David I Gozzard
Consultant Haematologist, Betsi Cadwaladr University Health Board, North Wales, UK
High-dose single-administration intravenous iron therapy (HDIT) has evolved over the past 70 years. Initial experience using iron compounds in human patients revealed their toxicity even in small quantities, and while subjects exhibited an individual tolerance to iron doses, the maximum quantities infused totalled only a few tens of milligrams. The iron oxyhydroxide complex that was used in the early days was replaced by the introduction of compounds in which a central core of iron was surrounded by a carbohydrate shell, thus protecting the fragile intravenous environment from the potentially toxic iron. The commercial introduction of a dextran-based iron compound (Imferon®, Fisons Limited) in the early 1950s led to an increase in the toleration of intravenous therapy, but also revealed a range of other toxicities considered to be immune-mediated mechanisms directly attributable to the dextran shell. Dextran-reactive antibodies can react with high-molecular-weight dextran molecules, thereby forming large immune complexes. These complexes can be associated with severe reactions including rare anaphylactic reactions, and more common but less severe reactions, including arthralgia.
In the 1990s a safe sucrose-containing iron preparation (Venofer®, Vifor Limited) challenged the dominance of the iron-dextran market. This product was not licensed for total-dose infusion but required several clinic appointments to complete a course of iron therapy.
In 1993, withdrawal of Imferon® in the UK led to the cessation of the use of total-dose infusion. Yet in 2001, the introduction of Cosmofer® (Vitaline Limited), a low molecular weight iron dextran formulation, led to high-dose single-administration replacement of iron becoming a safe and reliable therapy. This re-introduction of total-dose iron treatment, based on a low-molecular-weight dextran complex, led to the reappearance of concerns of dextran-based formulations.
Indeed, physicians with experience of Imferon® focused strongly on the historical safety issues, without
realising the safer profile offered by low-molecular-weight dextran in the Cosmofer formulation.
More recently, the introduction of newer intravenous iron preparations, such as ferric carboxymaltose (Ferinject®, Vifor Limited), and iron isomaltoside 1000 (Monofer®, Pharmacosmos Limited) has resolved the problems of the lengthy infusion times associated with Cosmofer® and the need for a test dose.
Several intravenous iron products are now available to the physician to treat iron deficiency anaemia associated with a number of clinical indications. What are these indications, how do the different formulations compare, and are there any therapeutic or economic advantages to the single dose formulations?
Comparison of HDIT formulations
A comparison of the formulations available for HDIT is shown in Table 1.
Logistics of administration
A comparison of the logistics of ferric carboxymaltose and iron isomaltoside 1000 administration is shown in Table 2.2
There are several well-documented areas where the use of HDIT is indicated:
1.Non-dialysis-dependent phase of chronic kidney disease (CKD)
There is no doubt that the lives of patients with CKD have been transformed since the introduction of erythropoietin (EPO) therapy. The inconvenient, costly, yet commonplace treatment with recurrent blood transfusions, was replaced with simple regimens of regular EPO injections. As transfusions jeopardise the prospects of finding a matching kidney for renal transplantation, there are now guidelines indicating that transfusion should be avoided where possible. In the early stages of CKD anaemia the blood count may be sustained with iron supplementation alone. Most patients will ultimately require EPO and it is during this early phase that patients benefit from HDIT. The Ganzoni formula is used widely to calculate the intravenous iron dose.
2.Inflammatory bowel disease
Over one-third of patients with these conditions have associated anaemia: commonly a combination of iron deficiency and anaemia of chronic disease. Using transferrin saturation levels to monitor iron replacement, it is suggested that iron administration may be continued up to a limit of 50% transferrin saturation. International guidelines indicate that the intravenous route for iron replacement is preferred as it is considered more effective, better tolerated and improves quality of life when compared to oral iron replacement. High doses of iron have been shown to overcome the hepcidin-mediated block of iron absorption witnessed in the anaemia of chronic disease, in addition to the blocked mobilisation of iron stores. Success with intravenous iron alone can produce improvement in 70-80% of patients with anaemia of chronic disease.
During pregnancy, serum ferritin levels produce an accurate and reproducible measurement of iron deficiency. Quality of life issues are affected by anaemia during pregnancy. The management of ID in the antenatal period can be effected using intravenous iron, which optimises the haemoglobin levels prior to delivery, with the aim of reducing the risk of haemorrhage and the need for blood transfusions. Furthermore, as the transfer of iron from the mother to
the foetus occurs mainly in the four weeks prior to delivery, IV iron supplementation offers a means of correcting maternal ID late in pregnancy, benefiting the mother and reducing the likelihood of future neonatal ID and IDA. HDIT may be required, as studies have shown that there may be a considerable iron deficit of up to 1600mg7 during pregnancy. HDIT is 100% reliable in delivering this treatment, whereas oral iron replacement has extremely poor compliance, often achieving suboptimal outcomes despite multiple clinical interventions.
4.Heavy uterine bleeding.
Heavy cyclical menstrual bleeding, with the loss of 80ml or more of blood per cycle, may produce an iron deficit of between 1000 and 1500mg of iron annually. Two studies have shown the effectiveness of intravenous iron, but in the study by Van Wyck et al9, patients treated with HDIT reported greater gains in vitality, physical function and improved symptoms of fatigue. HDIT appears to be highly effective in correcting iron deficiency and iron deficiency anaemia in women with menorrhagia.
5. Anaemia associated with cancer and its treatment.
EPO plus intravenous iron can be used to address anaemia caused by cancer treatment and can replace the use of blood transfusions. This area is complex, particularly with fears about possible cancer progression: whether suspected as due to EPO or the haemoglobin level itself. However, guidelines from the European Organisation for Research and Treatment of Cancer (EORTC) recognise that treating anaemia in cancer patients improves their quality of life and reduces the requirement for emergency blood transfusions. It is now recognised as a measure that can produce temporary symptom relief. Studies have used both HDIT alone or in combination with EPO, and showed improvement in the majority of patients treated.
Health economics and benefits
The main therapeutic advantage of HDIT is the improvement in haemoglobin level, witnessed in conditions where atemporary or regular transfusion would be necessary. A recently published cost-minimisation study of iron isomaltoside 1000 and ferric carboxymaltose identified comparative costs and cost savings when these high-dose iron therapies were substituted for blood transfusion.11 Cost elements such as nursing time, drug costs and transportation were included. Although blood is, in some countries, not charged to the local health organisation, it was felt that there was a cost to the health economy and therefore the costs used in this modelling were those charged in England and Wales for 2009/10. The results indicate that the HDIT offered cost savings at three dose levels and across a range of sensitivities when compared to blood and iron sucrose, which are considered to be the current standard of care.
The inadequate treatment of patients presenting with iron deficiency has been recognised in the UK. Much attention has been given to their diagnosis, and pathways abound. However, the responsibility for iron therapy often falls between primary and secondary care, and monitoring of patients to check compliance and adequate response to treatment is non-standardised. Many such patients require treatment with a therapeutic endpoint in sight, either an operation or another intervention requiring optimisation of the haemoglobin level. There are now several models of ‘anaemia clinic’ in the UK, where HDIT is routinely used to ensure adequate iron replacement, therefore allowing the patient to be in optimal condition prior to the planned intervention. The business case for such a clinical service is complex, as additional unit staff costs, location of the service (and associated capital costs), and drug costs suggest an additional expense; whereas, cash-releasing benefits are often spread across a variety of other budgets. Cancelled operations, ‘emergency’ blood transfusions and delays in patient pathways (for example, late diagnosis of cancers) all have their associated costs which, if reduced or eliminated, increase the likelihood of shifting the balance to a cost-saving from anaemia clinics.
What is the potential for HDIT?
Although there are few reliable figures,
it is generally believed that compliance with oral iron therapy is poor. In the patient this will present as a suboptimal anticipated rise in haemoglobin level, and a delay in reaching optimal haemoglobin level.
Where the anaemia is of primary concern then such delays may be encompassed through several clinical visits and blood tests. However, where IDA is found in a patient on a pathway for some intervention, it is reasonable to ensure adequate and complete treatment of their iron deficit through HDIT. There are several situations in which the use of HDIT might be used:
- Intolerance or non-compliance to oral iron preparations
- Lack of effect of oral iron therapy
- Malabsorption of oral iron (for example, due to gastrointestinal disease or surgery)
- When the chronic iron loss exceeds the rate of replacement possible with oral iron
- When there is a clinical need for rapid delivery of iron to iron stores (for example, post-operative and post-partum patients or in cases of autologous blood donation)
- Functional or absolute iron deficiency in connection with erythropoietin therapy
The reliability of HDIT in restoring optimal iron status makes this therapy ideal in the above situations and is likely to provoke interest in clinicians, managers and health economists alike