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Wednesday 20 March 2019
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Chronic kidney disease: A pathway to administer intravenous iron

Michelle Cooke RGN BSc (Hons)
Sunil Bhandari MBChB FRCP PhD MClin Edu
Hull And East Yorkshire Hospitals NHS Trust, Hull York Medical School, Kingston-upon-Hull, UK
There are currently approximately 15 million people in England with a long-term condition and this accounts for 70% of the NHS health and care spend. Many of these patients will have iron-deficiency anaemia (IDA). Despite the recommendations from NHS Blood and Transplant policies, many patients with chronic IDA continue to receive a blood transfusion without evidence of acute blood loss. Blood continues to be a declining resource and the safety issues involved with administering blood have improved greatly over the years, but it still has established risks to patients and has a substantial financial burden to the NHS.(1) 
Many strategies have emerged to reduce the risk of contamination of blood products, which have reduced the number of potential suitable donors, which in turn has reduced the availability of blood.(2) The National Blood Transfusion Service has encouraged the conservation and appropriate use of blood and blood products. This has resulted in NHS hospitals implementing policies restricting the use of blood products to enable practitioners to minimise risks to patients at both the administration and cross-matching stages while also preserving a valuable resource. This has coincided with a growing understanding of the clinical effects and importance of IDA in chronic diseases. These studies have demonstrated a direct link between IDA and both mortality and quality of life.(3) 
Indeed, in several clinical situations, correction of IDA can bring about improvements in symptoms and exercise tolerance for example: chronic kidney disease with or without erythropoietin-stimulating agents (ESAs); haematology; elderly population; gynaecology/pregnancy; cardiology; oncology/ chemotherapy; post-operatively; inflammatory bowel disease; chronic heart failure; IDA associated with chronic conditions.
In these conditions, iron repletion allows erythropoiesis to occur which improves haemoglobin (Hb) and oxygen-carrying potential. Anaemias of chronic diseases, such as rheumatoid arthritis, are difficult to treat with oral iron, owing to the inflammatory effects resulting in increased levels of the regulatory protein hepcidin, which acts on the ferroportin transporter both block absorption via the gastrointestinal tract and mobilisation of stored iron. Use of IV iron potentially obviates the need to rely on this pathway. 
Oral iron is also often insufficient to replete iron stores owing to its poor bioavailability and associated poor compliance among patients. Therefore continuation of oral iron therapy for a prolonged period is often a false economy because of poor clinical gains and patient benefits. IV iron overcomes this reduced ability to absorb iron. A total dose infusion of 1g of parenteral iron can lead to an average improvement in Hb concentrations of 0.6–2.7 g/dl.(4) 
The chronic kidney population (CKD) has a high incidence of IDA. It has been estimated that around 68% of the CKD Stage 3b population referred to a nephrologist for the first time are biochemically anaemic, with 61% having absolute (depleted iron stores) or functional (depleted available circulating iron) iron deficiency. Decline in renal function has a direct correlation with reduced Hb. Thirty per cent of patients with an estimated glomerular filtration rate (eGFR) <30ml/min/1.73m2 have a Hb of <12g/dl (males and post-menopausal women) or <11g/dl (pre-menopausal).(5) The Renal National Service Framework and Renal Association best practice guidelines advocate correction of anaemia(6) and the National Institute for Health and Clinical Excellence guidelines(7) suggest that correction of IDA is beneficial to CKD patients before commencing ESAs. This is especially relevant, with the increasing emerging concerns of stroke, thrombosis and cancer with use of ESAs.(8) 
Iron repletion has become an important treatment intervention for patients with CKD. This has resulted in the development of a comprehensive IV iron pathway for patients locally. The region (North Yorkshire, Humberside and Lincolnshire) undertakes approximately 500 treatments of parenteral iron therapy each year to non-haemodialysis CKD patients as outpatients and approximately 1000 IV iron treatments to haemodialysis patients during dialysis sessions. The number of non-acute blood loss transfusions given by the renal unit is therefore minimised. The challenge to services is developing a process that will deliver a cost-effective IV iron service to a large geographical area while providing patients flexibility in time and venue. 
The current available pharmacological preparations have been evaluated to assess safety, efficacy, risk and cost effectiveness. Comparative data on the safety and efficacy of established IV irons – iron sucrose (Venofer®) and iron dextran (Cosmofer®) – is available.(9) Venofer has the disadvantage of requiring multiple visits to replete iron while a test dose and potentially lengthy (three hours) administration time for Cosmofer even after accelerated dosing makes it a less than optimal preparation.(10,11) The recent introduction of the two novel iron preparations – ferric carboxymaltose (Ferinject®) and iron isomaltoside (Monofer®) – provides greater choice as neither of these preparations requires a test dose and each has the advantage of being given rapidly in less than one hour in sufficient repletion doses. 
The increased flexibility of being able to offer a total repletion iron infusion dose in less than one hour has allowed services to look at new ways of working. Both of these preparations comprise a carbohydrate complex, that either completely surrounds the iron core (Ferinject) or is enmeshed in the iron forming a matrix (Monofer), which in both cases allows a more gradual release of iron into the circulation. This ensures only minimal quantities of catalytic iron are released from their carbohydrate shell/matrix, preventing the risk of potential anaphylactoid reactions and reducing adverse drug events that rarely occur with the other older IV iron preparations. When planning a strategy for managing IV iron services it might be beneficial to have the ability to extend the venues to treat patients to the community environment, thereby allowing patient choice and convenience.(12) 
Affordability, sustainability and quality are key issues for the NHS; the review of the renal IV iron service has, for example, allowed the development and delivery of a service to meet the needs of patients in a large geographical area. Research with patients receiving IV iron therapy in the hospital found that issues such as transport, car parking, time off from work and carer commitments made a hospital appointment difficult to manage and costly in terms of both time and money.(12) Redevelopment of the pathway for the delivery of iron therapy, recognising patients' needs, to benefit both patients and the organisation without adverse consequences, has incorporated the use of novel IV iron preparations given in one hour in a community setting. This will afford patients the opportunity to receive a treatment in a reduced time period and in a community health centre near to their home. 
Working in partnership with primary care has enabled the formulation of a pathway for patients to receive IV iron as near to home as possible, thereby ensuring patients receive high-quality care and timely interventions while limiting the impact on their work and family life through reduced visits to hospital setting and reduced treatment times. This has also resulted in a cost reduction to the NHS, with a reduction in tariff for commissioners of the service saving up to £180 per patient treatment episode. A comparative analysis of the pharmacoeconomic aspects of the available irons on the market shows that the increased cost of the novel irons ferric carboxymaltose (Ferinject) and iron isomaltoside (Monofer) are compensated by the increased thoroughfare in patients and reduced nursing time to administer therapy. A recent review of each iron product available compared the cost of administrating the two novel IV iron molecules against the cost of administrating a blood transfusion. 
The cost module included transportation, nursing and equipment costs.(13,14) In most instances, blood transfusions would have been traditionally the treatment of choice with IV iron used predominately within the haemodialysis population; this has progressively begun to change, with IV iron been used in more and more specialties. Within the renal specialty, the use of ESAs has been progressively more discerning, owing to concerns over use, so IV iron has become a standard treatment option for renal patients with IDA. This has enabled the service to make the pharmacoeconomic comparison. A large proportion of patients attending for IV iron require hospital transport, and, in the comparison shown, the authors assume 20% of patients attending for treatments will require help with mobility. These comparative analyses have demonstrated economic benefits that could be realised by modification of service delivery.
IDA is common in long-term chronic conditions. The risks of blood transfusions are well documented and the reduction in the numbers of appropriate donors has made blood both a more expensive and precious commodity, requiring use in only essential clinical situations. Providing a comprehensive IV iron service is suggested as a means of treating patients cost effectively and conveniently in locations near to home. The availability of several novel IV iron preparations provides flexible alternatives to patients in terms of choice of venue and time scale of treatment. The proposed pathway discussed in this article can be demonstrated to be cost-effective to services despite offering patients this flexible choice of service. 
Once established within the renal population it can be utilised and expanded to serve any specialty requiring IV iron therapy (for example, gastroenterology) and can provide a universal iron repletion service, thus reducing the need for blood transfusion in non-acute blood loss and preventing unnecessary visits to hospital. The potential economic gain to healthcare providers is huge, in addition to the benefits to patient quality of life.
  1. Rawn J. The silent risks of blood transfusions.Current Opin Anaesthesiol 2008;21(5):664–8. 
  2. Department of Health. Better blood transfusion: Safe and appropriate use of blood. Health Service Circular HSC 2007/001. London;DH:2007.
  3. Musallam K et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery : a retrospective cohort study. Lancet 2011;378:1396–407.
  4. Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. Am J Hematol 2008;83:580–8.
  5. de Silva R et al. Anemia, renal dysfunction, and their interaction in patients chronic heart failure. Am J Cardiol 2006;98(3):391–8.  
  6. Department of Health. The Renal National Service Framework. London;DH:2004.
  7. National Institute for Health and Clinical Excellence. Anaemia management in people with chronic kidney disease (CKD). Clinical guidance CG114;2011.
  8. Pfeffer MA et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019–32.
  9. Moniem KA, Bhandari S. Tolerability and efficacy of parenteral iron therapy in patients a comparison of two preparations. Transfusion Alternatives in Transfusion Medicine 2007;9(1):37–42.
  10. Sinha S et al. Accelerated total dose infusion of low molecular weight iron dextran is safe and efficacious in chronic kidney disease patients. Quart J Med 2011;104(3):221–30. 
  11. Cooke M et al. Efficacy and tolerability of accellerated dose low molecular weight iron dextran (Cosmofer) in patients with chronic kidney disease. Am J Nephrol 2012;35:69–74.
  12. Bhandari S, Naudeer S. Improving efficiency and value in health care. Intravenous iron management for anaemia associated with chronic kidney disease: linking treatment to an outpatient clinic, optimizing service provision and patient choice. J Eval Clin Pract 2008;14:996–1001.
  13. Bhandari S. A hospital-based cost minimization study of the potential financial impact on the UK health care system of introduction of iron isomaltoside 1000. Ther Clin Risk Manag 2011;7:1–11.
  14. Bhandari S. A comparative analysis following the introduction of newly available IV iron therapies to hospital practice. Ther Clin Risk Manage 2011,7:501–5.

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