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Vol. 22, No. , 2006, 731–737
doi:10.1185/030079906X100096
All rights reserved: reproduction in whole or part not permitted recommendationsIvor Cavill a, Michael Auerbach b, George R. Bailie c, Peter Barrett-Lee d, Yves Beguin e, Peter Kaltwasser f, Tim Littlewood g, Iain C Macdougall h and Keith Wilson ia Medical School, Cardiff University, UKb Georgetown University School of Medicine, Washington DC, USAc Albany College of Pharmacy, Albany, New York, USAd Velindre Cancer Centre, Cardiff, UKe University of Liège, Belgiumf J. W. Goethe Universität, Frankfurt am Main, Germanyg John Radcliffe Hospital, Oxford, UKh King’s College Hospital, London, UKi Welsh Blood Service, Cardiff, UK Address for correspondence:  Dr Ivor Cavill, Department of Haematology, Cardiff University School of 
Medicine, Heath Park, Cardiff, CF4 4XW. Tel./Fax: +44 1291 641615; email: icavill@ukanaemia.co.uk
Key words:  Anaemia – Chronic disease – Erythropoiesis – Iron
Background: The incidence of anaemia is high in process is common to all chronic anaemias. The many chronic conditions, yet it often receives little aim of anaemia management should be to restore patient functionality and quality of life by restoring Scope/methods: A panel of international experts effective red cell production. Blood transfusion can with experience in haematology, nephrology, elevate haemoglobin concentration in the short term but does nothing to address the underlying convened to prepare strategic guidelines. A disorder; red cell transfusion is, therefore, not focused literature search was conducted after an appropriate treatment for chronic anaemia. key issues had been identified. A series of Patients with anaemia of chronic disease may recommendations was agreed, backed, wherever benefit from iron therapy and/or erythropoiesis possible, by published evidence which is included stimulating agents (ESAs). Intravenous iron should be considered since this can be given Recommendations: Anaemia is a critical issue safely to patients with chronic diseases while for patients with chronic diseases. Healthcare intramuscular iron causes unacceptable adverse professionals need to recognise that anaemia effects and oral iron has limited efficacy in is a frequent companion of cancer and chronic conditions such as rheumatoid arthritis and heart Conclusion: The management of anaemia failure. It reduces patients’ quality of life and can calls for the development of a specialist service increase morbidity and mortality. Anaemia should together with education of all healthcare be considered as a disordered process in which professionals and transfer of skills from areas of the rate of red cell production fails to match the good practice. Improvement in the management rate of destruction which leads eventually to a of anaemia requires a fundamental change of reduction in haemoglobin concentration; this attitude from healthcare professionals.
Introduction
answered. In developing the recommendations it was therefore necessary to extrapolate findings between Anaemia is common in patients with chronic condi­ different patient groups since the bulk of current tions of inflammation, infection or malignancy. Despite knowledge stems from the experience of the use of being the commonest side effect of cancer and cancer erythropoietic and iron therapies in renal medicine. chemotherapy, and often having a profound effect on The recommendations are, therefore, evidence­based patients’ quality of life, anaemia remains an orphan as far as possible but, when evidence is lacking, they are issue. While lip service is paid by many clinicians to based on clinical experience. The underlying evidence the importance of anaemia, it is often overlooked and is presented in the discussion/annotations section.
undertreated. UK Anaemia called a meeting of experts from Europe and the United States of America with experience in haematology, nephrology, oncology, Discussion and annotations
rheumatology and pharmacy to address these issues in 1.  Anaemia is a critical issue for patients,  May 2005. The aim was to develop recommendations especially those with chronic diseases.  on the approach to, and the management of, anaemia It can reduce patients’ quality of life and  based on published evidence and practical experience.
increase morbidity and mortality The recommendations from the meeting take the • Anaemia can significantly impair quality of life form of a broad strategy. This should form the basis and is associated with increased morbidity and for more specific and detailed treatment guidelines mortality1,2. In cancer patients, fatigue has a which can be developed to meet the needs of different specialties and regions. Therapies are discussed greater impact on daily life than pain3.
generically, as the availability of treatments and Anaemia and its associated symptoms affect not diagnostic techniques vary between countries.
only patients with chronic diseases but also those A focused literature search was performed after caring for and living with them. A study from the key issues had been identified. Publications were United States has shown that cancer patients with identified from Medline and from the reference lists anaemia require more care than those without of retrieved documents in addition to those identified anaemia and this has a direct impact on their by panel members. However, it became clear that the evidence base is incomplete and that many important • Untreated anaemia can affect economic product­ questions about anaemia have not been raised, let alone ivity, which will also affect patients’ families5,6.
Key Issues and Strategic Recommendations
• Anaemia is a critical issue for patients, especially those with chronic diseases. It can reduce patients’ quality of life and increase morbidity and mortality.
• Anaemia is a frequent companion of cancer and chronic conditions such as rheumatoid arthritis.
• Healthcare professionals too often accept anaemia and its consequences with equanimity – it is the patient • There is a need to raise awareness of anaemia, its detection, investigation and management among healthcare professionals who treat patients with chronic diseases.
• Anaemia should be considered as a disordered process in which the rate of red cell production fails to match the rate of destruction, which eventually leads to a reduction in haemoglobin concentration – whatever the causation. This process is common to all chronic anaemias.
• The aim of anaemia management should be to restore patient functionality and quality of life, and to reduce morbidity and mortality, by restoring effective red cell production.
• Blood transfusion can elevate haemoglobin concentration in the short term but does nothing to address the underlying disorder. Red cell transfusion is not an appropriate treatment for chronic anaemia.
• Patients with anaemia of chronic disease may benefit from iron therapy and/or erythropoiesis stimulating • Oral iron causes side­effects, is associated with drug–drug interactions, and has limited efficacy in chronic • Intramuscular iron is associated with unacceptable adverse effects and should not be given.
• Intravenous (iv) iron can be given safely to patients with chronic diseases.
• The management of anaemia calls for the development of a specialist service, education of all healthcare professionals and transfer of skills from areas of good practice.
732 Iron and the anaemia of chronic disease: a review and strategic recommendations 2006 LIBRAPhARM LTd – Curr Med Res Opin 2006; 22() • People with anaemia may not have access to • A survey in the United States found that anaemia information about their condition and may, there­ prevalence increased with age and that more than fore, be unaware of the treatment possibilities.
20% of those aged over 85 years were anaemic18.
• The long­term and widespread under­treatment • Patients with chronic infection, inflammation or of chemotherapy­induced anaemia may have malignancy may also be prone to anaemia because contributed to the misconception that anaemia of poor dietary intake and poor absorption of is an unavoidable consequence of cancer and its • Until recently there have been no organisations 3. Healthcare professionals too often accept  representing people with anaemia. This contrasts anaemia and its consequences with equa­ with the rise of successful advocacy groups such nimity – it is the patient who pays the price as those for breast cancer which have lobbied • Clinicians often underestimate the effects of anaemia effectively for better and more patient­centred care.
on patients. However, studies have shown that cancer • The World Health Organization estimates that patients are often more concerned by fatigue than by ‘as many as 4–5 billion people, 66–80% of the world’s population, may be iron deficient; 2 billion people – over 30% of the world’s population – are anaemic’ 4.  There is a need to raise awareness of  anaemia, its detection, investigation and  management among healthcare profession­ 2.  Anaemia is a frequent companion of  als who treat patients with chronic diseases cancer and chronic conditions such as  • In the assessment of anaemia, many clinicians rely on one or two measurements taken from the • The recent European Cancer Anaemia Survey blood count and chemistry. The selection of these (ECAS), which involved over 15 000 patients in measurements is often determined by history and 24 countries, found that about 40% of adult cancer patients had haemoglobin (Hb) concentration • Haemoglobin concentration is the key measure­ < 12 g/dL at the start of the survey. The incidence ment, but it is a late reflection of the anaemic of anaemia rose to around 60% over the course of process, and in some circumstances, chiefly the survey9. A literature review has suggested that pregnancy, may not reflect changes in the red cell 30–90% of patients with cancer are anaemic10.
mass. In some cultures, the haematocrit is used as • Similarly, a Dutch study has found that about a surrogate for measuring Hb concentration.
60% of patients with rheumatoid arthritis (RA) • The productivity of the erythroid marrow can be assessed reliably using the reticulocyte count. • Long­term use of non­steroidal anti­inflammatory The reticulocyte percentage can give an inverse drugs (NSAIDs) can cause gastrointestinal blood reflection of red cell life span (when it is > 2.5% loss resulting in iron­deficiency anaemia13.
• Patients with chronic inflammatory conditions • The adequacy of iron supply to the developing such as RA may also have inflammation­related erythron can be assessed from a variety of parameters, the most direct of which is the MCH • Renal impairment can cause anaemia; Hb concen­ (mean cell Hb). This is available as part of every trations are correlated with the glomerular filtration full (complete) blood count but is rarely used. rate. The incidence of anaemia is relatively low MCH is, however, a late reflection of the adequacy in people with mild renal impairment but rises of iron supply. Mean cell volume (MCV) may to over 90% in those receiving dialysis (if left mirror changes in MCH but can be confounded untreated) and is independently associated with by a variety of factors. A more immediate measure of iron supply is provided by the reticulocyte Hb • Anaemia can be both a cause and a consequence content while the percentage of hypochromic red of chronic heart failure (CHF) and can exacerbate cells offers an intermediate assessment (where symptoms of breathlessness and fatigue15. Falling haemoglobin concentrations in patients with CHF • The adequacy of iron in reticuloendothelial iron have been associated with increased morbidity ‘stores’ can be assessed by measuring serum ferritin levels, but again there are a number of • In patients with HIV, anaemia is a predictor confounding factors. Ferritin is an acute phase of progression to AIDS and is independently reactant so this measure may be unreliable in associated with an increased risk of death17.
sick patients. Moreover, the presence of iron in 2006 LIBRAPhARM LTd – Curr Med Res Opin 2006; 22() Iron and the anaemia of chronic disease: a review and strategic recommendations Cavill et al. 733 these ‘stores’ does not mean it is available for 6.  The aim of anaemia management   erythropoiesis. The flow of iron from these ‘stores’ should be to restore patient functionality  to the marrow may be assessed by measurement and quality of life, and to reduce morbidity  of serum iron and Total Iron Binding Capacity and mortality, by restoring effective red cell  (TIBC) but this measurement is biologically labile • Several studies in patients with cancer, renal • In some circumstances, it may be appropriate to failure or inflammatory diseases have shown assess the stimulus to the marrow by measuring a correlation between correcting anaemia and serum EPO or the degree of erythroid inhibition by an indicator of inflammation such as erythrocyte • Anaemia is often diagnosed and treated by sedimentation rate (ESR) or C­reactive protein reference to the Hb concentration, but this is not directly related to what patients feel. Clinicians should, therefore, concentrate on preventing 5.  Anaemia should be considered as a  and alleviating the associated symptoms such as disordered process in which the rate of  fatigue and breathlessness which can markedly red cell production fails to match the rate  impair functionality and lead to a vicious spiral of of destruction which eventually leads to a  reduced physical and social activity.
reduction in haemoglobin concentration  – whatever the causation. This process is  7.  Blood transfusion can elevate  common to all chronic anaemias haemoglobin concentration in the short term  • The red cell mass is maintained at a constant level but does nothing to address the underlying  by the balance of red cell production and destruc­ disorder. Red cell transfusion is not an  tion. Changes in this balance will be manifest appropriate treatment for chronic anaemia as a change in Hb concentration. However, the • Transfusion of allogeneic blood or blood products relatively slow turnover of mature red cells means is a logical approach to acute situations of blood that this process has a high degree of inertia and a loss such as trauma or surgery when patients fall in Hb concentration is a very late reflection of require haemodynamic support. However, in cases of chronic inflammation, infection or malignancy, • The making of red cells and the control of red cell or when anaemia is caused iatrogenically by production is fundamentally the same whatever myelosuppression, the administration of blood or the condition. In chronic conditions associated with blood products has no effect on the disordered infection, inflammation and malignancy, erythro­ process and is, therefore, inappropriate.
poiesis will be suppressed by a common process • The benefits of red blood cell transfusions have involving the inflammatory cytokines. These counter never been properly assessed, and their legendary the pro­erythropoietic activity of erythropoietin20.
life­saving properties have never been tested. A low Hb concentration is a consequence of a Indeed, some studies have shown that transfusion disordered erythropoietic process. Anaemia may is associated with a poorer prognosis in cancer be predicted from measures of erythropoietic activity by the reticulocyte count before Hb • Clinical trials in which anaemic patients were concentrations reach traditional levels at which randomised to receive an ESA or standard • A low reticulocyte count (e.g. < 30 × 109/L), or treatment (the control group) which consisted falling Hb concentration should, therefore, be of blood transfusion have shown significant the stimulus to correct the disorder and prevent differences in quality of life between the ESA and control group. Patients in the control group • Use of erythropoiesis stimulating agents (ESAs) received significantly more blood transfusions without adequate iron support can create a than those receiving an ESA yet tended to have a Functional Iron Deficiency (FID) in which, although total iron storage levels may be normal, insufficient • Clinical experience also suggests that transfusion­ iron is transported to the bone marrow to support dependent patients may have a poor quality of erythropoiesis22. FID is suggested by MCH < 28, life despite maintaining Hb concentrations at reticulocyte Hb content < 29, hypochromic red acceptable levels. This contrasts with patients cells > 5–10%; the transferrin saturation may be treated with ESAs supported with intravenous < 20%. Measurement of serum ferritin alone cannot (iv) iron who often experience a noticeable indicate FID, since this can occur when the serum improvement in quality of life almost immediately ferritin concentration is normal or even high.
after starting treatment for their anaemia.
734 Iron and the anaemia of chronic disease: a review and strategic recommendations 2006 LIBRAPhARM LTd – Curr Med Res Opin 2006; 22() 8.  Patients with anaemia of chronic disease  a significantly different response from those may benefit from iron therapy and/or  receiving no iron in terms of Hb and ferritin erythropoiesis stimulating agents (ESAs) • A number of ESAs have now been licensed for • Oral iron has several disadvantages including poor use in various countries, including darbepoetin compliance and a high incidence of adverse gastro­ intestinal effects (nausea, vomiting, constipation, erythropoietin. The range of iv iron preparations bloating and bleeding) and a high potential for available to clinicians has also increased recently with the introduction of iron sucrose and sodium • Oral iron should, therefore, be avoided.
ferric gluconate in addition to iron dextran.
• In most countries, ESAs are used most extensively 10.  Intramuscular (im) iron is associated with  in renal dialysis patients, although their use in unacceptable adverse effects and should  oncology is increasing, especially in patients receiving myelosuppressive chemotherapy28. The • Intramuscular iron is no more effective than iv iron experience built up in renal units, including the but is painful to deliver and may cause staining optimisation of ESA therapy by the use of iv iron, of the injection site and has been associated with should be transferred to other specialties. However, specific clinical trials should be performed in a number of chronic conditions for confirmation and 11.  Intravenous (iv) iron can be given safely  to determine special considerations for different to patients with chronic diseases populations. Similarly, the different ESAs and iron preparations should be compared systematically to • Data from over 32 000 haemodialysis patients determine the best and most cost­effective treatment in the United States have shown no association between all­cause mortality and cumulative • A study of 30 patients with rheumatoid arthritis and Hb < 12 g/dL (for women) or < 13 g/dL (for men) • A French study of over 6000 patient­months showed benefits of treatment with an ESA and iv of haemodialysis found no association between iron in terms of the proportion of hypochromic total dose of iv iron, or ferritin levels, and risk of red blood cells, serum ferritin concentration and quality of life (SF­36 measure of vitality)30.
• Serious adverse reactions to all iv iron preparations • The effectiveness of ESA treatment is enhanced by are rare44. Two studies have suggested that the co­administration of iv iron. Use of iv iron can anaphylactic reactions with iron dextran occur accelerate or increase the response to the ESA31–34.
with 0.6–0.7% of doses33,41. Another study reported • Use of iv iron may reduce the dose of ESA lower rates of adverse events associated with low required to achieve a given response34.
molecular weight iron dextran than with high • In some cases, use of iv iron alone (i.e. without an ESA) can provide substantial improvements35–37.
• A recent analysis suggests rates of anaphylaxis • Other adjuncts to ESAs (e.g. vitamin C, vitamin E, of around three per million doses with iv iron androgens, carnitine, pentoxifylline and statins) have dextran and less than one per million doses of iron not consistently been shown to be useful, or have been shown to pose an unacceptable risk of adverse • The real clinical consequences of oxidative stress effects, and are, therefore, not recommended38.
associated with free iron release after iv admin­istration have not been determined.
9.  Oral iron causes side­effects, is  • Use of iv iron was traditionally avoided in RA associated with drug–drug interactions, and  because of concerns about disease flares. However, has limited efficacy in chronic anaemia a more recent study has shown that not only may • In one study of 155 cancer patients (whose iv iron be given safely to people with RA, but its compliance with oral iron treatment was carefully use, in combination with ESAs, is associated with monitored), the increase in Hb concentration a reduction in disease activity score30.
in those receiving oral iron and an ESA was not • IV iron should not be given to patients with active significantly different from those who received no iron, whereas those receiving iv iron plus an ESA • Animal studies using very high doses have experienced a significant increase in Hb31.
suggested that iron may promote tumour growth • In another study of dialysis patients receiving but these findings have not been reflected in an ESA, those receiving oral iron did not have clinical experience and probably do not apply 2006 LIBRAPhARM LTd – Curr Med Res Opin 2006; 22() Iron and the anaemia of chronic disease: a review and strategic recommendations Cavill et al. 735 to patients with normal levels of transferrin Acknowledgements
saturation. They may also not be relevant to the doses of iv iron given in normal clinical practice47. Funding for the expert meeting and the preparation However, caution should be exercised in patients of this publication were provided by UK Anaemia, with high transferrin saturation (above 50%) since a registered charity that aims to provide a scientific use of iv iron in this population may, theoretically, and clinical resource for healthcare professionals. Liz be associated with enhanced tumour growth or Wager (of Sideview) provided editorial assistance and unwanted effects such as increased cardiotoxicity David Larder (of STAC Consultancy) provided logistic • Bone marrow and tumour cells may compete for available iron. However, in patients with normal levels of transferrin saturation nearly all the iron from a therapeutic dose will be taken up Michael Auerbach has acted as a consultant for Watson by the bone marrow cells since their transferrin Pharmaceutical. George R. Bailie has been a consultant receptors are much more numerous, and have a for American Regent, Inc. and Vifor International greater affinity for iron, than those present on and has received honoraria from Amgen, Inc. He is a tumour cells. In addition, exposure of tumour member of the Advisory Board for NKF’s K/DOQI cells to excess transferrin iron will be short­lived and is a member of the workgroup for the K/DOQI because it will be rapidly quarantined in the Anaemia Clinical Practice Guidelines. Peter Barrett­Lee has taken part in advisory boards and received honoraria from Amgen and Roche, and received research funding 12.  The management of anaemia calls for  from Roche. Yves Beguin has been on advisory boards the development of a specialist service,  for Amgen, Roche and Vifor. Ivor Cavill has acted as a education of all healthcare professionals and  consultant for Vifor International and Syner­Med and has transfer of skills from areas of good practice received honoraria for speaking from American Regent, • Following the recognition of the high prevalence Amgen UK, Roche Pharmaceutical Products and Ortho of anaemia in patients undergoing dialysis, manage­ Biotech (Janssen­Cilag). His position at the University of Cardiff is supported by UK Anaemia. J. P. Kaltwasser ment is currently coordinated best in renal has taken part in an advisory board for Amgen and medicine. According to international clinical prac­ received recombinant human erythropoietin (Recormon) tice guidelines, patients receiving dialysis now from Boehringer Mannheim (now part of Roche) for a receive treatment with ESAs and iv iron2. However, clinical trial. Tim Littlewood has acted as a consultant in other specialties, training and experience in these for Amgen, Ortho Biotech and Roche. Iain Macdougall therapies may be lacking and anaemia management has acted as a consultant for Affymax Ltd, Amgen UK, is ill coordinated. The increasing specialisation Roche Pharmaceutical Products and Ortho Biotech within haematology has resulted in advances in the treatment of leukaemia but a decline in the treatment of anaemia49. The development of nurse consultants in anaemia (in the UK) serving a wide References
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ASH Newsletter 2005;2:2 CrossRef links are available in the online published version of this paper: Paper CMRO­3323_3, Accepted for publication: 22 February 2006 2006 LIBRAPhARM LTd – Curr Med Res Opin 2006; 22() Iron and the anaemia of chronic disease: a review and strategic recommendations Cavill et al. 737

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