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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Manito, J.M. Cerqueiro, J. Comín-Colet, J.M. García-Pinilla, A. González-Franco, J. Grau-Amorós, J.R. Peraira, L. Manzano" "autores" => array:8 [ 0 => array:4 [ "nombre" => "N." "apellidos" => "Manito" "email" => array:1 [ 0 => "nml@bellvitgehospital.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.M." "apellidos" => "Cerqueiro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Comín-Colet" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "J.M." "apellidos" => "García-Pinilla" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "A." 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"apellidos" => "Manzano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "h" "identificador" => "aff0040" ] ] ] ] "afiliaciones" => array:8 [ 0 => array:3 [ "entidad" => "Unidad de Insuficiencia Cardíaca y Trasplante Cardíaco, Hospital Universitario de Bellvitge, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital de Lugo, Lugo, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Grupo de Investigación Biomédica en Enfermedades del Corazón, Instituto Hospital del Mar de Investigaciones Médicas (IMIM), Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Unidad de Insuficiencia Cardiaca y Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad de Insuficiencia Cardíaca, Hospital Universitario Central de Asturias, Oviedo, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Municipal de Badalona, Barcelona, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Cardiología, Hospital Sant Joan de Déu de Martorell, Barcelona, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Unidad ICC y del Anciano, Hospital Ramón y Cajal, Madrid, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Documento de consenso de la Sociedad Española de Cardiología y la Sociedad Española de Medicina Interna sobre el diagnóstico y tratamiento del déficit de hierro en la insuficiencia cardíaca" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1571 "Ancho" => 2822 "Tamanyo" => 268864 ] ] "descripcion" => array:1 [ "en" => "Treatment options for heart failure with iron deficiency. Abbreviations: Fe, iron; Hb, hemoglobin; HF, heart failure; TSAT, transferrin saturation index." ] ] ] "textoCompleto" => "BackgroundTreating 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 guidelines<a class="elsevierStyleCrossRef" href="#bib0340">1</a> 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 failureInitial approach: anemia in heart failureAnemia is currently considered an independent predictor of mortality in HF.<a class="elsevierStyleCrossRefs" href="#bib0345">2,3</a> Anemia has been shown to worsen symptoms and functional class and increase hospitalizations,<a class="elsevierStyleCrossRefs" href="#bib0355">4,5</a> all of which are correlated with a lower exercise capacity<a class="elsevierStyleCrossRef" href="#bib0365">6</a> and quality of life.<a class="elsevierStyleCrossRef" href="#bib0370">7</a> 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.<a class="elsevierStyleCrossRefs" href="#bib0375">8,9</a>Progress in the concept: iron enters the gameThe clinical trial FAIR-HF,<a class="elsevierStyleCrossRef" href="#bib0385">10</a> 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.<a class="elsevierStyleCrossRef" href="#bib0390">11</a> delved into these benefits and identified the impact on the reduction of hospitalizations, without adverse events. The publication of the RED-HF study,<a class="elsevierStyleCrossRef" href="#bib0395">12</a> 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 trial<a class="elsevierStyleCrossRef" href="#bib0400">13</a> 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 bodyIron'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 β-oxidation.<a class="elsevierStyleCrossRef" href="#bib0405">14</a> 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).<a class="elsevierStyleCrossRef" href="#bib0410">15</a> 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.<a class="elsevierStyleCrossRefs" href="#bib0415">16,17</a>Pathophysiological concepts of ironThe 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 spleen<a class="elsevierStyleCrossRef" href="#bib0425">18</a>; 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 or binding to iron–sulfur clusters. When cellular iron levels are low, the concentration of clusters decreases, producing less ATP.<a class="elsevierStyleCrossRef" href="#bib0430">19</a> 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.<a class="elsevierStyleCrossRef" href="#bib0435">20</a> 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.<a class="elsevierStyleCrossRef" href="#bib0440">21</a>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,<a class="elsevierStyleCrossRef" href="#bib0445">22</a> causing a reduction in its circulating concentration (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0450">23</a> 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.<a class="elsevierStyleCrossRef" href="#bib0455">24</a> 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.<a class="elsevierStyleCrossRef" href="#bib0455">24</a> This process would explain the findings of various studies of a gradual reduction in hepcidin levels over the course of HF.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Key points<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•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.</li><li class="elsevierStyleListItem" id="lsti0010">•The key to iron's central role lies in its participation in the processes of energy generation in the mitochondrial respiratory chain.</li><li class="elsevierStyleListItem" id="lsti0015">•Iron homeostasis is finely governed by hepcidin, which might have a specific behavior in HF.</li><li class="elsevierStyleListItem" id="lsti0020">•We are witnessing a change in the clinical paradigm of HF from the treatment of anemia to ID correction.</li></ul>Diagnosis of iron deficiency in heart failureID 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 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). 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.<a class="elsevierStyleCrossRefs" href="#bib0460">25–27</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Biological parametersSerum ferritinFerritin is, along with transferrin saturation, the most widely used parameter for confirming suspected ID.<a class="elsevierStyleCrossRefs" href="#bib0340">1–4</a> The prevalence of iron deficiency in HF varies between 30% and 50%, depending on the study.<a class="elsevierStyleCrossRef" href="#bib0475">28</a> 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 <100μg/L or ferritin levels between 100 and 300μg/L with a transferrin saturation <20% are diagnostic for ID.<a class="elsevierStyleCrossRef" href="#bib0470">27</a> In HF, the underlying inflammatory process stimulates the tissue expression of ferritin. The cutoff is therefore higher than that for the healthy population (100μg/L).<a class="elsevierStyleCrossRef" href="#bib0480">29</a>Transferrin, total iron-binding capacity and transferrin saturationTransferrin 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 iron-binding 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 reactant<a class="elsevierStyleCrossRef" href="#bib0480">29</a> (thus its limitation in acute HF). Nevertheless, the reduction in TSAT is more sensitive than ferritin for detecting ID in HF.<a class="elsevierStyleCrossRef" href="#bib0465">26</a> Anemia associated with low TSAT values has often been observed in HF in advanced NYHA stages.<a class="elsevierStyleCrossRef" href="#bib0475">28</a>Soluble transferrin receptorThis 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).<a class="elsevierStyleCrossRef" href="#bib0465">26</a> An increase in this receptor reflects unsatisfied cellular requirements (functional ID).<a class="elsevierStyleCrossRef" href="#bib0485">30</a> 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 ≥1.59mg/L is a marker of functional ID, and a hepcidin level <14.5ng/mL is a marker of absolute ID.<a class="elsevierStyleCrossRef" href="#bib0490">31</a>HepcidinThe behavior of hepcidin is similar to that of ferritin, and its reduction reflects iron deposit depletion.<a class="elsevierStyleCrossRef" href="#bib0495">32</a> Hepcidin is mainly eliminated renally, and its concentration therefore increases in renal failure.<a class="elsevierStyleCrossRef" href="#bib0500">33</a> In HF, increased hepcidin levels have been observed in early phases and decreased levels in more advanced phases.<a class="elsevierStyleCrossRef" href="#bib0455">24</a>HemogramThe earliest expression of erythropoiesis with ID is the reduction in the reticulocyte hemoglobin content (CHr), less than 28pg. 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,<a class="elsevierStyleCrossRefs" href="#bib0475">28,29</a> 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).<a class="elsevierStyleCrossRef" href="#bib0505">34</a>Red blood cell distribution widthThis width is a quantitative index of homogeneity of the size of red blood cells, which helps monitor the effect of iron therapy.<a class="elsevierStyleCrossRefs" href="#bib0475">28,35</a> Normal values for red blood cell distribution width are 11.5–14.5%. This width is a prognostic marker for chronic<a class="elsevierStyleCrossRef" href="#bib0515">36</a> and acute HF.<a class="elsevierStyleCrossRef" href="#bib0520">37</a> The decrease in width after intravenous iron therapy is correlated with improvements in the distance traveled in the 6-min walk test (T6M).<a class="elsevierStyleCrossRef" href="#bib0525">38</a>Serum ironSerum iron shows significant individual variations and offers less information on iron metabolism than ferritin and should not be used to assess ID in HF.<a class="elsevierStyleCrossRef" href="#bib0465">26</a>Bone marrow biopsyPrussian blue staining is the gold standard for assessing bone marrow deposits of iron.<a class="elsevierStyleCrossRef" href="#bib0485">30</a> Its practical limitations restrict its use to questionable cases after a study of the previously mentioned parameters.Imaging techniquesThe 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.<a class="elsevierStyleCrossRef" href="#bib0530">39</a>Diagnosis of iron deficiencyBased on the existing evidence, a number of ID detection criteria have been proposed in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>. In general, we use the 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 follows<a class="elsevierStyleCrossRefs" href="#bib0385">10,38–43</a>: (a) ferritin <100μg/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 <800μg/L and when TSAT values are <20%.<a class="elsevierStyleCrossRef" href="#bib0400">13</a> These definitions come from the nephrology setting, given the considerable similarity between chronic kidney disease and HF.<a class="elsevierStyleCrossRef" href="#bib0555">44</a> 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.<a class="elsevierStyleCrossRef" href="#bib0560">45</a> A hepcidin concentration <40μg/mL, which is indicative of iron deposit depletion, and an sTfR >1.59mg/L, which shows an increase in iron demand due to cellular metabolism, are probably more sensitive markers of ID.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>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.Key points<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">•The study of ID in HF should be based on ferritin and TSAT. We define ID as a ferritin level <100μg/L or between 100 and 300μg/L along with a TSAT <20%.</li><li class="elsevierStyleListItem" id="lsti0030">•The sTfR is an accurate tool in the diagnosis of ID and can be especially useful in questionable cases (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</li><li class="elsevierStyleListItem" id="lsti0035">•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).</li><li class="elsevierStyleListItem" id="lsti0040">•In HF, a basic study of the iron profile should be performed systematically at least annually and any time the disease progresses.</li></ul>Drug treatment of iron deficiency in heart failureIn 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.<a class="elsevierStyleCrossRefs" href="#bib0565">46,47</a> 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.<a class="elsevierStyleCrossRefs" href="#bib0455">24,48</a>Effects of iron therapy on heart failureID therapy has positives effects on: (1) quality of life,<a class="elsevierStyleCrossRef" href="#bib0580">49</a> (2) creatinine concentrations,<a class="elsevierStyleCrossRef" href="#bib0585">50</a> (3) functional class,<a class="elsevierStyleCrossRef" href="#bib0385">10</a> (4) exercise capacity,<a class="elsevierStyleCrossRef" href="#bib0385">10</a> (5) maximum oxygen consumption (VO2),<a class="elsevierStyleCrossRef" href="#bib0545">42</a> (6) LVEF<a class="elsevierStyleCrossRef" href="#bib0590">51</a> and (7) hospital readmissions.<a class="elsevierStyleCrossRef" href="#bib0400">13</a>Oral ironThe use of oral iron has significant limitations for patients with HF due to the poor gastrointestinal tolerance<a class="elsevierStyleCrossRef" href="#bib0425">18</a> and erratic absorption due to several mechanisms (e.g., high hepcidin levels, polypharmacy).<a class="elsevierStyleCrossRef" href="#bib0595">52</a> 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 (<a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02188784">NCT02188784</a>) study is to determine, in patients with HF and LVEF <40%, whether oral iron polysaccharide is superior 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.<a class="elsevierStyleCrossRef" href="#bib0600">53</a>Parenteral ironParenteral 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.<a class="elsevierStyleCrossRef" href="#bib0605">54</a> 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.<a class="elsevierStyleCrossRef" href="#bib0610">55</a>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.<a class="elsevierStyleCrossRef" href="#bib0605">54</a> Iron sucrose is not associated with fatal anaphylactic reactions due to immunogenicity; however, anaphylactoid and pseudoallergic reactions have been reported (estimated rate, 0.0022%)<a class="elsevierStyleCrossRef" href="#bib0615">56</a> 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 7–12h and has minimal renal elimination. Ferric carboxymaltose has a better safety profile and allows for larger administered doses of iron (up to 20mg/kg, maximum 1000mg per session a week), with a shorter infusion time. The rate of severe adverse events related to ICM is low,<a class="elsevierStyleCrossRef" href="#bib0620">57</a> 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 failureThere are several studies with various methodologies (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0385">10,13,42,51,58</a> These include FAIR-HF,<a class="elsevierStyleCrossRef" href="#bib0385">10</a> 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 200mg of intravenous ICM weekly until they reached the necessary dose to correct the ID (calculated using the Ganzoni formula<a class="elsevierStyleCrossRef" href="#bib0630">59</a>). The group was then administered 200mg intravenously monthly for 6 months (maintenance phase). The primary endpoint was the quality of life and symptom improvement at week 24. The secondary 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 <100μg/L or 100–300μg/L with a TSAT <20%, LVEF <40% or <45% in patients with a previous hospitalization for HF, and hemoglobin levels of 9.5–13.5mg/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±7m vs. 277±10m; p<.001), but there were no differences in the mortality rate or adverse events.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Lastly, the CONFIRM-HF study,<a class="elsevierStyleCrossRef" href="#bib0400">13</a> designed by the same FAIR-HF group to determine the benefit and safety of long-term intravenous ICM, included 152 patients per arm, using higher doses in the anemia correction phase, followed by quarterly maintenance doses of 500mg. The group treated with intravenous iron achieved a 33m 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)<a class="elsevierStyleCrossRef" href="#bib0635">60</a> 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 cost-effectiveness model based on the financial data published by official bodies of the United Kingdom and Spain.<a class="elsevierStyleCrossRefs" href="#bib0640">61,62</a> 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.<a class="elsevierStyleCrossRef" href="#bib0650">63</a>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 <100μg/L or serum ferritin levels between 100 and 299μg/L and a transferrin saturation index <20%) to relieve symptoms and to improve exercise capacity and quality of life.<a class="elsevierStyleCrossRef" href="#bib0470">27</a>Key points<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045">•ID correction by itself is a therapeutic objective in HF, even without the presence of anemia.</li><li class="elsevierStyleListItem" id="lsti0050">•Treatment for ID is indicated provided the patient presents symptoms (NYHA ≥II) despite therapeutic optimization of the HF.</li><li class="elsevierStyleListItem" id="lsti0055">•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.</li><li class="elsevierStyleListItem" id="lsti0060">•ID correction should be considered for asymptomatic patients with HF when associated with anemia.</li><li class="elsevierStyleListItem" id="lsti0065">•Patients need to be euvolemic and undergoing optimal medical treatment before treatment with ID can be considered.</li><li class="elsevierStyleListItem" id="lsti0070">•The benefit of ID treatment has only been shown for patients with depressed systolic function.</li><li class="elsevierStyleListItem" id="lsti0075">•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.<a class="elsevierStyleCrossRef" href="#bib0655">64</a></li><li class="elsevierStyleListItem" id="lsti0080">•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.<a class="elsevierStyleCrossRefs" href="#bib0550">43,65,66</a></li><li class="elsevierStyleListItem" id="lsti0085">•According to the protocols of the FAIR-HF<a class="elsevierStyleCrossRef" href="#bib0385">10</a> and CONFIRM-HF studies,<a class="elsevierStyleCrossRef" href="#bib0400">13</a> we have 2 ID treatment regimens (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>): (a) 200mg/week until the deficiency has been corrected (calculated by the Ganzoni formula), followed by 200mg/month as maintenance<a class="elsevierStyleCrossRef" href="#bib0385">10</a> or (b) 1000mg as an initial dose, plus 500mg at 7 days in some cases depending on the deficiency calculated in the simplified formula, followed by 500mg every 3 months.<a class="elsevierStyleCrossRef" href="#bib0400">13</a> In both cases, the maintenance dose will be based on the blood count values and the ferrokinetics prior to the new dose.<elsevierMultimedia ident="fig0015"></elsevierMultimedia></li></ul>ConclusionsAfter 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 interestVifor 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." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres790043" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec788315" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres790042" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec788316" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "The importance of iron deficiency in the pathophysiology of heart failure" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Initial approach: anemia in heart failure" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Progress in the concept: iron enters the game" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "The role of iron in the body" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Pathophysiological concepts of iron" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Hepcidin; does it have central role?" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Key points" ] 7 => array:3 [ "identificador" => "sec0045" "titulo" => "Diagnosis of iron deficiency in heart failure" "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0050" "titulo" => "Biological parameters" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Serum ferritin" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Transferrin, total iron-binding capacity and transferrin saturation" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Soluble transferrin receptor" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Hepcidin" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Hemogram" ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "Red blood cell distribution width" ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "Serum iron" ] ] ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "Bone marrow biopsy" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Imaging techniques" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Diagnosis of iron deficiency" ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Key points" ] ] ] 8 => array:3 [ "identificador" => "sec0110" "titulo" => "Drug treatment of iron deficiency in heart failure" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0115" "titulo" => "Effects of iron therapy on heart failure" ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Oral iron" ] 2 => array:2 [ "identificador" => "sec0125" "titulo" => "Parenteral iron" ] 3 => array:2 [ "identificador" => "sec0130" "titulo" => "Evidence of parenteral iron therapy in heart failure" ] ] ] 9 => array:2 [ "identificador" => "sec0135" "titulo" => "Key points" ] 10 => array:2 [ "identificador" => "sec0140" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0145" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack264450" "titulo" => "Acknowledgements" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec788315" "palabras" => array:4 [ 0 => "Iron deficiency" 1 => "Anemia" 2 => "Heart failure" 3 => "Intravenous iron" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec788316" "palabras" => array:4 [ 0 => "Déficit de hierro" 1 => "Anemia" 2 => "Insuficiencia cardiaca" 3 => "Hierro intravenoso" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "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." ] "es" => array:2 [ "titulo" => "Resumen" "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 Españolas 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." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "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 Española de Cardiología y la Sociedad Española de Medicina Interna sobre el diagnóstico y tratamiento del déficit de hierro en la insuficiencia cardíaca. Rev Clin Esp. 2017;217:35–45." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1294 "Ancho" => 2095 "Tamanyo" => 196364 ] ] "descripcion" => array:1 [ "en" => "Hepcidin regulation." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Jankowska et al.<a class="elsevierStyleCrossRef" href="#bib0490">31</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1410 "Ancho" => 2697 "Tamanyo" => 176997 ] ] "descripcion" => array:1 [ "en" => "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." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1571 "Ancho" => 2822 "Tamanyo" => 268864 ] ] "descripcion" => array:1 [ "en" => "Treatment options for heart failure with iron deficiency. Abbreviations: Fe, iron; Hb, hemoglobin; HF, heart failure; TSAT, transferrin saturation index." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: TSAT, transferrin saturation index; sTfR, soluble transferrin receptor; TIBC, total iron-binding capacity." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameters \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Absolute iron deficiency \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Functional iron deficiency \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum iron \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ferritin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or increased \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Transferrin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or reduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TSAT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or reduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TIBC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">sTfR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or reduced \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hepcidin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal or increased \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Medular iron deposits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduced \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1319695.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Laboratory studies that help the differential diagnosis between absolute and functional iron deficiency." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "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." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Author \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Study type \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Formulation IV Fe \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No. of patients</th><th class="td" title="table-head " align="left" valign="top" scope="col">Mean age, years \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Mean LVEF % (both groups) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Mean Hb g/dL (both groups) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Treatment duration, weeks \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Follow-up duration, weeks \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Results (IV Fe vs. placebo) \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">IV Fe \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control placebo \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bolger 2006<a class="elsevierStyleCrossRef" href="#bib0625">58</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Open \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sucrose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">68±11.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.2±0.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Hb at 12.6±1.2g/dL NYHA improvement −14 on the MLFHQ +44m T6M \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Toblli 2007<a class="elsevierStyleCrossRef" href="#bib0590">51</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sucrose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75±7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Hb (11.8 vs. 9.8g/dl) ↓ 333.4pg/mL NT-proBNP ↓ CRP (2.3 vs. 6.5mg/dL) ↑ LVEF (35.7 vs. 28.8%) NYHA improvement (2 vs. 3.3) ↓ 18 on the MLFHQ +56m T6M \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Okonko 2008<a class="elsevierStyleCrossRef" href="#bib0545">42</a> (FERRIC-HF) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Single blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sucrose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">64±13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Hb (13 vs. 12.6g/dL) NYHA improvement (2.1 vs. 2.6) ↑ tissue oxygen \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Usmanov 2008<a class="elsevierStyleCrossRef" href="#bib0670">67</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Open \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sucrose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49.4±5.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Hb in 3g/dL Improvement NYHA is class III ↑ LVEF if class III \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anker 2009<a class="elsevierStyleCrossRef" href="#bib0385">10</a> (FAIR-HF) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carboxymaltose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">304 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">155 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">↑ Hb (13 vs. 12.5g/dL) +7 in the KCCQ +35±8m 6-min Test. NYHA improvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ponikowski 2014<a class="elsevierStyleCrossRef" href="#bib0400">13</a> (CONFIRM-HF) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Carboxymaltose \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">152 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">152 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+33m 6-min Test. −0.6 Dyspnea scale +1.3 in the KCCQ +2.8 in the EQ-5D \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">+36m T6M −0.7 Dyspnea scale +4.5 in the KCCQ +2.6 in the EQ-5D \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1319696.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Studies with iron preparations performed with patients with heart failure and anemia or iron deficiency." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:67 [ 0 => array:3 [ "identificador" => "bib0340" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "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" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.A. 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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

Documento de consenso de la Sociedad Española de Cardiología y la Sociedad Española de Medicina Interna sobre el diagnóstico y tratamiento del déficit de hierro en la insuficiencia cardíaca

N. Manitoa,

Corresponding author

nml@bellvitgehospital.cat

Corresponding author.

, J.M. Cerqueirob, J. Comín-Coletc, J.M. García-Pinillad, A. González-Francoe, J. Grau-Amorósf, J.R. Perairag, L. Manzanoh

a Unidad de Insuficiencia Cardíaca y Trasplante Cardíaco, Hospital Universitario de Bellvitge, Barcelona, Spain

b 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

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studies aimed at correcting anemia in patients with renal disease have shown that&#44; although the patients&#8217; functional situation is improved&#44; there can be increased number of cardiovascular complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">8&#44;9</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Progress in the concept&#58; iron enters the game</span><p id="par0015" class="elsevierStylePara elsevierViewall">The clinical trial FAIR-HF&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a> which showed the benefits for quality of life&#44; functional class and exercise capacity of administering intravenous iron to patients with chronic systolic HF&#44; was essential in distinguishing between anemia and ID&#46; The meta-analysis published by Kapoor et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">11</span></a> delved into these benefits and identified the impact on the reduction of hospitalizations&#44; without adverse events&#46; The publication of the RED-HF study&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">12</span></a> which showed neutral results with the use of darbepoetin in patients with HF and systolic dysfunction&#44; and the presentation in 2014 of the positive results of the CONFIRM-HF trial<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a> that used iron carboxymaltose &#40;ICM&#41; in patients with HF and systolic dysfunction have contributed to the definitive separation between the concept of anemia and ID in the development&#44; prognosis and treatment of HF&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">The role of iron in the body</span><p id="par0020" class="elsevierStylePara elsevierViewall">Iron&#39;s fundamental mission is to generate the hemo group during erythropoiesis&#46; Iron is also an essential element in a large number of molecular systems&#44; including the oxidative metabolism &#40;mitochondrial respiratory chain&#44; oxidative enzymes&#41; and fatty acid &#946;-oxidation&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">14</span></a> These functions explain why the consequences of ID are not limited to erythropoiesis but also affect cell energy production &#40;e&#46;g&#46;&#44; in myocytes and cardiomyocytes&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">15</span></a> When cellular iron levels are low&#44; the activity of the mitochondrial respiratory chain decreases&#44; producing less adenosine triphosphate &#40;ATP&#41;&#44; which in turn causes a reduction in exercise capacity and increased fatigue&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">16&#44;17</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pathophysiological concepts of iron</span><p id="par0025" class="elsevierStylePara elsevierViewall">The biological cycle of iron is composed of 2 pathways that ensure its supply to the body&#58; the first enables the recovery of iron from red blood cells that are destroyed in the mononuclear phagocytic system &#40;MPS&#41; of the spleen<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">18</span></a>&#59; the second pathway is through the absorption of ingested iron through enterocytes&#46; Iron is then passed to the bloodstream and binds to transferrin&#44; which facilitates its insertion into iron receptor cells&#46; Once inside the cells&#44; iron can follow 3 routes&#58; binding to ferritin&#44; transport to the mitochondria or binding to iron&#8211;sulfur clusters&#46; When cellular iron levels are low&#44; the concentration of clusters decreases&#44; producing less ATP&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">19</span></a> This process explains why exercise capacity improves after correcting ID&#44; regardless of the presence of anemia&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Hepcidin&#59; does it have central role&#63;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Hepcidin is a peptide hormone synthesized in the liver that exerts a key regulatory action on iron metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">20</span></a> Hepcidin is an acute-phase reactant that intervenes in the antimicrobial immune response&#44; reducing the release of iron into the blood &#40;thereby decreasing its availability for exogenous pathogens&#41;&#44; preventing extracellular oxidative stress and modulating the inflammatory response&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">21</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Hepcidin induces a block in the cellular excretion of iron&#44; such that iron absorption in the duodenum and its recycling in the MPS is reduced&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">22</span></a> causing a reduction in its circulating concentration &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">23</span></a> In the initial phases of HF&#44; hepcidin production is stimulated &#40;hepcidin upregulation&#41;&#44; which retains iron in the MPS&#44; thereby reducing its circulating concentrations and availability to target tissues&#46; This process has 2 objectives&#58; preventing the harmful effects of excess iron &#40;oxidative stress&#41; and reducing the development of inflammatory reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">24</span></a> Both are crucial mechanisms that underlie the progression of cardiovascular damage&#46; Subsequently&#44; when cardiovascular disease is in an advanced phase and ID has been generated&#44; with its consequent energy deficit&#44; an opposite process develops &#40;hepcidin downregulation&#41;&#44; which attempts to reverse this situation&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">24</span></a> This process would explain the findings of various studies of a gradual reduction in hepcidin levels over the course of HF&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Key points</span><p id="par0040" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Recent studies have contributed to the definitive separation between the concept of anemia and that of ID in HF&#46; ID goes beyond a mere comorbidity&#44; consolidating its role in the pathophysiology&#44; prognosis and treatment of HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">The key to iron&#39;s central role lies in its participation in the processes of energy generation in the mitochondrial respiratory chain&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Iron homeostasis is finely governed by hepcidin&#44; which might have a specific behavior in HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">We are witnessing a change in the clinical paradigm of HF from the treatment of anemia to ID correction&#46;</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagnosis of iron deficiency in heart failure</span><p id="par0065" class="elsevierStylePara elsevierViewall">ID has classically been divided into absolute and functional&#46; The first type has ID in the deposits &#40;liver and MPS&#41;&#44; which hinders the body&#39;s needs&#46; In the second type&#44; the amount of available iron decreases&#44; generally by inflammatory mechanisms &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The symptoms associated with ID in HF are nonspecific&#58; reduced exercise capacity&#44; worsening of the New York Heart Association &#40;NYHA&#41; functional class&#44; cognitive and behavior disorders and worsening of depressive symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">25&#8211;27</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Biological parameters</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Serum ferritin</span><p id="par0070" class="elsevierStylePara elsevierViewall">Ferritin is&#44; along with transferrin saturation&#44; the most widely used parameter for confirming suspected ID&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">1&#8211;4</span></a> The prevalence of iron deficiency in HF varies between 30&#37; and 50&#37;&#44; depending on the study&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">28</span></a> The most commonly used diagnostic criterion for ID in the context of HF is that recommended by the European Guidelines of Cardiology&#44; which established that ferritin levels &#60;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L or ferritin levels between 100 and 300<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L with a transferrin saturation &#60;20&#37; are diagnostic for ID&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">27</span></a> In HF&#44; the underlying inflammatory process stimulates the tissue expression of ferritin&#46; The cutoff is therefore higher than that for the healthy population &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Transferrin&#44; total iron-binding capacity and transferrin saturation</span><p id="par0075" class="elsevierStylePara elsevierViewall">Transferrin is a hepatic synthesis protein and the main transporter of iron from the iron-releasing cells &#40;intestinal and macrophage&#41; to the specific receptors &#40;e&#46;g&#46;&#44; erythroblasts&#41;&#46; The lack of iron stimulates its synthesis and raises its plasma concentrations&#46; A similar parameter is serum&#39;s total iron-binding capacity &#40;TIBC&#41;&#44; which indicates the capacity of blood proteins to bind to iron&#46; Both reflect the quantity of iron in the circulating pool&#59; its increase would therefore reflect functional ID&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The transferrin saturation index &#40;TSAT&#41; or percentage of transferrin with iron bound to it is the main parameter for calculating the availability of circulating iron&#46; Its reduction &#40;TSAT &#60;20&#37;&#41; is a marker of functional ID&#46; ID progresses with an increase in transferrin levels and TIBC and a reduction in TSAT&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">As with ferritin&#44; transferrin &#40;and thus TIBC and TSAT&#41; has significant limitations&#58; daytime fluctuations in its value &#40;17&#8211;70&#37;&#41;&#44; reductions in cachexia&#44; malnutrition and chronic disease and increases in inflammatory processes by acting as an acute-phase reactant<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">29</span></a> &#40;thus its limitation in acute HF&#41;&#46; Nevertheless&#44; the reduction in TSAT is more sensitive than ferritin for detecting ID in HF&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">26</span></a> Anemia associated with low TSAT values has often been observed in HF in advanced NYHA stages&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Soluble transferrin receptor</span><p id="par0090" class="elsevierStylePara elsevierViewall">This is the ectodomain of the transferrin receptor &#40;responsible for the intracellular incorporation of iron&#41; and is expressed in the cell membrane according to the iron needs in the erythroblastic precursors and in the cells that take up iron &#40;e&#46;g&#46;&#44; cardiomyocytes&#44; myocytes&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">26</span></a> An increase in this receptor reflects unsatisfied cellular requirements &#40;functional ID&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">30</span></a> The receptor is not affected by the inflammatory condition&#44; and its concentration is less variable&#46; A recent study identified the prognostic importance of defining ID in acute HF &#40;where the acute-phase reactant levels are increased&#44; and there is significant variability in ferritin levels and TSAT&#41; according to the soluble transferrin receptor &#40;sTfR&#41; and hepcidin&#46; Thus an sTfR value &#8805;1&#46;59<span class="elsevierStyleHsp" style=""></span>mg&#47;L is a marker of functional ID&#44; and a hepcidin level &#60;14&#46;5<span class="elsevierStyleHsp" style=""></span>ng&#47;mL is a marker of absolute ID&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Hepcidin</span><p id="par0095" class="elsevierStylePara elsevierViewall">The behavior of hepcidin is similar to that of ferritin&#44; and its reduction reflects iron deposit depletion&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">32</span></a> Hepcidin is mainly eliminated renally&#44; and its concentration therefore increases in renal failure&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">33</span></a> In HF&#44; increased hepcidin levels have been observed in early phases and decreased levels in more advanced phases&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Hemogram</span><p id="par0100" class="elsevierStylePara elsevierViewall">The earliest expression of erythropoiesis with ID is the reduction in the reticulocyte hemoglobin content &#40;CHr&#41;&#44; less than 28<span class="elsevierStyleHsp" style=""></span>pg&#46; The CHr reflects the available iron for erythropoiesis and is an early marker of the response to iron therapy&#46; Later expressions include the increase in the percentage of hypochromic red blood cells&#44;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">28&#44;29</span></a> and reductions in mean corpuscular volume&#44; mean corpuscular hemoglobin&#44; mean corpuscular hemoglobin concentration and hemoglobin&#46; In practice&#44; we suspect ID whether the mean corpuscular volume decreases &#40;which can go unnoticed if there is vitamin B12 deficiency&#44; folate deficiency or inflammatory processes such as HF&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Red blood cell distribution width</span><p id="par0105" class="elsevierStylePara elsevierViewall">This width is a quantitative index of homogeneity of the size of red blood cells&#44; which helps monitor the effect of iron therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">28&#44;35</span></a> Normal values for red blood cell distribution width are 11&#46;5&#8211;14&#46;5&#37;&#46; This width is a prognostic marker for chronic<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">36</span></a> and acute HF&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">37</span></a> The decrease in width after intravenous iron therapy is correlated with improvements in the distance traveled in the 6-min walk test &#40;T6M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Serum iron</span><p id="par0110" class="elsevierStylePara elsevierViewall">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&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">26</span></a></p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Bone marrow biopsy</span><p id="par0115" class="elsevierStylePara elsevierViewall">Prussian blue staining is the gold standard for assessing bone marrow deposits of iron&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">30</span></a> Its practical limitations restrict its use to questionable cases after a study of the previously mentioned parameters&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Imaging techniques</span><p id="par0120" class="elsevierStylePara elsevierViewall">The reduction in myocardial iron content&#44; detected with cardiovascular magnetic resonance T2 sequencing&#44; has recently been related to poorer left ventricular systolic function and an increased risk of adverse events in nonischemic HF&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Diagnosis of iron deficiency</span><p id="par0125" class="elsevierStylePara elsevierViewall">Based on the existing evidence&#44; a number of ID detection criteria have been proposed in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; In general&#44; we use the serum values of iron&#44; ferritin and transferrin &#40;iron and transferrin enable the calculation of TSAT&#41;&#46; The cutoffs used by most studies to identify ID are as follows<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">10&#44;38&#8211;43</span></a>&#58; &#40;a&#41; ferritin &#60;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L for absolute ID and &#40;b&#41; ferritin&#46; Other authors&#44; due to the relevance of the underlying inflammatory disorder&#44; consider functional ID when ferritin levels are &#60;800<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L and when TSAT values are &#60;20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a> These definitions come from the nephrology setting&#44; given the considerable similarity between chronic kidney disease and HF&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">44</span></a> The cutoff points mentioned above are not valid for acute HF&#44; because ferritin levels increase as the inflammatory and oxidative process increases&#44; and TSAT rises artificially due to the increase in the accompanying catabolism and malnutrition&#44; which reduces transferrin levels&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">45</span></a> A hepcidin concentration &#60;40<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; which is indicative of iron deposit depletion&#44; and an sTfR &#62;1&#46;59<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; which shows an increase in iron demand due to cellular metabolism&#44; are probably more sensitive markers of ID&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">For patients with HF&#44; we recommend performing a study of the iron parameters in the following circumstances&#58; &#40;a&#41; systematically at least once a year&#59; &#40;b&#41; if there is clinical progression of the HF&#44; an increase in natriuretic peptide levels or a reduction in the ejection fraction&#59; and &#40;c&#41; if there is anemia&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Key points</span><p id="par0135" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0140" class="elsevierStylePara elsevierViewall">The study of ID in HF should be based on ferritin and TSAT&#46; We define ID as a ferritin level &#60;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L or between 100 and 300<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L along with a TSAT &#60;20&#37;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">The sTfR is an accurate tool in the diagnosis of ID and can be especially useful in questionable cases &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Although studies have been conducted mostly on patients with systolic HF&#44; we recommend also studying ID in those with preserved left ventricular ejection fraction &#40;LVEF&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0155" class="elsevierStylePara elsevierViewall">In HF&#44; a basic study of the iron profile should be performed systematically at least annually and any time the disease progresses&#46;</p></li></ul></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Drug treatment of iron deficiency in heart failure</span><p id="par0160" class="elsevierStylePara elsevierViewall">In recent years&#44; the impact of anemia on the worsening condition of patients with HF has been observed&#46; We do not yet know precisely whether anemia contributes to the worsening of the prognosis or is only a marker of HF severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">46&#44;47</span></a> More recently&#44; ID has emerged as an important element in the progression of HF&#44; regardless of hemoglobin concentrations&#44; which suggests its direct participation in the pathophysiology of HF due to its extra-hematopoietic functions&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">24&#44;48</span></a></p><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Effects of iron therapy on heart failure</span><p id="par0165" class="elsevierStylePara elsevierViewall">ID therapy has positives effects on&#58; &#40;1&#41; quality of life&#44;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">49</span></a> &#40;2&#41; creatinine concentrations&#44;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">50</span></a> &#40;3&#41; functional class&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a> &#40;4&#41; exercise capacity&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a> &#40;5&#41; maximum oxygen consumption &#40;VO<span class="elsevierStyleInf">2</span>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">42</span></a> &#40;6&#41; LVEF<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">51</span></a> and &#40;7&#41; hospital readmissions&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Oral iron</span><p id="par0170" class="elsevierStylePara elsevierViewall">The use of oral iron has significant limitations for patients with HF due to the poor gastrointestinal tolerance<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">18</span></a> and erratic absorption due to several mechanisms &#40;e&#46;g&#46;&#44; high hepcidin levels&#44; polypharmacy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">52</span></a> Additionally&#44; ID has a slow recovery&#44; given that only 10&#37; of iron ingested orally is absorbed&#46; We also have no large studies that endorse the use of oral iron&#46; The goal of the currently underway IRONOUT &#40;<a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02188784">NCT02188784</a>&#41; study is to determine&#44; in patients with HF and LVEF &#60;40&#37;&#44; whether oral iron polysaccharide is superior to placebo in improving functional capacity&#44; as measured by changes in peak VO<span class="elsevierStyleInf">2</span>&#46; To date&#44; we only have the results of the IRON-HF study&#44; which compared 8 patients with intravenous iron and 7 patients with oral iron&#46; Although both formulations corrected the hemoglobin levels&#44; parenteral iron was superior in improving the functional capacity measured by ergospirometry&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Parenteral iron</span><p id="par0175" class="elsevierStylePara elsevierViewall">Parenteral iron is more effective in correcting anemia and iron deficiency than oral preparations&#46; At this time&#44; we have various presentations for intravenous use that differ in their physical and biochemical characteristics&#46; Each compound consists of an iron nucleus &#40;<span class="elsevierStyleSmallCaps">III</span>&#41; coated by a carbohydrate layer&#44; which&#44; depending on its composition and size&#44; confers stability to the complex and modulates the rate of iron release&#46; This composition determines its usage and safety profile&#44; dosage&#44; infusion rate and administration interval&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">54</span></a> The carbohydrate part can cause anaphylactic reactions&#44; seemingly due to its size and structure&#44; which is much less in the new preparations&#58; carboxymaltose and isomaltoside&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">55</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Iron sucrose&#46;</span> Iron sucrose is an iron <span class="elsevierStyleSmallCaps">III</span> hydroxide complex very similar to ferritin combined with a moderately stable carbohydrate&#44; which&#44; due to its molecular weight&#44; is not eliminated renally or by dialysis&#46; After its intravenous administration&#44; iron sucrose is rapidly distributed bound to plasma proteins&#44; mainly apotransferrin and ferritin&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">54</span></a> Iron sucrose is not associated with fatal anaphylactic reactions due to immunogenicity&#59; however&#44; anaphylactoid and pseudoallergic reactions have been reported &#40;estimated rate&#44; 0&#46;0022&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">56</span></a> in relation to the administration of dosages greater than recommended or to very rapid infusions&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Ferric carboxymaltose&#46;</span> Ferric carboxymaltose is an iron complex with carbohydrate polymers&#46; Once in the bloodstream&#44; ferric carboxymaltose is distributed rapidly toward the bone marrow and is deposited in the liver and spleen&#46; Its half-life is 7&#8211;12<span class="elsevierStyleHsp" style=""></span>h and has minimal renal elimination&#46; Ferric carboxymaltose has a better safety profile and allows for larger administered doses of iron &#40;up to 20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; maximum 1000<span class="elsevierStyleHsp" style=""></span>mg per session a week&#41;&#44; with a shorter infusion time&#46; The rate of severe adverse events related to ICM is low&#44;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">57</span></a> which include reports of headache&#44; urticaria&#44; metallic taste&#44; back pain&#44; chest pain&#44; gastrointestinal symptoms&#44; edema&#44; bradycardia and hypotension&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Evidence of parenteral iron therapy in heart failure</span><p id="par0190" class="elsevierStylePara elsevierViewall">There are several studies with various methodologies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">10&#44;13&#44;42&#44;51&#44;58</span></a> These include FAIR-HF&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a> the first large&#44; multicenter&#44; randomized&#44; double-blind&#44; placebo-controlled &#40;2&#58;1&#41; study on parenteral iron therapy in 459 outpatients with HF and ID&#44; with or without anemia&#46; The treatment group was administered 200<span class="elsevierStyleHsp" style=""></span>mg of intravenous ICM weekly until they reached the necessary dose to correct the ID &#40;calculated using the Ganzoni formula<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">59</span></a>&#41;&#46; The group was then administered 200<span class="elsevierStyleHsp" style=""></span>mg intravenously monthly for 6 months &#40;maintenance phase&#41;&#46; The primary endpoint was the quality of life and symptom improvement at week 24&#46; The secondary endpoints included assessing these parameters at weeks 4 and 12&#44; the distance traveled in the T6M&#44; the score on the Kansas City Cardiomyopathy Questionnaire&#44; hospitalization for HF and mortality&#46; The inclusion criteria were as follows&#58; NYHA class II-III&#44; ferritin levels &#60;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L or 100&#8211;300<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L with a TSAT &#60;20&#37;&#44; LVEF &#60;40&#37; or &#60;45&#37; in patients with a previous hospitalization for HF&#44; and hemoglobin levels of 9&#46;5&#8211;13&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46; Fifty percent of the intervention group presented moderate or clear symptomatic improvement compared with 28&#37; of the placebo group &#40;OR&#44; 2&#46;51&#59; 95&#37; CI 1&#46;75&#8211;3&#46;61&#41;&#46; The improvement in functional class was also greater at week 24 for the treated group&#44; 47 vs&#46; 30&#37; &#40;OR&#44; 2&#46;40&#59; 95&#37; CI 1&#46;55&#8211;3&#46;71&#41;&#46; There were no significant differences between the patients with and without anemia&#46; The distance traveled in the T6M was also greater in the patients treated with iron &#40;313<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7<span class="elsevierStyleHsp" style=""></span>m vs&#46; 277<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>m&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; but there were no differences in the mortality rate or adverse events&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">Lastly&#44; the CONFIRM-HF study&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a> designed by the same FAIR-HF group to determine the benefit and safety of long-term intravenous ICM&#44; included 152 patients per arm&#44; using higher doses in the anemia correction phase&#44; followed by quarterly maintenance doses of 500<span class="elsevierStyleHsp" style=""></span>mg&#46; The group treated with intravenous iron achieved a 33<span class="elsevierStyleHsp" style=""></span>m improvement in the T6M &#40;main study endpoint&#41; after 6 months&#44; compared with the placebo group&#44; which was maintained up to 12 months&#46; This improvement was independent of the presence of anemia&#44; prior ferritin concentration and functional class&#44; which was more relevant in the patients with diabetes or renal failure&#46; In addition&#44; the secondary endpoints such as quality of life&#44; fatigue and improvement in the functional class at week 24 showed significant differences in favor of the patients treated with ICM&#46; It is worth noting that there was a significant reduction in the risk of hospitalization for HF in the treatment arm &#40;relative risk &#91;RR&#93;&#44; 0&#46;39&#59; 95&#37; CI 0&#46;19&#8211;0&#46;82&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;009&#41;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The data from a meta-analysis that included 4 studies &#40;FER-CARS-01&#44; FAIR-HF&#44; EFFICACY-HF and CONFIRM-HF&#41;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">60</span></a> with 839 patients treated with ICM versus placebo were recently presented&#46; The results show a significant reduction of 41&#37; in cardiovascular mortality and hospitalizations due to cardiovascular causes &#40;RR&#44; 0&#46;59&#59; 95&#37; CI 0&#46;40&#8211;0&#46;88&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;009&#41; with ICM&#46; There was also a significant reduction of 59&#37; in hospitalizations for HF &#40;RR&#44; 0&#46;41&#59; 95&#37; CI 0&#46;23&#8211;0&#46;73&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;003&#41;&#46; The safety analysis reported no severe hypersensitivity reactions&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Two substudies of the FAIR-HF applied a cost-effectiveness model based on the financial data published by official bodies of the United Kingdom and Spain&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">61&#44;62</span></a> In the case of the Spanish model&#44; the cost of treatment with ICM per quality-adjusted life year gained was 6123&#46;78 euros&#44; markedly lower than the 30&#44;000 euros&#44; which is the threshold under which a treatment is considered cost-effective in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">63</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Finally&#44; the recent HF guidelines of the European Society of Cardiology have given a class IIa recommendation &#40;a level of evidence A&#41; to treatment with ICM for symptomatic patients with reduced LVEF and ID &#40;serum ferritin levels &#60;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L or serum ferritin levels between 100 and 299<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L and a transferrin saturation index &#60;20&#37;&#41; to relieve symptoms and to improve exercise capacity and quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">27</span></a></p></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Key points</span><p id="par0215" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0220" class="elsevierStylePara elsevierViewall">ID correction by itself is a therapeutic objective in HF&#44; even without the presence of anemia&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Treatment for ID is indicated provided the patient presents symptoms &#40;NYHA &#8805;<span class="elsevierStyleSmallCaps">II</span>&#41; despite therapeutic optimization of the HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Treatment of ID through the use of ICM is recommended in the 2016 clinical practice guidelines for HF of the European Society of Cardiology&#44; with a class IIa recommendation and level of evidence A&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0235" class="elsevierStylePara elsevierViewall">ID correction should be considered for asymptomatic patients with HF when associated with anemia&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Patients need to be euvolemic and undergoing optimal medical treatment before treatment with ID can be considered&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0245" class="elsevierStylePara elsevierViewall">The benefit of ID treatment has only been shown for patients with depressed systolic function&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Patients with HF and chronic renal failure who are not on dialysis&#44; have low hemoglobin levels and have been readmitted for HF can especially benefit from iron replenishment&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">64</span></a></p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Various observational studies have suggested that the impact of ID on the prognosis&#44; functional capacity and quality of life of patients with HF and preserved LVEF is similar to that observed in patients with reduced LVEF&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">43&#44;65&#44;66</span></a></p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8226;</span><p id="par0260" class="elsevierStylePara elsevierViewall">According to the protocols of the FAIR-HF<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a> and CONFIRM-HF studies&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a> we have 2 ID treatment regimens &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#58; &#40;a&#41; 200<span class="elsevierStyleHsp" style=""></span>mg&#47;week until the deficiency has been corrected &#40;calculated by the Ganzoni formula&#41;&#44; followed by 200<span class="elsevierStyleHsp" style=""></span>mg&#47;month as maintenance<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a> or &#40;b&#41; 1000<span class="elsevierStyleHsp" style=""></span>mg as an initial dose&#44; plus 500<span class="elsevierStyleHsp" style=""></span>mg at 7 days in some cases depending on the deficiency calculated in the simplified formula&#44; followed by 500<span class="elsevierStyleHsp" style=""></span>mg every 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a> In both cases&#44; the maintenance dose will be based on the blood count values and the ferrokinetics prior to the new dose&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></li></ul></p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conclusions</span><p id="par0265" class="elsevierStylePara elsevierViewall">After the publication of important studies on patients with HF that differentiated the concept of anemia and ID&#44; there is sufficient clinical evidence for a change in paradigm&#46; ID is more than a comorbidity&#44; and it is possible that ID plays a role in the pathophysiology of HF&#46; Thus&#44; the diagnosis of ID and its clinical approach have consolidated as a key factor in treating HF&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">The monitoring of iron kinetics by determining ferritin levels and TSAT has to be performed after the diagnosis of HF&#44; for episodes of decompensation and annually for the early detection of ID&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">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&#46; The various existing treatment regimens must be adapted to the patient&#39;s clinical profile&#44; the need for rapid correction and the healthcare setting&#44; either in the hospital or outpatient setting&#46; ICM could be the treatment of choice due to its safety&#44; efficacy and easy administration&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interest</span><p id="par0280" class="elsevierStylePara elsevierViewall">Vifor Pharma Spain S&#46;L&#46; facilitated the workgroup meetings for the drafting of this document but did not participate in the study design&#59; data collection&#44; analysis or interpretation&#59; drafting of the manuscript&#59; or in the decision to send it for publication&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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            0 => "D&#233;ficit de hierro"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Iron deficiency in patients with heart failure is a medical problem of recent particular interest&#46; 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&#46; However&#44; applying the evidence from these studies in clinical practice is still controversial&#44; both in terms of the diagnostic criteria for iron deficiency &#40;absolute and functional&#41; and the optimal method for iron replenishment&#46; This article is a consensus document that integrates the recommendations of the Spanish Society of Internal Medicine and the Spanish Society of Cardiology&#46; The article reviews the scientific evidence and proposes a diagnostic and therapeutic performance protocol for iron deficiency in heart failure&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El d&#233;ficit de hierro en los pacientes con insuficiencia cardiaca es un problema m&#233;dico que &#250;ltimamente suscita un inter&#233;s particular&#46; Esto se debe a la publicaci&#243;n de varios ensayos cl&#237;nicos que demuestran que la administraci&#243;n de hierro intravenoso en estos pacientes mejora su capacidad funcional&#44; e incluso reduce los ingresos por descompensaci&#243;n de insuficiencia cardiaca&#46; Sin embargo&#44; la aplicaci&#243;n de la evidencia aportada por estos estudios en la pr&#225;ctica cl&#237;nica es a&#250;n controvertida&#44; tanto en los criterios diagn&#243;sticos del d&#233;ficit de hierro&#44; absoluto y funcional&#44; como en la forma &#243;ptima de reposici&#243;n del hierro&#46; Este art&#237;culo es un documento de consenso que integra las recomendaciones de las Sociedades Espa&#241;olas de Medicina Interna y Cardiolog&#237;a en el que se revisa la evidencia cient&#237;fica y se propone un protocolo de actuaci&#243;n diagn&#243;stica y terap&#233;utica del d&#233;ficit de hierro en la insuficiencia cardiaca&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Manito N&#44; Cerqueiro JM&#44; Com&#237;n-Colet J&#44; Garc&#237;a-Pinilla JM&#44; Gonz&#225;lez-Franco A&#44; Grau-Amor&#243;s J&#44; et al&#46; Documento de consenso de la Sociedad Espa&#241;ola de Cardiolog&#237;a y la Sociedad Espa&#241;ola de Medicina Interna sobre el diagn&#243;stico y tratamiento del d&#233;ficit de hierro en la insuficiencia card&#237;aca&#46; Rev Clin Esp&#46; 2017&#59;217&#58;35&#8211;45&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Hepcidin regulation&#46;</p>"
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        "fuente" => "Source&#58; Jankowska et al&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">31</span></a>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for iron deficiency in heart failure&#46; Abbreviations&#58; HF&#44; heart failure&#59; TSAT&#44; transferrin saturation index&#59; sTfR&#44; soluble transferrin receptor&#46; <span class="elsevierStyleSup">a</span> Start&#58; follow-up or decompensation&#46; <span class="elsevierStyleSup">b</span> For acute HF with a doubtful diagnosis&#44; measuring hepcidin and sTfR levels could be useful after measuring ferritin and TSAT&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Treatment options for heart failure with iron deficiency&#46; Abbreviations&#58; Fe&#44; iron&#59; Hb&#44; hemoglobin&#59; HF&#44; heart failure&#59; TSAT&#44; transferrin saturation index&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; TSAT&#44; transferrin saturation index&#59; sTfR&#44; soluble transferrin receptor&#59; TIBC&#44; total iron-binding capacity&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameters&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Absolute iron deficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Functional iron deficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum iron&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ferritin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Transferrin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TSAT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TIBC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">sTfR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hepcidin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Normal or increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Medular iron deposits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Laboratory studies that help the differential diagnosis between absolute and functional iron deficiency&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; EQ-5D&#44; EuroQoL-5D Health Questionnaire&#59; IV Fe&#44; intravenous iron&#59; LVEF&#44; left ventricular ejection fraction&#59; Hb&#44; hemoglobin&#59; KCCQ&#44; Kansas City Cardiomyopathy Questionnaire&#59; MLFHQ&#58; Minnesota Living With Heart Failure Questionnaire&#59; NT-ProBNP&#44; N-terminal brain natriuretic propeptide&#59; NYHA&#44; New York Heart Association&#59; CRP&#44; C-reactive protein&#59; T6M&#58; 6-min test&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Author&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Study type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Formulation IV Fe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46; of patients</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Mean age&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Mean LVEF &#37; &#40;both groups&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Mean Hb g&#47;dL &#40;both groups&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Treatment duration&#44; weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Follow-up duration&#44; weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Results &#40;IV Fe vs&#46; placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">IV Fe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Control placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bolger 2006<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Open&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sucrose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Hb at 12&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;2<span class="elsevierStyleHsp" style=""></span>g&#47;dL<br>NYHA improvement<br>&#8722;14 on the MLFHQ<br>&#43;44<span class="elsevierStyleHsp" style=""></span>m T6<span class="elsevierStyleHsp" style=""></span>M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Toblli 2007<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sucrose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Hb &#40;11&#46;8 vs&#46; 9&#46;8<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#41;<br>&#8595; 333&#46;4<span class="elsevierStyleHsp" style=""></span>pg&#47;mL NT-proBNP<br>&#8595; CRP &#40;2&#46;3 vs&#46; 6&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;<br>&#8593; LVEF &#40;35&#46;7 vs&#46; 28&#46;8&#37;&#41;<br>NYHA improvement &#40;2 vs&#46; 3&#46;3&#41;<br>&#8595; 18 on the MLFHQ<br>&#43;56<span class="elsevierStyleHsp" style=""></span>m T6<span class="elsevierStyleHsp" style=""></span>M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Okonko 2008<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">42</span></a><br>&#40;FERRIC-HF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Single blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sucrose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Hb &#40;13 vs&#46; 12&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;<br>NYHA improvement &#40;2&#46;1 vs&#46; 2&#46;6&#41;<br>&#8593; tissue oxygen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Usmanov 2008<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">67</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Open&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sucrose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Hb in 3<span class="elsevierStyleHsp" style=""></span>g&#47;dL<br>Improvement NYHA is class <span class="elsevierStyleSmallCaps">III</span><br>&#8593; LVEF if class <span class="elsevierStyleSmallCaps">III</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anker 2009<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">10</span></a><br>&#40;FAIR-HF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double<br>blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Carboxymaltose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">304&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">155&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Hb &#40;13 vs&#46; 12&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;<br>&#43;7 in the KCCQ<br>&#43;35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>m 6<span class="elsevierStyleMonospace">-</span>min Test&#46;<br>NYHA improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ponikowski 2014<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">13</span></a><br>&#40;CONFIRM-HF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Carboxymaltose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">152&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">152&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;33<span class="elsevierStyleHsp" style=""></span>m 6<span class="elsevierStyleMonospace">-</span>min Test&#46;<br>&#8722;0&#46;6 Dyspnea scale<br>&#43;1&#46;3 in the KCCQ<br>&#43;2&#46;8 in the EQ-5D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;36<span class="elsevierStyleHsp" style=""></span>m T6<span class="elsevierStyleHsp" style=""></span>M<br>&#8722;0&#46;7 Dyspnea scale<br>&#43;4&#46;5 in the KCCQ<br>&#43;2&#46;6 in the EQ-5D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2016.10.003

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