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

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

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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.

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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+

3

Macrophage

Fe2+

Endocytosis of senescent erythrocyte

Ferritin

2+

Fe

Lysosomal degradation of ferroportin

Fe2+

Ferritin

Degradación lisosómica de la ferroportina

Fe2+ Ferroportin

Ferroportin

Hepcidin

Fe2+

Hepcidin

Fe3+

Transferrin

Fe2+

Fe3+

Reduced transferrin saturation

Figure 1

Hepcidin regulation.

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

Reduced Reduced

Transferrin

Increased

TSAT

Reduced

TIBC sTfR

Increased Increased

Hepcidin

Reduced

Medular iron deposits

Reduced

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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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

High sTfRb

No No iron deficiency

Yes No iron deficiency

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

Key points

Oral iron

• 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

Author

Study type

Formulation IV Fe

No. of patients IV Fe

Control placebo

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

Bolger 200658

Open

Sucrose

16

---

68 ± 11.5

26

11.2 ± 0.7

1.7

12

Toblli 200751

Double blind

Sucrose

20

20

75 ± 7

31

10.3

5

24

Okonko 200842 (FERRIC-HF)

Single blind

Sucrose

24

11

64 ± 13

30

12.5

16

18

Usmanov 200867

Open

Sucrose

32

---

49.4 ± 5.7

32

10.2

26

6 months

Anker 200910 (FAIR-HF)

Double blind

Carboxymaltose

304

155

68

32

11.9

24

-

Ponikowski 201413 (CONFIRM-HF)

Double blind

Carboxymaltose

152

152

69

36.5

12.4

24

52

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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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

Table 2

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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

Repletion

≥ 70 kg

35-70 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.

14. 15.

References 1. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:154---235. 2. Szachniewicz J, Petruk-Kowalczyk J, Majda J, Kaczmarek A, Reczuch K, Kalra PR, et al. Anaemia is an independent predictor of poor outcome in patients with chronic heart failure. Int J Cardiol. 2003;90:303---8. 3. Sánchez-Torrijos J, Gudín-Uriel M, Nadal-Barangé M, JacasOsborn V, Trigo-Bautista A, Giménez-Alcalá M, et al. Valor pronóstico de las cifras de hemoglobina en el momento del alta en pacientes hospitalizados por insuficiencia cardiaca. Rev Esp Cardiol. 2006;59:1276---82. 4. Salisbury AC, Kosiborod M. Outcomes associated with anemia in patients with heart failure. Heart Fail Clin. 2010;6:359---72. 5. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:1780---6. 6. Kalra PR, Bolger AP, Francis DP, Genth-Zotz S, Sharma R, Ponikowski PP, et al. Effect of anemia on exercise tolerance in chronic heart failure in men. Am J Cardiol. 2003;91:888---91. 7. Adams KF, Pi˜ na IL, Ghali JK, Wagoner LE, Dunlap SH, Schwartz TA, et al. Prospective evaluation of the association between hemoglobin concentration and quality of life in patients with heart failure. Am Heart J. 2009;158:965---71. 8. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085---98. 9. Pfeffer MA, Burdmann EA, Chen C-Y, Cooper ME, de Zeeuw D, Eckardt K-U, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019---32. 10. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436---48. 11. Kapoor M, Schleinitz MD, Gemignani A, Wu W-C. Outcomes of patients with chronic heart failure and iron deficiency treated with intravenous iron: a meta-analysis. Cardiovasc Hematol Disord Drug Targets. 2013;13:35---44. 12. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368:1210---9. 13. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, et al. Beneficial effects of

16.

17.

18. 19.

20.

21.

22.

23. 24.

25.

26.

27.

28.

29.

30.

31.

9

long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36:657---68. Cairo G, Bernuzzi F, Recalcati S. A precious metal: iron, an essential nutrient for all cells. Genes Nutr. 2006;1:25---39. Haas JD, Brownlie T. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr. 2001;131:676S---88S [discussion 688S---90S]. Guzmán Mentesana G, Báez AL, Lo Presti MS, Domínguez R, Córdoba R, Bazán C, et al. Functional and structural alterations of cardiac and skeletal muscle mitochondria in heart failure patients. Arch Med Res. 2014;45:237---46. Bayeva M, Gheorghiade M, Ardehali H. Mitochondria as a therapeutic target in heart failure. J Am Coll Cardiol. 2013;61:599---610. Handelman GJ, Levin NW. Iron and anemia in human biology: a review of mechanisms. Heart Fail Rev. 2008;13:393---404. Schultz IJ, Chen C, Paw BH, Hamza I. Iron and porphyrin trafficking in heme biogenesis. J Biol Chem. 2010;285: 26753---9. Singh B, Arora S, Agrawal P, Gupta SK. Hepcidin: a novel peptide hormone regulating iron metabolism. Clin Chim Acta. 2011;412:823---30. Kroot JJC, Tjalsma H, Fleming RE, Swinkels DW. Hepcidin in human iron disorders: diagnostic implications. Clin Chem. 2011;57:1650---69. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142:24---38. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122:78---86. Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, von Haehling S, et al. Iron status in patients with chronic heart failure. Eur Heart J. 2013;34:827---34. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013;34:816---29. Cohen-Solal A, Leclercq C, Deray G, Lasocki S, Zambrowski JJ, Mebazaa A, et al. Iron deficiency: an emerging therapeutic target in heart failure. Heart. 2014;100:1414---20. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2129---200. Nanas JN, Matsouka C, Karageorgopoulos D, Leonti A, Tsolakis E, Drakos SG, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol. 2006;48: 2485---9. Peyrin-Biroulet L, Williet N, Cacoub P. Guidelines on the diagnosis and treatment of iron deficiency across indications: a systematic review. Am J Clin Nutr. 2015;102:1585---94. Koulaouzidis A, Said E, Cottier R, Saeed AA. Soluble transferrin receptors and iron deficiency, a step beyond ferritin. A systematic review. J Gastrointestin Liver Dis. 2009;18:345---52. Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Ole´skowska-Florek W, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J. 2014;35:2468---76.

+Model

ARTICLE IN PRESS

10 32. Franchini M, Montagnana M, Lippi G. Hepcidin and iron metabolism: from laboratory to clinical implications. Clin Chim Acta. 2010;411:1565---9. 33. Tsuchiya K, Nitta K. Hepcidin is a potential regulator of iron status in chronic kidney disease. Ther Apher Dial. 2013;17:1---8. 34. Dugdale AE. Predicting iron and folate deficiency anaemias from standard blood testing: the mechanism and implications for clinical medicine and public health in developing countries. Theor Biol Med Model. 2006;3:34. 35. Constantino BT. Red cell distribution width, revisited. Lab Med. 2013;44:e2---9. 36. Al-Najjar Y, Goode KM, Zhang J, Cleland JGF, Clark AL. Red cell distribution width: an inexpensive and powerful prognostic marker in heart failure. Eur J Heart Fail. 2009;11:1155---62. 37. Pascual-Figal DA, Bonaque JC, Redondo B, Caro C, ManzanoFernandez S, Sánchez-Mas J, 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---6. 38. Van Craenenbroeck EM, Conraads VM, Greenlaw N, Gaudesius G, Mori C, Ponikowski P, et al. The effect of intravenous ferric carboxymaltose on red cell distribution width: a subanalysis of the FAIR-HF study. Eur J Heart Fail. 2013;15:756---62. 39. Nagao M, Matsuo Y, Kamitani T, Yonezawa M, Yamasaki Y, Kawanami S, et al. Quantification of myocardial iron deficiency in nonischemic heart failure by cardiac T2* magnetic resonance imaging. Am J Cardiol. 2014;113:1024---30. 40. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J. 2010;31:1872---80. 41. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011;17:899---906. 42. Okonko DO, Grzeslo A, Witkowski T, Mandal AKJ, Slater RM, Roughton M, 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---12. 43. Klip IJT, Comin-Colet J, Voors AA, Ponikowski P, Enjuanes C, Banasiak W, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165, 575---82.e3. 44. KDOQI Clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50:471---530. 45. Jankowska EA, Wojtas K, Kasztura M, Mazur G, Butrym A, Kalicinska E, et al. Bone marrow iron depletion is common in patients with coronary artery disease. Int J Cardiol. 2015;182:517---22. 46. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, van Veldhuisen DJ, et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J Am Coll Cardiol. 2008;52:818---27. 47. Klapholz M, Abraham WT, Ghali JK, Ponikowski P, Anker SD, Knusel B, et al. The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure. Eur J Heart Fail. 2009;11:1071---7. 48. Witte KKA, Desilva R, Chattopadhyay S, Ghosh J, Cleland JGF, Clark AL. Are hematinic deficiencies the cause of

N. Manito et al.

49.

50.

51.

52.

53.

54.

55.

56.

57. 58.

59.

60.

61.

62.

63.

64.

anemia in chronic heart failure? Am Heart J. 2004;147: 924---30. Comin-Colet J, Lainscak M, Dickstein K, Filippatos GS, Johnson P, Lüscher TF, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study. Eur Heart J. 2013;34:30---8. Ponikowski P, Filippatos G, Colet JC, Willenheimer R, Dickstein K, Lüscher T, et al. The impact of intravenous ferric carboxymaltose on renal function: an analysis of the FAIR-HF study. Eur J Heart Fail. 2015;17:329---39. Toblli JE, Lombra˜ na A, Duarte P, di Gennaro F. 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---65. Sandek A, Rauchhaus M, Anker SD, von Haehling S. The emerging role of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care. 2008;11:632---9. Beck-da-Silva L, Piardi D, Soder S, Rohde LE, Pereira-Barretto AC, de Albuquerque D, et al. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol. 2013;168:3439---42. Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis. 2001;38:988---91. Neiser S, Rentsch D, Dippon U, Kappler A, Weidler PG, Göttlicher J, et al. Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose. Biometals. 2015;28:615---35. European Medicines Agency. Assessment report for: iron containing intravenous (IV) medicinal products; 2013. Procedure number: EMEA/H/A-31/1322. Available from: http://www. ema.europa.eu/docs/en GB/document library/Referrals document/IV iron 31WC500150771.pdf [accessed 13.09.13]. Keating GM. Ferric carboxymaltose: a review of its use in iron deficiency. Drugs. 2015;75:101---27. Bolger AP, Bartlett FR, Penston HS, O’Leary J, Pollock N, Kaprielian R, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol. 2006;48:1225---7. Koch TA, Myers J, Goodnough LT. Intravenous iron therapy in patients with iron deficiency anemia: dosing considerations. Anemia. 2015:763576, doi:10.1155/2015/763576. Anker SD, Comin-Colet J, Filippatos G, Ruschitzka F, Arutyunov GP, Motro M, et al. Ferric carboxymaltose in iron deficient heart failure patients: a meta-analysis on individual patient data. Eur Heart J. 2015;36 Suppl. 1:494 [P2796]. Gutzwiller FS, Pfeil AM, Comin-Colet J, Ponikowski P, Filippatos G, Mori C, et al. Determinants of quality of life of patients with heart failure and iron deficiency treated with ferric carboxymaltose: FAIR-HF sub-analysis. Int J Cardiol. 2013;168:3878---83. Comín-Colet J, Rubio-Rodríguez D, Rubio-Terrés C, EnjuanesGrau C, Gutzwiller FS, Anker SD, et al. Evaluación económica de la utilización de hierro carboximaltosa en pacientes con deficiencia de hierro e insuficiencia cardiaca crónica en Espa˜ na. Rev Esp Cardiol. 2015;68:846---51. Sacristán JA, Oliva J, del Llano J, Prieto L, Pinto JL. ¿Qué na? Gac Sanit. es una tecnología sanitaria eficiente en Espa˜ 2002;16:334---43. Silverberg DS, Wexler D, Iaina A. The importance of anemia and its correction in the management of severe congestive heart failure. Eur J Heart Fail. 2002;4:681---6.

+Model

ARTICLE IN PRESS

Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine 65. Comín-Colet J, Enjuanes C, González G, Torrens A, Cladellas M, Mero˜ no O, et al. Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status. Eur J Heart Fail. 2013;15:1164---72. 66. Enjuanes C, Klip IJT, Bruguera J, Cladellas M, Ponikowski P, Banasiak W, et al. Iron deficiency and health-related quality

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of life in chronic heart failure: results from a multicenter European study. Int J Cardiol. 2014;174:268---75. 67. Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. J Nephrol. 2008;21:236---42.