Heart J 2021;doi:10.1093/eurheartj/ehab368]

Intravenous ferric carboxymaltose in HF patients with ID
Randomized controlled trials (RCTs) such as the FAIR-HF, CONFIRM-HF, and EFFECT-HF have shown that treatment with intravenous ferric carboxymaltose improves functional capacity, exercise tolerance, symptoms, and quality of life in stable HF patients with HFrEF and ID for up to 52 weeks. [N Engl J Med 2009;361:2436-2448; Eur Heart J 2013;34:30-38; ESC Heart Fail 2014;52-58; Circulation 2017; 136:1374-1383]

AFFIRM AHF was a multicentre RCT conducted in 121 sites in Europe, South America, and Singapore. Patients hospitalized for HF with LVEF <50 percent and concomitant ID were randomized to intravenous ferric carboxymaltose or placebo. Results showed that treatment with ferric carboxymaltose significantly reduced the risk of total HF hospitalizations (p=0.013), with no effect on the risk of CV death (p=0.81). Analysis of the primary composite endpoint (total HF hospitalizations and CV death) narrowly missed statistical significance (p=0.059). As the follow-up of patients was affected by the pandemic, a prespecified COVID-19 sensitivity analysis was conducted, which revealed statistically significant differences in favour of ferric carboxymaltose for the primary and secondary outcomes. Importantly, the effects of ferric carboxymaltose were not impacted by anaemia status. [Lancet 2020;396:1895-1904]

In addition, a meta-analysis showed that the mortality results in AFFIRM AHF were consistent with prior studies of intravenous iron in HFrEF. There was also no significant difference in adverse events or serious adverse events between the iron treatment group and the control group. [Postgrad Med J 2020;96:766-776]

An individual patient data meta-analysis also suggested that treatment of ID with intravenous ferric carboxymaltose in ambulatory HFrEF patients may decrease recurrent CV hospitalizations. [Eur J Heart Fail 2018;20:125-133]

Oral iron therapy falls short of efficacy in HF with ID
Oral iron products have been shown to have little efficacy in HF. In IRONOUT HF study evaluating oral iron supplementation in HFrEF patients with ID, oral iron therapy was not effective for iron repletion and did not improve exercise capacity in patients. [JAMA 2017;317:1958-1966]

Thus, oral iron supplementation is not recommended for the treatment of ID in HF patients.

What about other intravenous iron products?
Apart from ferric carboxymaltose, other IV iron complexes available include iron sucrose, sodium ferric gluconate, and low molecular weight iron dextran. Intravenous iron products are complex nanoparticles formulated as colloidal solutions, belonging to the class of nonbiological complex drugs. This implies that the various iron complex drugs are metabolized in a complex-specific way, with differences in clinical efficacy and tolerability. Thus, the clinical outcome and safety data of ferric carboxymaltose should not be extrapolated to other IV iron formulations. [ESC Heart Fail 2019;6:241-253]

Intravenous ferric carboxymaltose supported by robust data
Currently, ferric carboxymaltose is the only intravenous iron product that has been extensively studied in RCTs of chronic HF patients. It has shown significant and sustainable improvements in functional capacity, symptoms, and QoL, as well as significant reduction in hospitalizations for worsening HF. Therefore, substitution with other intravenous iron products is not recommended. [ESC Heart Fail 2019;6:241-253]

Summary
ID is highly prevalent in patients with chronic HF, and is independently associated with worse HF symptoms and greater risk of hospitalization. This justifies correction of ID in carefully selected patients. Ferric carboxymaltose has been extensively studied in RCTs of vulnerable chronic HF population. It is recommended by international guidelines for the treatment of ID in HF to bring about symptom relief and reduce HF hospitalizations in patients with HFrEF and ID.