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Mr Ivan J Nunez-Gil
Mr Juan Roberto Peraira-Moral
Intravenous iron has emerged as a well tolerated and effective therapy to improve symptoms and quality of life in both anaemic and non-anaemic heart failure patients with iron deficiency. Iron deficiency can be easily detected with simple laboratory tests.
Anaemia, although common in heart failure patients, reduces functional status, quality of life and is an independent risk factor for hospital admissions and mortality (1,2). Intravenous iron therapy benefits these patients and provides cardiologists with a means for more accurate management. Prevalence of anaemia in heart failure (HF) patients depending on the defining criteria that is used, ranges from 7 to over 50% (3). Indeed, the World Health Organisation holds a haemoglobin (Hb) concentration under 13 g/dl in men and 12 g/dl in women as aneamia whereas the National Kidney Foundation defines anaemia as Hb < 12 g/dl in men and postmenopausal women. Anaemia is always more frequent in older patients, advanced HF, chronic renal failure, in females and African-Americans (3) - regardless or whether heart failure is systolic or diastolic. Multiple mechanisms have been identified as causes (Fig. 1) (4). Iron deficiency (ID) appears most important, followed by gastrointestinal absorption, increased macrophage iron storage and gastrointestinal bleeding. These factors may contribute to ID and ultimately, lead to anaemia.
Figure 1: Causes and mechanisms of anaemia in heart failure. Figure legend: ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker, ASA: acetylsalicylic acid, EPO: epoetin.
Routine diagnostic evaluation (1,5) includes:
Red blood cell distribution width is a numerical measure of the variability in the size of circulating erythrocytes, taken during a standard blood count test. Ineffective erythropoiesis causes heterogeneity in erythrocytes size and a higher RDW. RDW has recently emerged as a new prognostic marker of HF, regardless of Hb levels (6). Table 1: Most common laboratory findings suggesting iron deficiency anaemia (7)
Laboratory parameter / Result
Haemoglobin : < 13 g/dl (men)
Hematocrite : < 12 g/dl (women)
< 31-32 %
Mean corpuscular volume: -
Mean corpuscular hemoglobin : -
RBW : > 14 %
Serum iron concentration : -
Transferrin saturation : < 10-15%
Ferritin concentration : < 100 ng/ml 100-300 ng/ml and transferrin saturation < 20%
¯: decreased, RDW: red blood cell distribution width
Many studies have shown anaemia to increase mortality and morbidity in HF patients (1, 5, 8, 9) and to cause the following:
Current HF guidelines (1,2) have not fully established specific routine treatment. Blood transfusion is useful in critically ill patients with chronic cardiac disease and Hb less than 7 g/dl (10). However, blood transfusion is not recommended as long-term therapy because of associated risks, such as infection, HLA sensibilisation and iron overload (11). As figure 1 shows, impaired erythropoiesis is one of the mechanisms of anaemia in HF. Erythropoietin-stimulating agents (ESA) have been studied in the past decade in combined heart failure and anemia patients and it was found that ESA are associated with a reduction in HF hospitalisations and improvement in exercise tolerance, quality of life, brain-natriuretic peptide levels and left ventricular ejection fraction (12). Recently, intravenous iron therapy has been successfully incorporated into management of patients with HF, as well. Oral iron formulation are used for ID treatment. Nevertheless, poor absortion and gastrointestinal intolerance are common. Intravenous iron preparations used in these patients mainly are 1) iron sucrose (alone or combined with ESA) and 2) iron carboxymaltose.
Two studies showed improvement in Hb level, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score and 6-minute walk test distance (13, 14). In the very recent FERRIC-HF trial (15), 35 HF patients (NYHA class II or III) with ID treated with iron sucrose (200 mg weekly until ferritin > 500 ng/ml, 200 mg monthly thereafter) improved their exercise capacity and symptom status. These benefits were more evident in anaemic patients. Intravenous iron sucrose can be administered either as slow injection (over 10 minutes) or by infusion (11). Total iron dose required for iron repletion is calculated using the Ganzoni formula (body weight (kg) x 2.4 x [15 – patient's Hb (g/dl)] + 500 mg for stores). This treatment is usually well tolerated. Main side effects are taste disturbances, while less common side effects are nausea, vomiting, abdominal pain, diarrhoea, flushing, bronchospasm, fever, myalgia and injection site reactions.
Ferric carboxymaltose (FCM) consists of a ferric hydroxide core stabilised by a carbohydrate shell (16) that allows for controlled delivery of iron to target tissues. Several randomised trials have shown that intravenous FCM rapidly improves Hb levels and replenishes depleted iron stores in patients with ID anaemia, including, for example, those with chronic kidney disease (17). FCM is administered via drip infusion (up to a maximum single dose of 1000 mg of iron, but not exceeding 15 mg/kg or the calculated cumulative dose) or bolus injection - at a maximum single dose of up to 200 mg of iron up to three times per week (16). Anker et al (18) studied the effects of intravenous FCM versus placebo in 459 HF patients (left ventricular ejection fraction of 45 % or less, NYHA class II or III) with ID. Self-Reported Patient Global Assessment, NYHA class, 6-minute walk test distance and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score improved in the group treated with FCM. FCM is well tolerated. Most adverse effects associated with this treatment are mild to moderate in severity, and include gastrointestinal disturbances, dizziness, rash and injection-site reactions (16).
A large, recent study (19) found that ID (ferritin <100 μg/l, or ferritin 100–300 μg/l with transferrin saturation <20%) is present in 37% of stable chronic systolic HF patients. Iron deficiency was more prevalent in women, mostly with NYHA class IV, higher N-terminal pro-type B natriuretic peptide and C-reactive protein levels. Regarding outcome, a multivariable analysis showed that ID was associated with increased risk of death or heart transplantation, irrespective of the presence of anaemia. Authors suggest that iron supplementation could be considered to improve prognosis of all HF patients with ID. Benefit of iron supplementation was later analysed in the FERRIC-HF trial which found that non-anaemic iron-deficient HF patients had less benefit from intravenous iron sucrose than anaemic patients (15) whereas in the FAIR-HF trial, the patients receiving ferric carboxymaltose showed similar symptoms, 6-minute walk test distance, and quality of life improvements whether anaemic or non-anaemic HF patients (18).
Anaemia is a common and multifactorial condition associated with poor outcome in HF patients. One of the main causes of anaemia is ID. Iron deficiency can be easily detected with simple laboratory tests. Intravenous iron has emerged as a well tolerated and effective therapy to improve symptoms and quality of life in both anaemic and non-anaemic HF patients with iron deficiency. Nevertheless, larger-scale and longer-term studies are necessary to confirm the safety and efficacy of this therapy in HF patients, especially in those without anaemia.
1) Dickstein K, Cohen-Solal A, Filippatos G, et al. Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J 2008;29:2388-2442 2) Lindenfeld JA, Albert NM, Boehmer JP, et al. Executive Summary: HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Cardiac Fail 2010;16:475-539 3) Stamos TD, Silver MA. Management of anemia in heart failure. Curr Opin Cardiol 2010;25:148-154 4) Drakos SG, Anastasiou-Nana MI, Malliaras KG, Nanas JN. Anemia in Chronic Heart Failure. Congest Heart Fail 2009;15:87-92. 5) Ezekowitz JA, McDonald MA. Management of comorbidity in chronic heart failure. In: Greenberg BH, Barnard DD, Narayan SM, Teerlink JR, eds. Management of Heart Failure. Chichester, Wiley-Blackwell; 2010; 137-156 6) Pascual-Figal DA, Bonaque JC, Redondo B, et al. Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients. Eur J Heart Fail 2009;11:840-846 7) Wians FH, Urban JE, Keffer JH, Kroft SH. Discriminating Between Iron Deficiency Anemia and Anemia of Chronic Disease Using Tradicional Indices of Iron Status vs Transferrin Receptor Concentration. Am J Clin Pathol 2001;115:112-118. 8) Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol 2008;52:501-511. 9) He SW, Wang LX. The Impact of Anemia on the Prognosis of Chronic Heart Failure. A Meta-Analysis and Systemic Review. Congest Heart Fail 2009;15:123-130. 10) Hébert PC, Tinmouth A, Corwin HL. Controversies in RBC Transfusion in Critically Ill. Chest 2007;131:1583-1590. 11) Mak G, Murphy NF, McDonald K. Anemia in Heart Failure: to Treat or not to Treat? Curr Treat Options Cardiovasc Med 2008;10:455-464. 12) Lawler PR, Filion KB, Eisenberg MJ. Correcting Anemia in Heart Failure: The Efficacy and Safety of Erithropoiesis-Stimulating Agents. J Cardiac Fail 2010;16:649-658. 13) Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol 2006;48:1225-1227. 14) Toblli JE, Lombraña A, Duarte P, et al. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol 2007;50:1657-1665. 15) Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and Iron Deficiency. FERRIC-HF: A Randomized, Controlled, Observer-Blinded Trial. J Am Coll Cardiol 2008,51:103-112. 16) Lyseng-Williamson KA, Keating GM. Ferric carboxymaltose. A Review of its Use in Iron-Deficiency Anaemia. Drugs 2009;69:739-756. 17) Schaefer RM, Khasabov NN, Todorov NG, et al. The efficacy and safety of intravenous ferric carboxymaltose compared to iron sucrose in haemodialysis patients with iron deficiency anaemia [abstract no. MP375 plus poster]. 45th Congress of the European Renal Association and the European Dialysis and Transplant Association; 2008 May 10-13; Stockholm. 18) Anker SD, Comin Colet J, Filippatos G, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency. N Engl J Med 2009;361:2436-2448 19) Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency: an ominous sign in patients with systolic heart failure. Eur Heart J 2010;31:1872-1880.
Peraira-Moral J. Roberto*, MD, PhD and Núñez-Gil Ivan J.**, MD, PhD, FESC. * Heart Failure Unit. Cardiology Department. Instituto de Cardiología. Madrid. ** Coronary Care Unit. Cardiovascular Institute. Hospital Clínico San Carlos. Madrid. Authors' discosures: None declared.
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