Iron deficiency in patients with heart failure
Transcription
Iron deficiency in patients with heart failure
European Heart Journal – Cardiovascular Pharmacotherapy (2015) 1, 58–64 doi:10.1093/ehjcvp/pvu016 REVIEW Iron deficiency in patients with heart failure Sarah Fitzsimons* and Robert Neil Doughty Department of Medicine and National Institute for Health Innovation, University of Auckland, and Greenlane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand Received 6 October 2014; revised 16 October 2014; accepted 20 October 2014 Iron deficiency (ID) is a commonly present co-morbidity in patients with heart failure (HF). In iron deficient but otherwise healthy individuals, correction of ID restores exercise capacity and endurance regardless of the presence of anaemia. Recently, iron replacement in patients with HF with reduced ejection fraction has been shown to improve symptoms and exercise capacity. This article reviews the clinical relevance of ID in HF and evidence for iron replacement. ----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Heart failure † Iron deficiency Introduction Heart failure (HF) is a common condition and one that is projected to increase significantly in the coming decades due to the ageing population and increased survival of patients with complications of coronary artery disease. It is estimated that the number of patients living with HF in the USA will increase by 50% by 2030.1 Heart failure is a major cause of death with current 1 year mortality rates of 25–35% after an initial hospitalization with HF.2 Despite major advances in management, a large proportion of patients with HF remain symptom limited, with poor exercise capacity and at high risk of mortality.3,4 Further treatment targets to decrease this high morbidity and mortality burden are therefore needed. Iron deficiency (ID) is a commonly present co-morbidity in patients with HF. Recently a high prevalence of ID has been found in patients with HF with reduced ejection fraction (HF-REF) and regardless of the concomitant presence of anaemia it has been associated with increased mortality and a poorer quality of life. In iron deficient but otherwise healthy individuals, correction of ID restores exercise capacity and endurance regardless of the presence of anaemia.5,6 This review focuses on the clinical relevance of ID for patients with HF and the available evidence for iron replacement therapy. The review does not address the recent trials that include erythropoietic stimulating agents in the treatment of patients with HF with anaemia (although some of these studies did also include iron replacement). Metabolism of iron Iron is an active micronutrient and arguably the body’s most important biological catalyst.7 It is essential for the formation of haemoglobin (Hb) and myoglobin (oxygen transport and storage molecules) and is a co-factor for enzymatic reactions required for oxidative metabolism, including those occurring in the myocardium.7 – 11 It also plays a role in our host defence mechanisms.8 Iron is tightly regulated with pathology occurring in those with sustained iron overload or deficiency.8,11 As there is no active excretion of iron (with loss through sloughing of duodenal enterocytes into the bowel and bleeding only) it is the intake, recycling, and storage of iron that is regulated. Iron is absorbed in the duodenum with organic haem taken up via a haem-specific receptor (HCP1) into the duodenal enterocyte and then broken down into free iron and biliverdin intracellularly.11 Inorganic (non-haem) iron is absorbed via the divalent metal transporter 1 (DMT1).8,11 – 13 It exists in the ferric (Fe3+) form and requires reduction by ferric oxidoreductases, including duodenal cytochrome B, to ferrous (Fe2+) at the apical surface of the enterocyte before absorption.8,11 Once inside the enterocyte ferrous ions are either conjugated with apoferritin and remain intracellularly as ferritin or are converted back to the ferric state at the basolateral surface of the enterocyte and excreted via ferroportin into the blood stream where they bind to the plasma protein apotransferrin.11,12 Transferrin then transports the iron to target tissues for utilization or storage. Ferroportin is the iron export protein and its presence in the cell membrane of duodenal enterocytes, macrophages (site of iron recycling from senescent erythrocytes), and hepatocytes (site of iron storage) is regulated by hepcidin.8,12 Hepcidin is the iron regulatory hormone produced in the liver in response to both the fluctuating level of iron in the hepatocyte, and elevated cytokine (IL6) levels induced by inflammation or infection.8,14 – 16 The postulated role of hepcidin in inflammation and infection is to deprive pathogens of essential iron; forming part of our innate immunity.8 When iron or cytokine levels are high, hepcidin synthesis is stimulated resulting in the removal of ferroportin from * Corresponding author. Tel: +64 9 373 7599, Fax: +64 9 3677146 Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected] 59 Iron deficiency in patients with HF Table 1 Diagnosing iron deficiency Absolute ID Functional ID ................................................................................ Peripheral blood tests Ferritin Transferrin saturation ,100 mg/L Tsat decreased but the level does not contribute to diagnosis 100–300 mg/L Tsat ,20% BM examination Prussian Blue-stained BM aspirates for the presence or absence of iron granules has been considered the gold standard in evaluating iron-depleted states the duodenal enterocyte, macrophage, and hepatocyte cell membranes diminishing iron efflux into the bloodstream.8,15 Conversely, in ID and hypoxia, hepcidin synthesis is down-regulated allowing ferroportin to remain in the cell membrane and iron to be absorbed or released into the plasma.8,14,15 The exact mechanism for this remains unclear as experiments that exposed human hepatocytes directly to iron-saturated transferrin did not induce hepcidin synthesis and therefore a yet to be identified iron sensing intermediate which activates hepcidin production and release is likely to be present.14 Defining iron deficiency Iron deficiency can be characterized as absolute or functional, both of which can occur in patients with HF. Anaemia occurs when ID is severe enough to reduce erythropoiesis and decrease Hb production.17,18 Absolute ID is defined when iron stores are depleted though iron homeostasis is intact (Table 1). Bone marrow (BM) examination with the absence of iron on specific staining (Perls Prussian blue) remains the gold standard for diagnosis of absolute ID.17,19,20 Serum ferritin levels have been found to be an accurate reflection of BM iron stores in the well patient and ID can be diagnosed when the circulating ferritin level is below the reference range for the assay used (usually ,15 –30 mg/L).21 However, ferritin is a positive acute phase protein and in patients with chronic stable inflammatory conditions levels of up to 70–98 mg/L have been found to correlate with absent iron stores on BM examination.19,22 Functional ID is defined when iron supply is inadequate to meet iron demand despite potentially normal body stores. A transferrin saturation ,20% has been established as the most accurate measure of functional ID as it is a reflection of the circulating iron available for metabolism. Transferrin is a negative acute phase protein though it is not as affected by inflammation as ferritin.23 It has been suggested that serum-soluble transferrin receptor (sTfR) level is a more accurate measure of iron status as it is not affected by inflammation.24,25 Transferrin receptor production is increased when intracellular iron stores are low to aid the iron uptake into the cell. In a recent meta-analysis assessing the diagnostic accuracy of serum ferritin and soluble transferrin receptor in comparison to BM iron staining, sTfR appeared to have higher sensitivity but lower specificity than ferritin.17 Significant heterogeneity between the included studies was seen and the diagnostic cut-off for ferritin was not routinely adjusted for the presence of inflammation making definitive conclusions regarding the relative accuracies of the two tests difficult. There is no perfect test to diagnose ID. Regular BM biopsies are impractical, iron studies lack sensitivity in the presence of inflammation but are an easily accessible test, sTfR is not widely available, and may lack specificity and other markers of ID, e.g. RDW and MCV that have been shown to change in concordance with ID and replacement have not been validated for diagnostic use. Pragmatically, in most recent clinical studies, ID has been defined as a ferritin level ,100 mg/L or a normal ferritin (100 –300 mg/L) with a Tsat ,20%.4,26 – 33 Functional ID has been found to be more common in the earlier stages of HF with absolute ID developing as the disease progresses.7 To date, there are no clear indications whether sexspecific definitions of ID are required. Prevalence of iron deficiency in heart failure patients A high prevalence of ID has been found in patients with stable chronic HF regardless of the presence of concomitant anaemia, geographical location, or ethnicity (Table 2).4,7,29 In a study of 751 stable chronic HF patients from a multi-ethnic Asian population, 61.4% were ID compared with 39.3% of controls from the general population.30 In a study of 127 patients with stable chronic HF and an LVEF of ,45%, approximately one-third were ID (of whom three-quarters were not anaemic).31 In another report, involving 546 patients with chronic HF in Europe, 36% were found to be iron deficient, including 32% of the non-anaemic patients.29 The varying prevalence of ID depending on the definition is illustrated in a recent study where, firstly, 43% of 127 patients with HF were ID when defined using Tsat ,20% alone, if ferritin levels were included in the definition 36% were ID but not anaemic and 23% had ID and anaemia.7 Prevalence of ID appears higher among patients with acute decompensated HF (ADHF).24,27 In a study involving 823 patients with ADHF from 46 centres in France, two-thirds of men and threequarters of women were ID.27 As has been reported in patients with chronic HF, prevalence of ID was high even in the absence of anaemia, with 57% of men and 75% women having ID without anaemia. Few studies have reported BM data for patients with HF. In one small study involving 37 patients who were hospitalized with ADHF BM staining for iron demonstrated that 73% were ID. These data, while limited, suggest that the prior reported prevalence of ID of 75% is likely to be an accurate reflection of the true prevalence of ID among patients with ADHF.34 Pathophysiology of iron deficiency in heart failure Systemic iron homeostasis Inappropriate elevation of hepcidin is an important mechanism of anaemia of chronic disease.35 In inflammatory conditions, higher levels of hepcidin coincide with elevated inflammatory markers (IL6) and more severe disease.14,35 In HF, the opposite relationship has been demonstrated, with hepcidin levels found to be inversely 60 Table 2 S. Fitzsimons and R.N. Doughty Studies reporting prevalence of Iron deficiency in heart failure Study n LVEF cohort average (%) Age range (years) Ethnicity Prevalence of ID ...................................................................... Whole group (%) Non-anaemic patients (%) Anaemic patients (%) .............................................................................................................................................................................. Yeo et al.30 751 34.4 + 15.9 Rangel et al.31 Jankowska et al.29 127 546 28 + 9.1 26 + 7 1506 33 + 14 Klip et al.4 157 32 + 9 Okonko et al.43 Studies with ID defined by BM examination Nanas et al.34 37 22.5 + 5.9 62 + 12.2 Asian 61.4 59 65.3 53– 68 55 + 11 Portugese European 36 37 34 32 43 57 64 + 13 European 50 45.6 61.2 71 + 12 British 69 65 78 European 73 N/A N/A 57.9 + 10.9 related to the severity of disease. In a case –control study of 321 patients with chronic HF, high hepcidin levels were found in patients with mild symptoms of HF (NYHA I/II).10 Hepcidin levels were not associated with Hb levels, IL6 levels were low, and ferritin levels were high, suggesting that the elevation of hepcidin was secondary to high iron levels and that iron homeostasis was deranged. With increasing severity of disease prevalence of ID anaemia increased and hepcidin levels were lower, both regardless of increased levels of IL6, again suggesting that hepcidin levels are more responsive to iron than inflammatory markers in HF. While similar results were found in another smaller cohort of patients with HF,36 further studies are required in this area. Liver congestion may also play a role in the development of absolute ID in patients with HF. An animal study involving rats with ID anaemia induced by either liver congestion, haemolysis, or blood loss demonstrated that those with liver congestion had lower serum iron and transferrin levels, and higher hepcidin levels at any severity of anaemia.16 Furthermore, higher levels of haemosiderin laden macrophages were found in the liver of the congested rats relative to the other cohorts. The authors postulated that the liver congestion caused localized inflammation resulting in an elevated intra-hepatocyte iron content which in turn stimulated an inappropriately high release of hepcidin for the level of systemic circulating iron resulting in inappropriate sequestration of iron, decreased absorption and ultimately IDA in the rats with IDA secondary to LC. Whether liver congestion in part explains ID in HF patients with fluid overload remains to be determined in human studies. Myocardial iron homeostasis Cardiomyocytes have a high energy demand and are therefore susceptible to ID and abnormal iron utilization.29 Depletion of myocardial iron stores has been demonstrated in patients with end-stage HF referred for cardiac transplantation when compared with healthy hearts.18,25 Furthermore, sTfR levels were lower in the failing hearts explanted during heart transplantation compared with levels in donor hearts deemed not suitable for transplantation.25 Expression of sTfR was further reduced by exposure to neurohormones (noradrenaline and aldosterone) commonly elevated in HF.18 Sustained ID has been shown in animal models to result in LV hypertrophy and LV dilatation, mitochondrial swelling, sarcomere disruption, and release of reactive oxygen species that can trigger cell injury.37 While not yet completely understood, it appears that there is an interaction between the development and progression of HF with detrimental effects at multiple points in the complex regulatory pathway of iron. Gut interstitial oedema can decrease absorption (which can be compounded by a reduction in available dietary iron secondary to malnutrition) and liver congestion and chronic inflammation can alter the regulation of hepcidin causing reduction in the absorption, recycling, and release of iron from the body stores. Furthermore, neurohormones may mediate reduction in transferrin receptor expression on the cardiomyocyte resulting in intracellular ID which in turn may induce changes in the cardiomyocyte that decreases its ability to work and increases the risk of cellular apoptosis; an unwanted stress on a failing myocardium. The role of iron requires further research before definitive conclusions can be drawn regarding its place in the pathophysiology of HF. Risk factors for iron deficiency in the patients with heart failure Current data suggest that those patients with HF at highest risk of having concomitant ID are women, non-Caucasian, older, anaemic, and have more severe disease.4,7,29 NYHA functional class has consistently been shown to have an inverse relationship with iron status and strongly predicts the development of ID anaemia.4,7,29 Elevated NTpro-BNP and high-sensitive C-reactive protein levels have been shown to independently correlate with ID anaemia in the chronic HF population.4,7,29 It is notable that in the aforementioned study, even in those considered ‘low risk’ for ID the prevalence of ID was still 30%.29 With regards to pharmacotherapy, the use of anti-platelet and anti-coagulant medications have not been found to correlate with iron indices in patients with HF, suggesting that occult gastrointestinal bleeding is not a dominant cause of ID anaemia in this group of patients.4,7 Likewise angiotensin-converting enzyme inhibitors which have previously been found to correlate with the level of anaemia in HF patients do not appear to have a similar correlation with ID.4 61 Iron deficiency in patients with HF Clinical relevance of iron deficiency in heart failure Iron deficiency and quality of life Patients with HF report significant impairment in their ‘Healthrelated quality of life’ (HRQoL) compared with patients with other long-term conditions and healthy people,38 largely due to the physical limitations in daily living activities associated with HF.39 In a crosssectional study of 1278 patients with chronic HF in Europe, ID was found to have a negative impact on HRQoL independent of anaemia.28 In this study, 58% of the patients had ID and 35% were anaemic. HRQoL (measured using the Minnesota Living with Heart Failure questionnaire) was worse among those patients with ID anaemia and ID without anaemia, when compared with those without ID or anaemia [unadjusted global MLHQF score ID 42 + 25 vs. non-ID 37 + 25 (P , 0.001), anaemic 46 + 25 vs. non-anaemic 37 + 25; P , 0.001]. This difference was maintained regardless of the Hb level. This finding was consistent with an earlier-reported post hoc analysis of an HF cohort which reported worse MHLFQ scores in patients with ID compared with patients without ID independent of the presence of anaemia.39 Iron deficiency and exercise capacity Exercise intolerance is a cardinal symptom of HF associated with poor quality of life and high morbidity and mortality.40 Exercise tolerance has been shown to be reduced in patients with HF with ID, as in other non-HF populations with ID.7,40 In 443 patients with chronic HF with reduced LV ejection fraction (LVEF , 45%) who underwent cardiopulmonary exercise testing, 155 patients (35%) were ID.40 When compared with patients without ID, those with ID had lower peak VO2 (15.3 and 13.3, respectively; P , 0.05) and higher VE-VCO2 slope (50.9 and 43.1, P , 0.05). Iron deficiency had an independent inverse relationship with VO2max (including when controlling for the presence of anaemia). In a smaller study involving 48 patients with HF, Tsat ,20% independently predicted VO2max in the patients with ID although the same relationship was not seen among those without ID.30 Iron deficiency and mortality Iron deficiency appears to be an independent predictor of mortality with or without concomitant anaemia.4,29 In a pooled cohort of 1506 patients with chronic HF, patients with ID had higher mortality than those without ID after 6-month follow-up (8.7 vs. 3.6%, respectively; P , 0.001).4 During longer term follow-up, average 2.5 years, 440 (29%) patients had died. The adjusted hazard ratio for ID was 1.42 (95% CI 1.14–1.77, P , 0.002) and ID remained an independent predictor of mortality in patients with (HR 1.71, 95% CI 1.24– 2.36, P , 0.001) or without anaemia (HR 1.44, 95% CI 1.11– 1.87, P , 0.006). In the previously described study involving 546 patients with chronic HF, 38% of patients died or required heart transplantation during a mean follow-up of 731 days. Three-year survival rates were 59% in the patients with ID compared with 71% in those without ID (P , 0.0006).29 In multivariable analysis, ID was an independent predictor of increased mortality (HR 1.58, 95% CI 1.14–0.17, P , 0.01). In the study where ID was defined using Tsat ,20%, 27 (17%) patients died during a median follow-up time of 743 days.7 Patients with ID anaemia had a 4-fold greater risk of dying than iron replete patients with and without anaemia. Non-anaemic iron-deficient patients were also found to have a two-fold greater risk of death than anaemic non-iron-deficient patients, suggesting that ID is a more ominous finding than anaemia in patients with CHF. In a study of 165 patients hospitalized with acute HF, patients with ID (defined as a low serum hepcidin and a high sTfR) had a 5% in-hospital mortality rate and an increased risk of death in the following 12 months (HR 6.59, 95% CI 2.97–14.62, P , 0.001).24 This study is the first to use sTfR and hepcidin levels to define ID, and this was a more significant predictor of mortality than ID defined by low serum ferritin and Tsat levels (HR 6.16, 95% CI 2.7, 14.04, x 2 ¼ 18.72, P , 0.001 vs. HR 1.31, 95% CI 0.55, 3.09, x 2 ¼ 0.36, P ¼ 0.54). Whether this definition of ID is indeed more pertinent for the HF population requires confirmation in further studies. Overall these studies have demonstrated that the presence of ID in patients with acute and chronic HF is independently associated with mortality. Evidence for treating iron deficiency The available literature supports that ID is common among patients with HF, is associated with worse HRQoL, impaired exercise capacity, and is a predictor of mortality independent of other prognostic markers. As a result, the role of correcting ID for patients with HF has been an area of recent major interest. All the trials conducted so far (Table 3) have used different formulations of intravenous iron and, as oral iron replacement has not been assessed in this patient group, a comparison of efficacy and safety between oral and intravenous (i.v.) therapy cannot be made. The first study of patients with HF treated with i.v. iron was reported in 2006.41 This small study involving 16 patients treated with iron sucrose demonstrated that iron treatment resulted in improved NYHA class, HRQoL, and 6-min walk time.41 The first randomized controlled trial involved 40 patients with chronic HF and moderate chronic kidney disease with ID anaemia who were treated with a weekly infusion of i.v. iron sucrose for 5 weeks or placebo (isotonic saline).42 At 6-month follow-up, the iron-treated patients when compared with the placebo group had significant improvements in Hb and Tsat levels, reduction in NTpro-BNP, and diuretic requirement, improved NYHA class, LVEF, and creatinine clearance. In the FERRIC HF study, i.v. iron replacement was given to 35 patients with ID and an LVEF of ,45% to assess the effect of iron replacement on exercise tolerance.43 The mean change in peak VO2 post iron repletion was 2.2 mL/kg/min. This improvement correlated with symptomatic improvement, a mean reduction in NYHA class of 0.5 and an increase in exercise duration. An increase in VO2 of 2.2 mL/kg/min compares favourably with that achieved in trials of exercise training and cardiac resynchronization.44,45 In a study of 40 patients with HF and ID, NYHA functional class, 6-min walk distance, and echocardiographic LV strain were evaluated before iron replacement and 4, 8, and 12 weeks following iron store replenishment with i.v. iron dextran.46 Significant improvements following iron replacement were demonstrated with an average NYHA functional class for the cohort improving by one level, the 6-min 62 Table 3 Studies assessing efficacy of iron replacement in patients with heart failure and iron deficiency Study n Inclusion criteria Age (years) Treatment FU Endpoints and results NYHA class II– III Systolic HF ID and anaemia Design: non-R, no control group NYHA class II– III LVEF ≤ 40% ID and anaemia Design: non-R, no control 68.3 + 11.5 Iron sucrose 200 mg on days 1, 3, and 5 92 days Improved NYHA class [all II at study end (P , 0.002)] Improved MLWHF score (33 + 19 to 19 + 14, P ¼ 0.02) Improved 6MWD (242 + 78 to 286 + 72, P ¼ 0.01) Increased Hb, iron and ferritin levels 57 + 13 Iron dextran 200 mg (i.v.) weekly (until ferritin 200– 300 mg/L or Tsat 30– 40%) 12 weeks Myocardial function: E/E′ decreased (BL 22 + 3, week 12 13 + 3, P , 0.001) Peak systolic strain rate improved (BL 20.72 + 0.11, week 12–1.09 + 0.37, P , 0.01) Functional capacity: Improvement in NYHA class (BL 3.0 + 0.4, week 12 2.1 + 0.3, P , 0.05) NYHA class II– IV LVEF ≤ 35% ID and anaemia Design: R DB PC 74 + 8 (control) 76 + 7 (treated) Iron sucrose 200 mg (iv) weekly for 5 weeks 6 months 35 NYHA class II– III LVEF ≤ 45% ID with or without anaemia Design: R, open control 62 + 11 (control) 64 + 14 (treated) Iron sucrose 200 mg (iv) weekly for 16 weeks or until ferritin .500 ng/mL 18 weeks Primary: Increase in Hb, ferritin, tsat and creatinine clearance (P , 0.01), reduced NT-proBNP (P , 0.01), CRP (P , 0.01) Secondary: Improved NYHA class, 6MWD (P ¼ 0.01), QOL and fewer hospitalizations (P ¼ 0.01) Primary: Increase in absolute pVO2 96 mL/min (P ¼ 0.08) Secondary: Increase in pVO2 by 2.2 mL/kg/min (P ¼ 0.01), Improvement in NYHA functional class (P ¼ 0.007), MLHFQ score (P ¼ 0.07), fatigue score (P ¼ 0.004) Anker et al.26 459 NYHA class II– III LVEF ≤ 40% ID with or without anaemia Design: R DB PC 67.8 + 10.3 (treated) 67.4 + 11.1 (placebo) Ferric carboxymaltose 200 mg weekly until iron replaced then 200 mg 4 weekly 24 weeks Ponikowski et al.33 304 NYHA class II– III LVEF ≤ 45% ID with or without anaemia Design: R DB PC 68.8 + 9.5 Ferric carboxymaltose 500 –2000 mg at week 1 and 6 (+500 mg at weeks 12, 24, 36 if still ID) 52 weeks ............................................................................................................................................................................................................................................. 41 16 Gaber et al.46 40 Toblli et al.42 40 Okonko et al.43 Bolger et al. 6MWD, 6-min walk distance; BL, baseline; ID, iron deficiency; KCCQ, Kansas City Cardiomyopahty Questionnaire; LVEF, left ventricular ejection fraction; MLWHF, Minnesota Living with Heart Failure questionnaire; NYHA, New York Heart Association function class; Study design; R, randomised; DB, double-blind; PC, placebo-controlled. S. Fitzsimons and R.N. Doughty Primary: Patient Global Assessment improved (OR 2.51, 95% CI 1.75, 3.61, P , 0.001); NYHA class improved (OR 2.40, 95% CI 1.55, 3.71 P , 0.001) Secondary: Improved 6MWD (P , 0.001), KCCQ score (P , 0.001) and EQ-5D score (P , 0.001) Primary: Improved 6MWD at wk 24 (+33 + 11 m, P ¼ 0.002) Secondary: Improvement in NYHA functional class, PGA score, KCCQ score, 6MWD at weeks 36 and 52 (36 + 11 m, P , 0.001), decreased risk of hospitalization for worsening HF (HR 0.39, 0.19– 0.82, P ¼ 0.009) 63 Iron deficiency in patients with HF walk test increasing by 50 m and echocardiographic parameters positively changing consistent with lower LV filling pressure (E/E′ decreased from 22 to 13, peak systolic strain rate 20.72 to 21.09). The first larger scale study of iron replacement in HF, the FAIR-HF trial, involved 459 patients with chronic HF with NYHA functional class II/III symptoms, reduced LVEF (,40– 45%), with ID and Hb between 95 and 135 g/L.26 Treatment with ferric carboxymaltose compared with placebo resulted in improvement in self-reported Patient Global Assessment (iron treated group 50% much/moderately improved compared with to 28% in placebo group: OR 2.51, 95% CI 1.75–3.61) and improved NYHA functional class (irontreated group 47% NYHA class I/II compared with 30% in the placebo group: P , 0.001). In addition, there was improvement in the 6-min walk distance and quality-of-life assessments in the treated group that was not seen in the placebo arm.26,47 Subgroup analysis demonstrated that similar results were seen in patients with and without anaemia,48 suggesting that the benefits of iron replacement therapy are not limited to patients with ID and anaemia. There were no serious adverse events related to the iron infusion (attributable to the newer i.v. preparations). These results have recently been replicated in the CONFIRM-HF trial which involved 304 patients with HF with an LVEF of ,45%, elevated natriuretic peptides, and ID who were randomized 1:1 to treatment with i.v. ferric carboxymaltose or placebo.33 The primary endpoint of 6-min walk distance improved in the iron-treated group compared with placebo after 6 months of treatment (+18 and 216 m, respectively, between group change over 6 months 33 m, P , 0.002). Changes seen in the first 6 weeks suggested that the benefit begins early post iron replacement, although these were not statistically significant. Significant improvement in secondary endpoints including NYHA class (P , 0.001), quality-of-life, and fatigue scores (P , 0.0002) and time to first hospitalization (HR 0.39, P , 0.0009) were reported and remained statistically significant up to a year post iron replacement. These studies have demonstrated an improvement in symptoms, exercise capacity, and HRQoL associated with iron treatment for patients with HF, although the effects on major clinical events remain uncertain. Other questions relating to the role of ID in patients with HF need to be addressed with larger scale randomized controlled trials, including duration of iron treatment, longer term sustainability of effects on symptoms and quality of life, effects on mortality, and hospitalization. Most of the trials to date have included patients with HF with reduced LVEF, and thus subsequent trials will be required to address the role of treating ID in patients with HF with preserved LVEF. Several studies designed to address these questions are in progress but patient recruitment to date has reportedly been slow. The burden of morbidity is high among patients with HF and, despite the limitations of the current evidence, an intervention that improves symptoms, NYHA functional class, exercise capacity, and quality of life is a welcome addition to the treatment armament. As a result, the 2012 ESC HF Guidelines recommend assessment and treatment of ID in patients with HF (class 1C recommendation).49 Given the current evidence-base from which these recommendations are derived, this should be for patients with HF with reduced LVEF, but testing for ID and iron replacement therapy if required could be considered either in a hospital or in a primary care setting. Future clinical trials will help to more clearly determine the role of iron therapy for the increasing numbers of patients with HF over the coming decades. Conflict of interest: none declared. References 1. 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