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

Disclosures

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

In This Article

Iron Formulations Administered in Patients With HF

Ferric Carboxymaltose

FCM [Ferinject® or Injectafer®, Vifor (International) Inc., Zurich, Switzerland] is useful for rapid and high-dose replenishment of depleted iron stores.[78,107–109] It has been observed that serum iron concentration increases rapidly after administration of a single dose of IV FCM equivalent to 100–1000 mg of iron.[110] FCM is rapidly distributed from plasma not only to bone marrow, but also liver and spleen.[111] Rapid iron uptake by the bone marrow occurs in the first 10 min following FCM administration, with subsequent uptake occurring at a slower but steady rate. In patients receiving a single dose of FCM equivalent to 100–1000 mg of iron, the half-life of elimination of FCM from the plasma is 7–12 h.[110] Renal elimination of iron is negligible.[111] Weekly administration of FCM (up to two infusions of 1000 mg of iron and four infusions of 500 mg of iron) does not result in accumulation of iron in the serum.[62] Being dextran-free, FCM does not react with anti-dextran antibodies and a test dose is not required.[110]

In the FAIR-HF study,[13,43] the Ganzoni formula[112] was applied to calculate the required total FCM dose. In the CONFIRM-HF study, FCM was administered according to a fixed scheme ( Table 3 ) based on the subject's weight and haemoglobin concentration at screening. The latter dosage scheme is convergent with a total iron dose administered to patients in the FAIR-HF study,[113] in which the median total iron dose during the correction phase was 1000 mg plus an additional 1000 mg in the maintenance phase.[113] Additional doses of FCM can be administered at weeks 12, 24, and 36 if the patient remains iron deficient. It is worth noting that more than 75% of treated patients required a maximum of two injections of FCM.[12]

Iron Sucrose

ISC (Venofer, Vifor Pharma Ltd.) contains iron(III)-hydroxide sucrose complex. In healthy volunteers, a single dose of ISC equivalent to 100 mg of elemental iron is quickly cleared from serum, with a half-life of 5 ± 2 h.[63] Renal elimination is negligible (on average <5%). Serum ferritin level increases significantly after 8–10 h and doubles after 24 h. In anaemic patients, a single-dose administration of radiolabelled ISC equivalent to 100 mg of elemental iron is followed by rapid uptake of this microelement by the liver, spleen, and bone marrow, reaching maximum rates at 10, 20 and 100 min after an administration, respectively.[64] Up to 97% of administered iron is utilized for erythropoiesis, and both ferritin and TSAT return to baseline levels within 3–4 weeks. The extensive safety and tolerability record of ISC (including a low prevalence of hypersensitivity reactions) supports the recommendations of the European Medicines Agency (2013) that a test dose need no longer be applied prior to ISC administration. Special caution is recommended with every dose of IV iron instead, even in patients who responded well previously. The total dose of ISC should be determined individually, based on the calculated total iron deficit according to Ganzoni's formula (depending on the target level of haemoglobin; the frequently applied concentration is 15 g/dL). A common dosing scheme of ISC in HF includes the drip infusion of 200 mg of ISC (in 0.9% sodium chloride solution) weekly for 3 or 5 weeks, depending on the total required dose.[13] A slow IV bolus infusion is also allowed. Doses and dosing schemes in clinical trials with HF are listed in Table 4 .

Iron Isomaltoside 1000

Iron isomaltoside 1000 (Monofer®, Pharmacosmos, Copenhagen, Denmark) consists of iron tightly bound in a carbohydrate matrix structure that guarantees a slow release of iron. The plasma half-life is 5 h for unbound circulating iron and 20 h for total iron (bound and circulating).[114] Due to the low anaphylactic potential, a test dose is not required, and this formulation can be administered in high doses (up to 20 mg/kg within 30–60 min).[114] To date, only one small study with iron isomaltoside 1000 has been performed in HF patients.[103]

Iron Dextran

There are two formulations of iron dextran: low-molecular-weight iron dextran (INFeD, Watson Pharmaceuticals)[115] and (CosmoFer, Pharmacosmos),[116] and high-molecular weight iron dextan (DexFerrum, Watson Pharmaceuticals)[105]). The molecular weight of INFeD and CosmoFer is lower than that for DexFerrum, and reduces the risk of anaphylaxis.[106] These products still require the test dose, and their parenteral use is associated with increased risk of anaphylactic reactions as compared with ISC and ferric gluconate.[117] CosmoFer can be administered in a maximal single dose of 20 mg/kg of body weight, but in a very slow IV infusion (over 4–6 h). The maximum daily dose of INFeD and DexFerrum should not exceed 2.0 mL (100 mg of iron).

Ferric Gluconate

Ferric gluconate (Ferrlecit) is a labile weak complex of iron and requires multiple IV injections with a maximal single dose of 125–250 mg.[118–120] The test dose is suggested only in patients who have had an iron allergy or other drug allergies. An intensive IV dosing scheme (250 mg in 2 h infusions twice daily) improves haematological parameters and is well tolerated in hospitalized patients with advanced HF.[104]

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