Iron Therapy in Patients With Heart Failure and Iron Deficiency

Review of Iron Preparations for Practitioners

Marcin Drozd; Ewa A. Jankowska; Waldemar Banasiak; Piotr Ponikowski


Am J Cardiovasc Drugs. 2017;17(3):183-201. 

In This Article

Oral Iron Supplementation

In healthy persons, an overall iron absorption depends on several factors, such as consumed form of iron, iron absorption enhancers or inhibitors, and the degree of iron depletion. Greater overall amount of consumed iron and a diet rich in iron compounds with better bioavailability increase total iron absorption. Haem iron is more easily absorbed than non-haem iron, and, for example, ascorbic acid promotes iron absorption.[21]

Iron absorption increases when body iron stores are low and decreases when they are sufficient.[62] An average absorption of iron from the whole diet is approximately 12–16%, but it varies between 1 and 50% (in the vast majority of studies analysed in the meta-analysis of Collings et al.,[63] the mean absorption was below 10 mg/day).[63]

In the general population, oral iron supplementation is usually "the first choice therapy" for ID, but frequently the response to the treatment is suboptimal. It is a reasonable option for healthy subjects without absorption disorders, in whom ID is usually mild and rapid replenishment is not necessary. The tolerance of iron differs depending on the used oral iron formulation. There are two forms of absorbable iron: ferrous (Fe2+) and ferric (Fe3+). Due to lower solubility, ferric iron is less bioavailable than ferrous iron.[64] Ferrous fumarate, ferrous sulphate, and ferrous gluconate are the major types of ferrous iron supplements, with comparable bioavailability.[65–67] The estimated absorption rate of the ferrous salts was found to be 10–15%, without significant differences among the three major formulations, in a small RCT.[68] The recommended therapeutic dosage ranges from 150 to 180 mg/day of elemental iron delivered in divided doses two to three times a day.[69] Importantly, the therapy with oral iron supplements can be complicated by gastrointestinal side effects, such as abdominal discomfort, nausea, vomiting, and constipation, to name a few. Enteric-coated iron supplements have fewer side effects.[70] The newest formulation of iron is a delayed-release polysaccharide iron complex (PIC). This is a combination of ferric iron and a low-molecular weight polysaccharide, which contains 150 mg of elemental iron. Its structure closely resembles endogenous carriers of iron. PIC has been designed to minimize gastrointestinal upset by delaying iron release in the intestines.[71–73] On the other hand, in Taiwanese populations, delayed release of iron from PIC results in slower treatment of IDA (improvement in ferritin and haemoglobin) as compared with an equivalent daily dose of ferrous fumarate.[74]

Iron supplements at doses of 60 mg or higher of elemental iron as ferrous sulphate increase serum hepcidin for up to 24 h and are associated with lower iron absorption on the following day. In iron-depleted (defined as plasma ferritin ≤20 μg/L), non-anaemic women, the fractional absorption is highest at low iron doses (40–80 mg) and consecutive-day dosing results in decreased iron bioavailability compared with every other day dosing. For total iron absorption, a twice-daily iron supplementation seems to have limited additional effect compared with a daily administration. The sTfR/ferritin ratio and hepcidin are equivalent predictors of iron absorption from supplements.[75] It is worth noting that in elderly patients over 80 years of age, low-dose iron supplementation (15 mg of elemental iron daily) appears to be a reasonable option for the treatment of IDA, as it significantly reduces adverse effects of the therapy.[76]

The majority of studies regarding oral iron supplementation and its effectiveness recruited subjects with IDA or patients with CKD. In patients with IDA and non-dialysis CKD in seven randomized studies, the superiority of intravenous (IV) iron over oral iron as a faster and more efficient support for erythropoiesis has been demonstrated.[77–83]

It needs to be acknowledged that available clinical evidence on the effectiveness of oral iron therapy in patients with HF and ID is very limited. In a retrospective study, regarding iron-deficient patients with HFrEF, oral iron supplementation over 180 days resulted in an increase in ferritin, TSAT, serum iron, and haemoglobin concentration. The authors suggested that oral iron supplementation could be an alternative for IV iron, but it is worth noting that after 5 months of the therapy, the level of ferritin was still far below the threshold for an absolute ID in HF (ferritin <100 μg/L). Moreover this study did not reveal any clinical benefits beyond improvement in serum iron indices and haemoglobin; particularly, there was no difference regarding re-hospitalization rates.[84] In another study in HF patients with anaemia, the use of oral iron for 1 year was not associated with any clinical benefits in the context of any improvement in NYHA status, measured exercise endurance, oxygen use during exercise, renal function and plasma B-type natriuretic peptide levels, and the need for hospitalization.[85] Additionally, in the recently presented prospective, randomized clinical trial (IRON-OUT), PIC (150 mg twice daily for 16 weeks) had little effect in replacing iron stores and did not improve peak VO2, 6-min walking distance, oxygen kinetics, ventilatory efficiency, and HRQoL score in anaemic HFrEF patients.[86,87]