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Revista Clínica Española www.elsevier.es/rce
Consensus Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine on the diagnosis and treatment of iron deﬁciency in heart failure夽 N. Manito a,∗ , J.M. Cerqueiro b , J. Comín-Colet c , J.M. García-Pinilla d , A. González-Franco e , J. Grau-Amorós f , J.R. Peraira g , L. Manzano h a
Unidad de Insuﬁciencia Cardíaca y Trasplante Cardíaco, Hospital Universitario de Bellvitge, Barcelona, Spain Servicio de Medicina Interna, Hospital de Lugo, Lugo, Spain c Grupo de Investigación Biomédica en Enfermedades del Corazón, Instituto Hospital del Mar de Investigaciones Médicas (IMIM), Barcelona, Spain d Unidad de Insuﬁciencia Cardiaca y Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain e Unidad de Insuﬁciencia Cardíaca, Hospital Universitario Central de Asturias, Oviedo, Spain f Servicio de Medicina Interna, Hospital Municipal de Badalona, Barcelona, Spain g Servicio de Cardiología, Hospital Sant Joan de Déu de Martorell, Barcelona, Spain h Unidad ICC y del Anciano, Hospital Ramón y Cajal, Madrid, Spain b
KEYWORDS Iron deﬁciency; Anemia; Heart failure; Intravenous iron
Abstract Iron deﬁciency in patients with heart failure is a medical problem of recent particular interest. This interest has resulted from the publication of several clinical trials that demonstrated that the administration of intravenous iron to such patients improved their functional capacity and even reduced the number of hospitalisations for heart failure decompensation. However, applying the evidence from these studies in clinical practice is still controversial, both in terms of the diagnostic criteria for iron deﬁciency (absolute and functional) and the optimal method for iron replenishment. This article is a consensus document that integrates the recommendations of the Spanish Society of Internal Medicine and the Spanish Society of Cardiology. The article reviews the scientiﬁc evidence and proposes a diagnostic and therapeutic performance protocol for iron deﬁciency in heart failure. © 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
Please cite this article as: Manito N, Cerqueiro JM, Comín-Colet J, García-Pinilla JM, González-Franco A, Grau-Amorós J, et al. Documento de consenso de la Sociedad Espa˜ nola de Cardiología y la Sociedad Espa˜ nola de Medicina Interna sobre el diagnóstico y tratamiento del déﬁcit de hierro en la insuﬁciencia cardíaca. Rev Clin Esp. 2016. http://dx.doi.org/10.1016/j.rce.2016.08.001 ∗ Corresponding author. E-mail address: [email protected]
(N. Manito). 2254-8874/© 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
RCENG-1302; No. of Pages 11
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PALABRAS CLAVE Déﬁcit de hierro; Anemia; Insuﬁciencia cardiaca; Hierro intravenoso
Documento de consenso de la Sociedad Espa˜ nola de Cardiología y la Sociedad Espa˜ nola de Medicina Interna sobre el diagnóstico y tratamiento del déﬁcit de hierro en la insuﬁciencia cardíaca Resumen El déﬁcit de hierro en los pacientes con insuﬁciencia cardiaca es un problema médico que últimamente suscita un interés particular. Esto se debe a la publicación de varios ensayos clínicos que demuestran que la administración de hierro intravenoso en estos pacientes mejora su capacidad funcional, e incluso reduce los ingresos por descompensación de insuﬁciencia cardiaca. Sin embargo, la aplicación de la evidencia aportada por estos estudios en la práctica clínica es aún controvertida, tanto en los criterios diagnósticos del déﬁcit de hierro, absoluto y funcional, como en la forma óptima de reposición del hierro. Este artículo es un documento de consenso que integra las recomendaciones de las Sociedades Espa˜ nolas de Medicina Interna y Cardiología en el que se revisa la evidencia cientíﬁca y se propone un protocolo de actuación diagnóstica y terapéutica del déﬁcit de hierro en la insuﬁciencia cardiaca. © 2016 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Treating heart failure (HF) according to clinical practice guidelines has improved its prognosis, although its mortality and especially readmissions are still high. This is mostly due to the comorbidities associated with HF, which are difﬁcult to control. Among these, anemia and iron deﬁciency (ID) occupy a decisive role. However, this association is not mentioned in the American Heart Association clinical guidelines1 up to 2005, at which point it was related to increased morbidity and mortality. It is notable that the presence of ID is only considered clinically relevant in the context of anemia. The latest data conﬁrm the importance of ID even without anemia. This document includes the consensus between the Spanish Society of Cardiology (SEC) and the Spanish Society of Internal Medicine (SEMI) on the potential beneﬁcial effects of using iron intravenous (IV) in patients with HF.
The importance of iron deﬁciency in the pathophysiology of heart failure Initial approach: anemia in heart failure Anemia is currently considered an independent predictor of mortality in HF.2,3 Anemia has been shown to worsen symptoms and functional class and increase hospitalizations,4,5 all of which are correlated with a lower exercise capacity6 and quality of life.7 However, studies aimed at correcting anemia in patients with renal disease have shown that, although the patients’ functional situation is improved, there can be increased number of cardiovascular complications.8,9
Progress in the concept: iron enters the game The clinical trial FAIR-HF,10 which showed the beneﬁts for quality of life, functional class and exercise capacity of administering intravenous iron to patients with chronic systolic HF, was essential in distinguishing between anemia
and ID. The meta-analysis published by Kapoor et al.11 delved into these beneﬁts and identiﬁed the impact on the reduction of hospitalizations, without adverse events. The publication of the RED-HF study,12 which showed neutral results with the use of darbepoetin in patients with HF and systolic dysfunction, and the presentation in 2014 of the positive results of the CONFIRM-HF trial13 that used iron carboxymaltose (ICM) in patients with HF and systolic dysfunction have contributed to the deﬁnitive separation between the concept of anemia and ID in the development, prognosis and treatment of HF.
The role of iron in the body Iron’s fundamental mission is to generate the hemo group during erythropoiesis. Iron is also an essential element in a large number of molecular systems, including the oxidative metabolism (mitochondrial respiratory chain, oxidative enzymes) and fatty acid ␤-oxidation.14 These functions explain why the consequences of ID are not limited to erythropoiesis but also affect cell energy production (e.g., in myocytes and cardiomyocytes).15 When cellular iron levels are low, the activity of the mitochondrial respiratory chain decreases, producing less adenosine triphosphate (ATP), which in turn causes a reduction in exercise capacity and increased fatigue.16,17
Pathophysiological concepts of iron The biological cycle of iron is composed of 2 pathways that ensure its supply to the body: the ﬁrst enables the recovery of iron from red blood cells that are destroyed in the mononuclear phagocytic system (MPS) of the spleen18 ; the second pathway is through the absorption of ingested iron through enterocytes. Iron is then passed to the bloodstream and binds to transferrin, which facilitates its insertion into iron receptor cells. Once inside the cells, iron can follow 3 routes: binding to ferritin, transport to the mitochondria
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Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine Erythrocyte Fe3+
Endocytosis of senescent erythrocyte
Lysosomal degradation of ferroportin
Degradación lisosómica de la ferroportina
Reduced transferrin saturation
or binding to iron---sulfur clusters. When cellular iron levels are low, the concentration of clusters decreases, producing less ATP.19 This process explains why exercise capacity improves after correcting ID, regardless of the presence of anemia.
Hepcidin; does it have central role? Hepcidin is a peptide hormone synthesized in the liver that exerts a key regulatory action on iron metabolism.20 Hepcidin is an acute-phase reactant that intervenes in the antimicrobial immune response, reducing the release of iron into the blood (thereby decreasing its availability for exogenous pathogens), preventing extracellular oxidative stress and modulating the inﬂammatory response.21 Hepcidin induces a block in the cellular excretion of iron, such that iron absorption in the duodenum and its recycling in the MPS is reduced,22 causing a reduction in its circulating concentration (Fig. 1).23 In the initial phases of HF, hepcidin production is stimulated (hepcidin upregulation), which retains iron in the MPS, thereby reducing its circulating concentrations and availability to target tissues. This process has 2 objectives: preventing the harmful effects of excess iron (oxidative stress) and reducing the development of inﬂammatory reactions.24 Both are crucial mechanisms that underlie the progression of cardiovascular damage. Subsequently, when cardiovascular disease is in an advanced phase and ID has been generated, with its consequent energy deﬁcit, an opposite process develops (hepcidin downregulation), which attempts to reverse this situation.24 This process would explain the ﬁndings of various studies of a gradual reduction in hepcidin levels over the course of HF.
Key points • Recent studies have contributed to the deﬁnitive separation between the concept of anemia and that of ID in HF. ID goes beyond a mere comorbidity, consolidating its
role in the pathophysiology, prognosis and treatment of HF. • The key to iron’s central role lies in its participation in the processes of energy generation in the mitochondrial respiratory chain. • Iron homeostasis is ﬁnely governed by hepcidin, which might have a speciﬁc behavior in HF. • We are witnessing a change in the clinical paradigm of HF from the treatment of anemia to ID correction.
Diagnosis of iron deﬁciency in heart failure ID has classically been divided into absolute and functional. The ﬁrst type has ID in the deposits (liver and MPS), which hinders the body’s needs. In the second type, the amount of available iron decreases, generally by inﬂammatory mechanisms (Table 1). The symptoms associated with ID in HF are nonspeciﬁc: reduced exercise capacity, worsening of the New York Heart Association (NYHA) functional class, cognitive and behavior disorders and worsening of depressive symptoms.25---27
Biological parameters Serum ferritin Ferritin is, along with transferrin saturation, the most widely used parameter for conﬁrming suspected ID.1---4 The prevalence of iron deﬁciency in HF varies between 30% and 50%, depending on the study.28 The most commonly used diagnostic criterion for ID in the context of HF is that recommended by the European Guidelines of Cardiology, which established that ferritin levels <100 g/L or ferritin levels between 100 and 300 g/L with a transferrin saturation <20% are diagnostic for ID.27 In HF, the underlying inﬂammatory process stimulates the tissue expression of ferritin. The cutoff is therefore higher than that for the healthy population (100 g/L).29
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N. Manito et al. Table 1 Laboratory studies that help the differential diagnosis between absolute and functional iron deﬁciency. Parameters
Absolute iron deﬁciency
Functional iron deﬁciency
Serum iron Ferritin
Medular iron deposits
Reduced Normal or increased Normal or reduced Normal or reduced Reduced Normal or reduced Normal or increased Increased
Abbreviations: TSAT, transferrin saturation index; sTfR, soluble transferrin receptor; TIBC, total iron-binding capacity.
Transferrin, total iron-binding capacity and transferrin saturation Transferrin is a hepatic synthesis protein and the main transporter of iron from the iron-releasing cells (intestinal and macrophage) to the speciﬁc receptors (e.g., erythroblasts). The lack of iron stimulates its synthesis and raises its plasma concentrations. A similar parameter is serum’s total ironbinding capacity (TIBC), which indicates the capacity of blood proteins to bind to iron. Both reﬂect the quantity of iron in the circulating pool; its increase would therefore reﬂect functional ID. The transferrin saturation index (TSAT) or percentage of transferrin with iron bound to it is the main parameter for calculating the availability of circulating iron. Its reduction (TSAT <20%) is a marker of functional ID. ID progresses with an increase in transferrin levels and TIBC and a reduction in TSAT. As with ferritin, transferrin (and thus TIBC and TSAT) has signiﬁcant limitations: daytime ﬂuctuations in its value (17---70%), reductions in cachexia, malnutrition and chronic disease and increases in inﬂammatory processes by acting as an acute-phase reactant29 (thus its limitation in acute HF). Nevertheless, the reduction in TSAT is more sensitive than ferritin for detecting ID in HF.26 Anemia associated with low TSAT values has often been observed in HF in advanced NYHA stages.28 Soluble transferrin receptor This is the ectodomain of the transferrin receptor (responsible for the intracellular incorporation of iron) and is expressed in the cell membrane according to the iron needs in the erythroblastic precursors and in the cells that take up iron (e.g., cardiomyocytes, myocytes).26 An increase in this receptor reﬂects unsatisﬁed cellular requirements (functional ID).30 The receptor is not affected by the inﬂammatory condition, and its concentration is less variable. A recent study identiﬁed the prognostic importance of deﬁning ID in acute HF (where the acute-phase reactant levels are increased, and there is signiﬁcant variability in ferritin
levels and TSAT) according to the soluble transferrin receptor (sTfR) and hepcidin. Thus an sTfR value ≥1.59 mg/L is a marker of functional ID, and a hepcidin level <14.5 ng/mL is a marker of absolute ID.31 Hepcidin The behavior of hepcidin is similar to that of ferritin, and its reduction reﬂects iron deposit depletion.32 Hepcidin is mainly eliminated renally, and its concentration therefore increases in renal failure.33 In HF, increased hepcidin levels have been observed in early phases and decreased levels in more advanced phases.24 Hemogram The earliest expression of erythropoiesis with ID is the reduction in the reticulocyte hemoglobin content (CHr), less than 28 pg. The CHr reﬂects the available iron for erythropoiesis and is an early marker of the response to iron therapy. Later expressions include the increase in the percentage of hypochromic red blood cells,28,29 and reductions in mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and hemoglobin. In practice, we suspect ID whether the mean corpuscular volume decreases (which can go unnoticed if there is vitamin B12 deﬁciency, folate deﬁciency or inﬂammatory processes such as HF).34 Red blood cell distribution width This width is a quantitative index of homogeneity of the size of red blood cells, which helps monitor the effect of iron therapy.28,35 Normal values for red blood cell distribution width are 11.5---14.5%. This width is a prognostic marker for chronic36 and acute HF.37 The decrease in width after intravenous iron therapy is correlated with improvements in the distance traveled in the 6-min walk test (T6M).38 Serum iron Serum iron shows signiﬁcant individual variations and offers less information on iron metabolism than ferritin and should not be used to assess ID in HF.26
Bone marrow biopsy Prussian blue staining is the gold standard for assessing bone marrow deposits of iron.30 Its practical limitations restrict its use to questionable cases after a study of the previously mentioned parameters.
Imaging techniques The reduction in myocardial iron content, detected with cardiovascular magnetic resonance T2 sequencing, has recently been related to poorer left ventricular systolic function and an increased risk of adverse events in nonischemic HF.39
Diagnosis of iron deﬁciency Based on the existing evidence, a number of ID detection criteria have been proposed in Fig. 2. In general, we use the
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Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine
HFa in NYHA class II-IV -Medical history and physical examination -Basic iron metabolism study: full blood count, ferritin and TSAT
TSAT ≥ 20%
TSAT < 20%
Ferritin > 800 μg/l
Ferritin 300-800 μg/l
Ferritin < 300 μg/l
Ferritin < 100 μg/l
Ferritin ≥ 100 μg/l
No No iron deficiency
Yes No iron deficiency
Figure 2 Diagnostic algorithm for iron deﬁciency in heart failure. Abbreviations: HF, heart failure; TSAT, transferrin saturation index; sTfR, soluble transferrin receptor. a Start: follow-up or decompensation. b For acute HF with a doubtful diagnosis, measuring hepcidin and sTfR levels could be useful after measuring ferritin and TSAT. Source: Jankowska et al.31
• In HF, a basic study of the iron proﬁle should be performed systematically at least annually and any time the disease progresses.
serum values of iron, ferritin and transferrin (iron and transferrin enable the calculation of TSAT). The cutoffs used by most studies to identify ID are as follows10,38---43 : (a) ferritin <100 g/L for absolute ID and (b) ferritin. Other authors, due to the relevance of the underlying inﬂammatory disorder, consider functional ID when ferritin levels are <800 g/L and when TSAT values are <20%.13 These deﬁnitions come from the nephrology setting, given the considerable similarity between chronic kidney disease and HF.44 The cutoff points mentioned above are not valid for acute HF, because ferritin levels increase as the inﬂammatory and oxidative process increases, and TSAT rises artiﬁcially due to the increase in the accompanying catabolism and malnutrition, which reduces transferrin levels.45 A hepcidin concentration <40 g/mL, which is indicative of iron deposit depletion, and an sTfR >1.59 mg/L, which shows an increase in iron demand due to cellular metabolism, are probably more sensitive markers of ID. For patients with HF, we recommend performing a study of the iron parameters in the following circumstances: (a) systematically at least once a year; (b) if there is clinical progression of the HF, an increase in natriuretic peptide levels or a reduction in the ejection fraction; and (c) if there is anemia.
In recent years, the impact of anemia on the worsening condition of patients with HF has been observed. We do not yet know precisely whether anemia contributes to the worsening of the prognosis or is only a marker of HF severity.46,47 More recently, ID has emerged as an important element in the progression of HF, regardless of hemoglobin concentrations, which suggests its direct participation in the pathophysiology of HF due to its extra-hematopoietic functions.24,48
• The study of ID in HF should be based on ferritin and TSAT. We deﬁne ID as a ferritin level <100 g/L or between 100 and 300 g/L along with a TSAT <20%. • The sTfR is an accurate tool in the diagnosis of ID and can be especially useful in questionable cases (Fig. 2). • Although studies have been conducted mostly on patients with systolic HF, we recommend also studying ID in those with preserved left ventricular ejection fraction (LVEF).
The use of oral iron has signiﬁcant limitations for patients with HF due to the poor gastrointestinal tolerance18 and erratic absorption due to several mechanisms (e.g., high hepcidin levels, polypharmacy).52 Additionally, ID has a slow recovery, given that only 10% of iron ingested orally is absorbed. We also have no large studies that endorse the use of oral iron. The goal of the currently underway IRONOUT (NCT02188784) study is to determine, in patients with HF and LVEF <40%, whether oral iron polysaccharide is superior
Drug treatment of iron deﬁciency in heart failure
Effects of iron therapy on heart failure ID therapy has positives effects on: (1) quality of life,49 (2) creatinine concentrations,50 (3) functional class,10 (4) exercise capacity,10 (5) maximum oxygen consumption (VO2 ),42 (6) LVEF51 and (7) hospital readmissions.13
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6 to placebo in improving functional capacity, as measured by changes in peak VO2 . To date, we only have the results of the IRON-HF study, which compared 8 patients with intravenous iron and 7 patients with oral iron. Although both formulations corrected the hemoglobin levels, parenteral iron was superior in improving the functional capacity measured by ergospirometry.53
Parenteral iron Parenteral iron is more effective in correcting anemia and iron deﬁciency than oral preparations. At this time, we have various presentations for intravenous use that differ in their physical and biochemical characteristics. Each compound consists of an iron nucleus (III) coated by a carbohydrate layer, which, depending on its composition and size, confers stability to the complex and modulates the rate of iron release. This composition determines its usage and safety proﬁle, dosage, infusion rate and administration interval.54 The carbohydrate part can cause anaphylactic reactions, seemingly due to its size and structure, which is much less in the new preparations: carboxymaltose and isomaltoside.55 Iron sucrose. Iron sucrose is an iron III hydroxide complex very similar to ferritin combined with a moderately stable carbohydrate, which, due to its molecular weight, is not eliminated renally or by dialysis. After its intravenous administration, iron sucrose is rapidly distributed bound to plasma proteins, mainly apotransferrin and ferritin.54 Iron sucrose is not associated with fatal anaphylactic reactions due to immunogenicity; however, anaphylactoid and pseudoallergic reactions have been reported (estimated rate, 0.0022%)56 in relation to the administration of dosages greater than recommended or to very rapid infusions. Ferric carboxymaltose. Ferric carboxymaltose is an iron complex with carbohydrate polymers. Once in the bloodstream, ferric carboxymaltose is distributed rapidly toward the bone marrow and is deposited in the liver and spleen. Its half-life is 7---12 h and has minimal renal elimination. Ferric carboxymaltose has a better safety proﬁle and allows for larger administered doses of iron (up to 20 mg/kg, maximum 1000 mg per session a week), with a shorter infusion time. The rate of severe adverse events related to ICM is low,57 which include reports of headache, urticaria, metallic taste, back pain, chest pain, gastrointestinal symptoms, edema, bradycardia and hypotension.
Evidence of parenteral iron therapy in heart failure There are several studies with various methodologies (Table 2).10,13,42,51,58 These include FAIR-HF,10 the ﬁrst large, multicenter, randomized, double-blind, placebo-controlled (2:1) study on parenteral iron therapy in 459 outpatients with HF and ID, with or without anemia. The treatment group was administered 200 mg of intravenous ICM weekly until they reached the necessary dose to correct the ID (calculated using the Ganzoni formula59 ). The group was then administered 200 mg intravenously monthly for 6 months (maintenance phase). The primary endpoint was the quality of life and symptom improvement at week 24. The secondary
N. Manito et al. endpoints included assessing these parameters at weeks 4 and 12, the distance traveled in the T6M, the score on the Kansas City Cardiomyopathy Questionnaire, hospitalization for HF and mortality. The inclusion criteria were as follows: NYHA class II-III, ferritin levels <100 g/L or 100---300 g/L with a TSAT <20%, LVEF <40% or <45% in patients with a previous hospitalization for HF, and hemoglobin levels of 9.5---13.5 mg/dL. Fifty percent of the intervention group presented moderate or clear symptomatic improvement compared with 28% of the placebo group (OR, 2.51; 95% CI 1.75---3.61). The improvement in functional class was also greater at week 24 for the treated group, 47 vs. 30% (OR, 2.40; 95% CI 1.55---3.71). There were no signiﬁcant differences between the patients with and without anemia. The distance traveled in the T6M was also greater in the patients treated with iron (313 ± 7 m vs. 277 ± 10 m; p < .001), but there were no differences in the mortality rate or adverse events. Lastly, the CONFIRM-HF study,13 designed by the same FAIR-HF group to determine the beneﬁt and safety of longterm intravenous ICM, included 152 patients per arm, using higher doses in the anemia correction phase, followed by quarterly maintenance doses of 500 mg. The group treated with intravenous iron achieved a 33 m improvement in the T6M (main study endpoint) after 6 months, compared with the placebo group, which was maintained up to 12 months. This improvement was independent of the presence of anemia, prior ferritin concentration and functional class, which was more relevant in the patients with diabetes or renal failure. In addition, the secondary endpoints such as quality of life, fatigue and improvement in the functional class at week 24 showed signiﬁcant differences in favor of the patients treated with ICM. It is worth noting that there was a significant reduction in the risk of hospitalization for HF in the treatment arm (relative risk [RR], 0.39; 95% CI 0.19---0.82; p = .009). The data from a meta-analysis that included 4 studies (FER-CARS-01, FAIR-HF, EFFICACY-HF and CONFIRM-HF)60 with 839 patients treated with ICM versus placebo were recently presented. The results show a signiﬁcant reduction of 41% in cardiovascular mortality and hospitalizations due to cardiovascular causes (RR, 0.59; 95% CI 0.40---0.88; p = .009) with ICM. There was also a signiﬁcant reduction of 59% in hospitalizations for HF (RR, 0.41; 95% CI 0.23---0.73; p = .003). The safety analysis reported no severe hypersensitivity reactions. Two substudies of the FAIR-HF applied a costeffectiveness model based on the ﬁnancial data published by ofﬁcial bodies of the United Kingdom and Spain.61,62 In the case of the Spanish model, the cost of treatment with ICM per quality-adjusted life year gained was 6123.78 euros, markedly lower than the 30,000 euros, which is the threshold under which a treatment is considered cost-effective in Spain.63 Finally, the recent HF guidelines of the European Society of Cardiology have given a class IIa recommendation (a level of evidence A) to treatment with ICM for symptomatic patients with reduced LVEF and ID (serum ferritin levels <100 g/L or serum ferritin levels between 100 and 299 g/L and a transferrin saturation index <20%) to relieve symptoms and to improve exercise capacity and quality of life.27
Formulation IV Fe
No. of patients IV Fe
Mean age, years
Mean LVEF % Mean Hb (both g/dL (both groups) groups)
Follow-up duration, weeks
Results (IV Fe vs. placebo)
↑ Hb at 12.6 ± 1.2 g/dL NYHA improvement −14 on the MLFHQ +44 m T6 M ↑ Hb (11.8 vs. 9.8 g/dl) ↓ 333.4 pg/mL NT-proBNP ↓ CRP (2.3 vs. 6.5 mg/dL) ↑ LVEF (35.7 vs. 28.8%) NYHA improvement (2 vs. 3.3) ↓ 18 on the MLFHQ +56 m T6 M ↑ Hb (13 vs. 12.6 g/dL) NYHA improvement (2.1 vs. 2.6) ↑ tissue oxygen ↑ Hb in 3 g/dL Improvement NYHA is class III ↑ LVEF if class III ↑ Hb (13 vs. 12.5 g/dL) +7 in the KCCQ +35 ± 8 m 6-min Test. NYHA improvement +33 m 6-min Test. −0.6 Dyspnea scale +1.3 in the KCCQ +2.8 in the EQ-5D +36 m T6 M −0.7 Dyspnea scale +4.5 in the KCCQ +2.6 in the EQ-5D
68 ± 11.5
11.2 ± 0.7
75 ± 7
Okonko 200842 (FERRIC-HF)
64 ± 13
49.4 ± 5.7
Anker 200910 (FAIR-HF)
Ponikowski 201413 (CONFIRM-HF)
Abbreviations: EQ-5D, EuroQoL-5D Health Questionnaire; IV Fe, intravenous iron; LVEF, left ventricular ejection fraction; Hb, hemoglobin; KCCQ, Kansas City Cardiomyopathy Questionnaire; MLFHQ: Minnesota Living With Heart Failure Questionnaire; NT-ProBNP, N-terminal brain natriuretic propeptide; NYHA, New York Heart Association; CRP, C-reactive protein; T6M: 6-min test.
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Treatment duration, weeks
Studies with iron preparations performed with patients with heart failure and anemia or iron deﬁciency.
Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine
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N. Manito et al.
HF with iron deficiency
CONFIRM-HF study regimen (carboxymaltose)
Initial studies regimen (sucrose)
Repletion: 200 mg/week
Maintenance: 200 mg/month if ferritin and TSAT show iron deficiency
Until needs are met according to the Ganzoni formula: Total dose in mg=(body weight in kg) x ((objective Hb–actual Hb) x 2.4)+500
≥ 70 kg
Weight Hb, g/dL Dose 1st week Dose 2nd week
Maintenance: 500 mg/3 months if ferritin and TSAT show iron deficiency
< 10 1000 mg 500 mg
≥ 10 - < 14 ≥ 14 1000 mg 500 mg -
< 10 1000 mg 1000 mg
≥ 10 - < 14 1000 mg 500 mg
≥ 14 500 mg -
Figure 3 Treatment options for heart failure with iron deﬁciency. Abbreviations: Fe, iron; Hb, hemoglobin; HF, heart failure; TSAT, transferrin saturation index.
Key points • ID correction by itself is a therapeutic objective in HF, even without the presence of anemia. • Treatment for ID is indicated provided the patient presents symptoms (NYHA ≥II) despite therapeutic optimization of the HF. • Treatment of ID through the use of ICM is recommended in the 2016 clinical practice guidelines for HF of the European Society of Cardiology, with a class IIa recommendation and level of evidence A. • ID correction should be considered for asymptomatic patients with HF when associated with anemia. • Patients need to be euvolemic and undergoing optimal medical treatment before treatment with ID can be considered. • The beneﬁt of ID treatment has only been shown for patients with depressed systolic function. • Patients with HF and chronic renal failure who are not on dialysis, have low hemoglobin levels and have been readmitted for HF can especially beneﬁt from iron replenishment.64 • Various observational studies have suggested that the impact of ID on the prognosis, functional capacity and quality of life of patients with HF and preserved LVEF is similar to that observed in patients with reduced LVEF.43,65,66 • According to the protocols of the FAIR-HF10 and CONFIRMHF studies,13 we have 2 ID treatment regimens (Fig. 3): (a) 200 mg/week until the deﬁciency has been corrected (calculated by the Ganzoni formula), followed by 200 mg/month as maintenance10 or (b) 1000 mg as an initial dose, plus 500 mg at 7 days in some cases depending on the deﬁciency calculated in the simpliﬁed formula, followed by 500 mg every 3 months.13 In both cases, the
maintenance dose will be based on the blood count values and the ferrokinetics prior to the new dose.
Conclusions After the publication of important studies on patients with HF that differentiated the concept of anemia and ID, there is sufﬁcient clinical evidence for a change in paradigm. ID is more than a comorbidity, and it is possible that ID plays a role in the pathophysiology of HF. Thus, the diagnosis of ID and its clinical approach have consolidated as a key factor in treating HF. The monitoring of iron kinetics by determining ferritin levels and TSAT has to be performed after the diagnosis of HF, for episodes of decompensation and annually for the early detection of ID. The treatment of ID for patients with symptomatic HF and depressed LVEF should be performed as soon as possible to improve their quality of life and prevent hospital readmissions. The various existing treatment regimens must be adapted to the patient’s clinical proﬁle, the need for rapid correction and the healthcare setting, either in the hospital or outpatient setting. ICM could be the treatment of choice due to its safety, efﬁcacy and easy administration.
Conﬂict of interest Vifor Pharma Spain S.L. facilitated the workgroup meetings for the drafting of this document but did not participate in the study design; data collection, analysis or interpretation; drafting of the manuscript; or in the decision to send it for publication. The authors declare that they have no conﬂict of interest.
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Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine
Acknowledgements The authors would like to thank Vifor Pharma Spain S.L. for facilitating the workgroup meetings for the drafting of this document.
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