2025 奥地利立场声明：慢性心力衰竭铁缺乏的诊断与治疗

Diagnosis and treatment of iron deficiency in chronic heart failure

Position statement of the heart failure working group of the Austrian Society of Cardiology

Moritz Messner · Gerhard Pölzl · Christopher Adlbrecht · Johann Altenberger · Johann Auer · Robert Berent · Jakob Dörler · Marc-Michael Zaruba · Christian Ebner $\cdot$ Friedrich Fruhwald · Martin Hülsmann · Deddo Mörtl · Peter P. Rainer · Anna Rab $\cdot$ Thomas Weber · Rudolf Berger · The Heart Failure Working Group of The Austrian Society for Cardiology

Accepted: 17 February 2025 © The Author(s) 2025

Dr. M. Messner ( ' ) · G. Pölzl · M.-M. Zaruba Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Tyrol, Austria moritz.messner@i-med.ac.at

C. Adlbrecht Imed19-privat, private clinical research center, Chimanistrasse 1, 1190 Vienna, Austria

J. Altenberger Center for Cardiovascular Rehabilitation, Lehrkrankenhaus der PMU, Pensionsversicherung Grossgmain, Grossgmain, Austria

J. Auer Department of Cardiology and Intensive Care, St Josef Hospital, Braunau, Upper Austria, Austria

R. Berent Center for Cardiovascular Rehabilitation, HerzReha Bad Ischl, Bad Ischl, Upper Austria, Austria

J. Dörler Department of Internal Medicine and Cardiology, Landeskrankenhaus Klagenfurt, Klagenfurt, Carinthia, Austria

C. Ebner Second Medical Department, Convent Hospital Elisabethinen, Linz, Upper Austria, Austria

F. Fruhwald Department of Internal Medicine, Division of Cardiology, Medical University Graz, Graz, Styria, Austria

M. Hülsmann University Clinic of Internal Medicine II, Department of Cardiology, Medical University Vienna, Vienna, Austria D. Mörtl Department of Internal Medicine 3, University Hospital St. Poelten, Karl Landsteiner Private University, St. Poelten, Lower Austria, Austria P. P. Rainer Department of Internal Medicine, St. Johann in Tirol General Hospital, St. Johann in Tirol, Austria University Heart Center, Medical University of Graz, Graz, Austria BioTechMed Graz, Graz, Austria A. Rab Department Internal Medicine I, Kardinal Schwarzenberg Klinikum, Schwarzach, Austria T. Weber Department of Cardiology, Klinikum Wels-Grieskirchen, Wels-Grieskirchen, Upper Austria, Austria R. Berger First Medical Department, Hospital of St. John of God, Eisenstadt, Burgenland, Austria

Summary Iron deficiency (ID) is a common comorbidity in heart failure (HF), affecting $55\%$ of chronic and up to $80\%$ of acute HF patients, regardless of ejection fraction (EF). An ID is associated with reduced quality of life, impaired exercise capacity $(\mathrm{V}\mathrm{O}_{2}$ peak), higher hospitalization rate and lower survival rate. It is also an independent predictor of HF outcomes. This consensus statement critically reviews the diagnostic criteria for ID in HF and provides recommendations for their use. The efficacy and safety of intravenous iron supplements, including ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), are analyzed highlighting the indications and potential adverse effects. Key clinical trials and guideline recommendations are summarized. In summary, the document addresses the diagnostics, treatment and monitoring of ID in HF.

Keywords Iron deficiency $\cdot$ Heart failure · Austrian consensus statement · Iron supplementation · Iron derisomaltose · Iron carboxymaltose

Introduction

Iron deficiency (ID) is one of the most common conditions in patients with heart failure (HF), affecting approximately $55\%$ of patients with chronic HF and up to $80\%$ of patients with acute HF, irrespective of the ejection fraction (EF). In HF patients, ID is associated with reduced quality of life (QoL), exercise capacity (as peak $\mathrm{VO_{2}}$ ) and survival as well as an increased risk of hospitalization. The presence of ID is a strong independent predictor of HF outcome [ 1 ] and thus independent of demographic and clinical variables, including anemia [ 2 ].

This document discusses criteria and expert opinions on the diagnosis of ID in HF, the benefits of IV supplementation with ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) and the monitoring of patients with ID in HF.

## Physiological role of iron and pathophysiology of ID

The human body contains about ${\mathrm{3-5}}\,\mathrm{g}$ of iron, which the body requires for the synthesis of hemoglobin. In addition to the transport of oxygen in the blood, iron as a central trace element is essential for the functionality of numerous other intracellular and mitochondrial processes in the respiratory chain. Iron is also involved in the synthesis and degradation of proteins, lipids and nucleic acids [ 3 – 5 ]. Especially in highly oxygen-consuming cells, such as cardiomyocytes and proximal renal tubular cells, iron is crucial for proper functionality [ 6 ].

The daily absorption of iron in the duodenum typically ranges from 1–3mg. Given that ferrous iron $(\mathrm{Fe}^{2})$ is highly reactive and cytotoxic, leading to oxidative damage and to a specialized form of iron-dependent

programmed cell death known as ferroptosis, complex regulatory mechanisms are essential for maintaining iron homeostasis [ 7 ]. On absorption in the duodenum, Fe 2 is stored primarily in reticuloendothelial cells and the liver. Hepcidin, a hormone produced by the liver, plays a crucial role in regulating systemic iron levels by modifying duodenal absorption of iron, inducing the degradation of ferroportin, the iron exporter on cellular membranes, thereby regulating iron release into the bloodstream [ 8 ].

In the circulation, ferric iron $\left(\mathrm{Fe^{3}}\right)$ , which is less reactive, binds to transferrin. The iron-transferrin complex is internalized into cells through receptor-mediated endocytosis via the transferrin receptor protein (TfR1). Once inside the cytoplasm, $\mathrm{Fe^{3}}$ is reduced to $\mathrm{Fe^{2}}$ for cellular utilization [ 7 ].

## Absolute and functional ID

Patients with HF can present with absolute or functional ID. In absolute ID, iron stores are depleted by loss (bleeding) or reduced uptake (malabsorption or dietary shortage). Absolute ID occurs in patients with HF due to occult gastrointestinal bleeding with or without antiplatelet or anticoagulant treatment [ 9 ] or due to reduced uptake when gastric acidity is reduced by proton pump inhibitor treatment [ 10 ]. Calcium channel blockers can disrupt the function of membrane-bound channels essential for iron uptake by enterocytes [ 11 ]. Chronic inflammation as well as hepatic congestion due to increased central venous pressures upregulates the expression of hepcidin, which further inhibits duodenal absorption of dietary iron [ 12 ]. In elderly HF patients, inadequate dietary iron intake may occur due to anorexia, while iron losses may be exacerbated by underlying gastrointestinal malignancies [ 13 – 15 ].

In functional ID, iron cannot be effectively mobilized from existing stores to meet the needs of tissues, leading to functional impairments in processes, such as cardiomyocyte function, skeletal muscle activity and erythropoiesis. Although there is sufficient iron in the body, it cannot be adequately released from the reticuloendothelial system (RES). Hepcidin serves as an important regulator of plasmatic iron homeostasis. Iron deficiency and erythropoietic stimulation suppress hepcidin production to provide adequate iron quantities [ 16 , 17 ].

In contrast, inflammation, such as chronic inflammation in HF, induces hepcidin production [ 8 , 18 ]. Elevated levels of hepcidin elicit functional ID, characterized by a reduction in transferrin-bound iron (transferrin saturation, TSAT). This results in a limited iron supply to cells. Inflammation leads to increased secretion of intracellular ferritin into the bloodstream, highlighting its role as an acute phase reactant. Consequently, higher serum ferritin level cut-offs are used for diagnosing ID in HF patients, who experience chronic inflammation [ 19 , 20 ].

Table 1 General overview of the laboratory parameters in ID based on [ 46 ]

|Parameter Absolute ID Functional ID Combined ID Transferrin ↑ ↓ / ⊥ ↓|Parameter Absolute ID Functional ID Combined ID Transferrin ↑ ↓ / ⊥ ↓|Parameter Absolute ID Functional ID Combined ID Transferrin ↑ ↓ / ⊥ ↓|Parameter Absolute ID Functional ID Combined ID Transferrin ↑ ↓ / ⊥ ↓| |---|---|---|---| |TSAT|↓|↓|| |Serum iron|↓|↓|| |sTfR|↑|⊥|| |Ferritin|↓|⊥ / ↑|| |Inflammatory markers||↑||

TSAT transferrin saturation, sTfR soluble transferrin receptor, ↓ reduced, ↑ increased, ⊥ normal

Table 2 Diagnostic criteria for ID in HF based on the ESC guidelines

| Diagnostic criteria for ID in HF based on the 2021 ESC HF guidelines | Potential new diagnostic criteria for ID in HF | |---|---| |Serum ferritin||

A simplified overview of the constellation of important parameters in absolute and functional ID is provided in Table 1 . For the sake of completeness, it should be mentioned that both conditions may be present at the same time.

Diagnosis of ID in HF

In HF the presence of ID (absolute or functional) affects cardiomyocytes and skeletal muscle, impairing functional capacity. The clinical manifestations of ID range from lethargy, weakness, fatigue, brittleness of the fingers, pallor of the skin and mucous membranes, to the presence of rhagades at the corners of the mouth [ 21 ].

Patients with HF often have functional ID [ 4 ]. Diagnostic criteria of functional ID in HF are commonly not based on clinical symptoms but on reduced TSAT (an indicator of low iron levels in the blood), with serum ferritin levels that rule out absolute ID [ 22 ]. The arbitrary higher serum ferritin threshold of $100\,\upmu\mathrm{g/L},$ in contrast to $30\,\upmu\mathrm{g/L}$ in the general population, is used to identify absolute ID in HF due to increased inflammatory activity. It is important to note, that this cut-off point was never tested in HF patients.

The diagnostic approach to ID should identify patients who may benefit from iron supplementation in hard outcomes, such as all-cause mortality and heart failure hospitalization, as well as functional parameters and quality of life.

The normal range of serum ferritin is wide $\begin{array}{r l r}{\left(\approx}&{{}20\mathrm{-}300\,\upmu\mathrm{g/L}\right)}&{}\end{array}$ , making it difficult to distinguish mild to moderate inflammation-related increases from normal levels in healthy adults. Thus, a serum ferritin level $\mathbf{>}20–30\,\upmu\mathrm{g/L}$ is not suitable to diagnose functional ID but is suitable to exclude absolute ID. When levels exceed $400{-}500\,\upmu\mathrm{g/L}$ in functional ID, the serum ferritin level indicates iron overload [ 23 ].

As increased ferritin is also caused by inflammation, a central trigger of HF, low levels can also be a biomarker of stable conditions. In contrast, high levels of ferritin can mirror advanced HF stage and

not iron overload. This double-edged sword makes interpretation difficult in all acute and chronic inflammatory processes.

In ID patients cardiomyocytic transferrin receptor 1 (TfR1) expression is high because cells are trying to take up more circulating iron when cytosolic levels are low. Independent of systemic iron, in failing hearts myocardial iron storage, mitochondrial activity, hepcidin and soluble transferrin receptor (sTfR) are decreased, whereas ferroportin is increased, indicating reduced entry and increased egress of iron from cardiomyocytes [ 6 , 24 ]. Chronic sympathetic stimulation and high plasma norepinephrine are linked to cardiac iron depletion and lower sTfR and TSAT levels in HF patients [ 25 ]. Functional ID, characterized by low TSAT, increased hepcidin and normal range serum ferritin, indicates poor response to oral iron in HF. Serum ferritin and hepcidin are less reliable for identifying ID due to various influencing factors, while more suitable sTfR levels, although linked to poor outcomes, are not yet standardized or widely used in clinical trials [ 23 ].

Serum ferritin (iron storage) and TSAT (iron mobilization) are considered suitable for assessing the iron status in chronic diseases. The current guidelines from the European Society of Cardiology (ESC) recommend identification of ID in patients with HF [ 26 ]. Accordingly, absolute ID is diagnosed when serum ferritin levels are below $100\,\mathrm{mg/L}$ . Serum ferritin levels of $\scriptstyle100-299\,\mathrm{mg/L}$ and TSAT of less than $20\%$ confirm functional ID (Table 2 ).

Critical comments on the current diagnostic criteria

The HF patients often show functional ID, with ineffective oral iron therapy due to markedly reduced absorption and macrophage trapping. The use of IV iron supplementation is based on the assumption that ID (absolute or functional) affects ATP production in cardiomyocytes and impairs skeletal muscle function causing exercise intolerance and weakness [ 27 ].

While about $50\%$ of HF patients meet the ferritinbased criteria for ID (serum ferritin ${<}100\,\upmu\mathrm{g/l}$ or serum ferritin $100{-}299\,\upmu\mathrm{g/l}$ and TSAT $<\!20\%$ ), only $20–25\%$ have deficient myocardial iron stores [ 28 ], which possibly leads to an overestimation of true ID [ 29 ]. Established iron biomarkers do not reliably indicate myocardial ID and systemic iron does not correlate with cardiac iron content [ 27 , 30 ]. In clinical practice, neither the measurement of hepcidin levels (poorly standardized assays) nor the identification of iron-overloaded macrophages in the bone marrow or hepatocytes (by magnetic resonance imaging, MRI), which reflects the iron status more accurately, are used routinely [ 31 , 32 ]. Serum ferritin and hepcidin levels also seem unreliable for identifying ID in chronic heart failure (CHF) [ 33 ]. This is also reflected by various studies, indicating that the ferritin level in CHF does not predict outcome, whereas TSAT of less than $20\%$ and serum iron levels below $300\,\upmu\mathrm{g/l}$ does [ 34 , 35 ].

Although a $\mathrm{TSAT}\!<\!20\%$ indicates deficient iron availability [ 22 ], it does not define an iron deficient state unless serum ferritin is $<\!300\,\upmu\mathrm{g/L}$ according to current guidelines [ 26 ]. Conversely, patients with high ferritin $(\geq300\,\upmu\mathrm{g}/\mathrm{L})$ but low iron $(\leq\!13\,\upmu\mathrm{mol}/\mathrm{L})$ , low TSAT $(<\!20\%)$ , or anemia who are at high risk are not identified by current guidelines. Of note, patients with ferritin $<\!100\,\upmu\mathrm{g/L}$ but normal iron and TSAT have a better prognosis [ 36 ].

Meta-analyses show that IV iron supplementation benefits patients with TSAT $<20\%$ but not with TSAT ≥ $20\%$ . The IRONMAN [ 37 ] and AFFIRM-AHF [ 27 ] (with baseline $\mathrm{TSAT}\,{\approx}\,15\%$ ) studies demonstrated benefits from IV iron, whereas the HEART-FID trial (with baseline TSAT $23–24\%$ ) did not. Additionally, in HEARTFID, as well as in IRONMAN participants with isolated low ferritin levels did not show improved outcomes with IV supplementation [ 38 ]. This leads to the assumption that low TSAT but not low ferritin, indicates the effectiveness of IV iron to reduce HF hospitalizations.

In summary, the available evidence suggests that patients with isolated ferritin $<100\,\upmu\mathrm{g/L}$ should not be considered for iron supplementation. This contradicts the recommendations of current guidelines. Ferritin levels $<\!20\,\upmu\mathrm{g/L}$ indicate absolute deficiency but in CHF few patients even with anemia have isolated ferritin $<\!20\,\upmu\mathrm{g/L}$ . Most patients with ferritin $<\!20\,\upmu\mathrm{g/L}$ also have $\mathrm{TSAT}\!<\!20\%$ . Experience is limited with IV iron supplementation in patients with TSAT $<20\%$ and ferritin $>400\,\upmu\mathrm{g/L},$ a rare profile in HF.

Efficacy analyses based on current eligibility criteria underestimate IV iron benefits. A meta-analysis of trials with FCM showed a reduction in cardiovascular (CV) death or HF hospitalizations by $13\%$ in patient with guideline-recommended criteria and by $33\%$ when only patients with $\mathrm{TSAT}\!<\!20\%$ and ferriti $\mathbf{n}\,{<}\,400\,\upmu\mathrm{g/L}$ were considered [ 39 ]. For instance, the IRONMAN study showed a $20\%$ risk reduction in patients with TSAT $<20\%$ , versus $4\%$ in those with

ferritin $<\!100\,\upmu\mathrm{g/L}$ and $\mathrm{TSAT\!>\!20\%}$ . This supports the view that ID should be better defined by TSAT< $20\%$ and serum ferritin $<400\,\upmu\mathrm{g/L}$ and serum ferritin $\cdot<$ $100\,\upmu\mathrm{g/L}$ should be discarded as the sole criterion.

Treatment of ID in HF

Absolute ID usually responds to oral iron supplementation due to hepcidin suppression, while functional ID, with elevated hepcidin, requires intravenous (IV) iron administration. The use of IV iron rapidly increases cytosolic iron levels, even with intracellular trapping in ferritin [ 33 ].

Randomized controlled trials have demonstrated that IV iron supplementation in HF patients with reduced EF (HFrEF) improves symptoms, functional capacity, peak oxygen consumption, QOL and reduces the risk of first hospitalization for worsening HF.

Consequently, IV FCM and FDI is recommended to correct ID and improve clinical outcomes in HFrEF patients. Despite the recognition of the clinical significance of ID in HF, the effects of IV iron on morbidity and mortality are still under debate.

Oral iron supplementation

Oral iron supplements are frequently used for the treatment of ID anemia due to their simplicity and cost-effectiveness.

Oral iron treatment generally yields favorable outcomes in patients with nutritional ID, bleeding anemia or in menstruating women without significant comorbidities; however, its efficacy is considerably lower in chronic diseases, such as renal anemia, rheumatic diseases and HF, where iron absorption and utilization may be impaired.

Oral iron supplementation has not shown benefits in patients with HF and reduced ejection fraction (IRONOUT trial), failing to improve any iron variable and thereby consequently also not exercise capacity, NT-proBNP levels and QOL [ 40 ].

Due to lack of efficacy in one controlled trial the current guidelines do not recommend the use of oral iron supplements in HF. Existing oral iron formulations require re-evaluation in light of recent advancements in dosing regimens and slow release technologies.

IV iron supplementation

The origins of IV iron treatment in HF can be traced back to studies exploring the role of anemia management and the combined use of erythropoiesis stimulating agents (ESAS) and iron supplementation, which has been a standard combination in renal anemia. This has led to promising results in small trials; however, ESAS did not demonstrate significant clinical benefits in HF patients but increased rates of thromboembolic events and septic shock (Reduc

tion of Events with Darbepoetin alfa in Heart Failure: RED-HF) [ 41 ], leading to a class III recommendation against its use.

In contrast, iron supplementation alone without ESAS has emerged as a promising therapeutic option for HF patients with ID. Figure 1 and Table 3 provide an overview of randomized controlled trials (RCT) with FCM and FDI in patients with HF. The first prospective trial to demonstrate improved prognosis, QOL and exercise capacity with FCM in HF patients independent of anemia was FAIR-HF [ 42 , 43 ].

The CONFIRM-HF trial [ 44 , 45 ], which included 304 ambulatory HF patients (NYHA class II–III, LVEF ≤ $45\%$ , elevated natriuretic peptides), confirmed the long-term safety and efficacy of IV iron. Patients with absolute or functional ID (serum ferritin $<100\,\upmu\mathrm{g/L}$ or $\scriptstyle100-299\,\upmu\mathrm{g/L}$ with TSAT< 20%, Table 2 ) were randomized to receive IV FCM or placebo for 52 weeks. The IV iron dosage was individualized based on body weight and hemoglobin levels (Table 4 ). The primary endpoint, a change in 6-minute walk distance (6MWD) at 24 weeks, showed a significant improvement of 33 m in the IV iron group compared to placebo. This benefit persisted through 52 weeks and was consistent across all predefined subgroups. Secondary endpoints, including NYHA class, patient global assessment (PGA), QOL, and HF-related hospitalizations, also signifi- cantly improved with IV iron treatment. The average dose required was 1500mg. The study reported no difference in mortality or adverse events between the two groups.

The subsequent EFFECT-HF study $(n\!=\!172)$ ) demonstrated a positive effect of IV FCM treatment on the exercise capacity of symptomatic patients with HF

and ID [ 47 ]. After 24 weeks there was a statistically significant difference in maximum oxygen uptake $\mathrm{(VO_{2})}$ ) for IV iron substitution compared to standard treatment, irrespective of the presence of anemia [ 47 ].

The recently published studies IRONMAN [ 37 ], HEART-FID [ 48 ] and AFFIRM-AHF [ 50 ] provide important additional information on the benefits of IV iron early after acute worsening of HF and demonstrating a beneficial effect not only for FCM but also for FDI in HF. Figure 1 provides an overview of RCT evaluating FCM und FDI in HF.

The AFFIRM-AHF ( $\cdot n\!=\!1132)$ ) study was the first RCT to evaluate the effects of IV FCM administration initiated at discharge, on mortality and morbidity in HF patients with ID hospitalized for an acute HF episode. The primary analysis tended to show a beneficial effect of IV FCM on its combined endpoint of HF hospitalization and CV death (RR 0.79; $95\%$ confidence interval, CI 0.62–1.01; $p\!=\!0.059)$ ). Due to coronavirus disease 2019 (COVID-19), the European Society of Cardiology – Heart Failure Association, the European Medicines Agency, and the US Food and Drug Administration (FDA) recommended a pre-COVID-19 sensitivity analysis. This analysis censored patients at the date when the first COVID-19 patient occurred and showed a significant $25\%$ reduction in the relative risk (RR) for the primary endpoint (RR 0.75; $95\%$ CI 0.59–0.96; $p\!=\!0.024)$ . This outcome was driven by a significant $26\%$ reduction in total HF hospitalizations $(p\!=\!0.013)$ ), whereas there was no difference in CV deaths. Significant benefits were also observed in time to first HF hospitalization or CV death. Notably, $80\%$ of patients required only 1–2 FCM injections and the treatment was well tolerated [ 27 ].

 Fig. 1 Chronological overview of major trials (with year of publication) and ongoing trials (with expected year of publication, green timeline ) evaluating the effects of iron deficiency treatment in heart failure. Trials with ferric derisomaltose are marked in red , those with ferric carboxymaltose in blue . FAIRHF Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency; CONFIRM-HF Ferric Carboxymaltose evaluation on performance in patients with Iron deficiency in combination with chronic Heart Failure; EFFECT-HF Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency; FERRIC-HF II Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency; AFFIRMAHF Ferric carboxymaltose for iron deficiency at discharge after acute heart failure; IRONMAN:Intravenous ferric derisoma

ltose in patients with heart failure and iron deficiency in the UK; HEART-FID Ferric Carboxymaltose in Heart Failure with Iron Deficiency; FAIR-HFpEF Ferric carboxymaltose and exercise capacity in heart failure with preserved ejection fraction and iron deficiency; FAIR-HF2 Intravenous iron in patients with systolic heart failure and iron deficiency to improve morbidity and mortality; IRON-MET HFpEF Impact of Intravenous Iron Repletion On Mechanisms of Exercise InTolerance in HFpEF; COREVIVE HFpEF The Effects of Ferric Derisomaltose in Patients with Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life; INFERRCT Effect of Intravenous Ferric Carboxymaltose Onmortality and Cardiovascular Morbidity, and Quality of Life in Iron Deficient Patients With Recent Myocardial infarction

Table 3 Overview of selected randomized trials investigating IV iron treatment in HF

|trial|Eligibility criteria|Design/ dosage|Primary endpoint|Secondary endpoints| |---|---|---|---|---| | FAiR-HF Ferric car- boxymaltose [43] |NYHA II + LVEF ||||

This table provides an overview and does not claim to be exhaustive FCM ferric carboxymaltose, NYHA New York Heart Association functional classification, LVEF left ventricular ejection fraction, TSAT transferrin saturation, Hb hemoglobin, SOC standard of care, 6MWD Six-minute walk distance, PGA patient global assessment, QOL quality of life, CV cardiovascular, HF heart failure, ID iron deficiency, NT-proBNP N-terminal pro-B-type natriuretic peptide, AF atrial fibrillation, BW body weight, ns not significant, IV intravenous

Table 4 Calculation of iron supplementation dosage for ( a ) single administration of FCM according to authorization in Austria (Z. Nr.: 1-27299) [ 29 ] and for FDI in ( b )

|Hb Patient body weight (a) FCM|Hb Patient body weight (a) FCM|Hb Patient body weight (a) FCM|Hb Patient body weight (a) FCM|Hb Patient body weight (a) FCM| |---|---|---|---|---| |g/dL|mmol/L|Below 35kg|35 to 70kg|70kg and above| |10|6.2|500mg|1500mg|2000mg| |10–14|6.2–8.7|500mg|1000mg|1500mg| |14|8.7|500mg|500mg|500mg| |(b) Dose regimen for FDI according to IRONMAN [ 37 ]|(b) Dose regimen for FDI according to IRONMAN [ 37 ]|(b) Dose regimen for FDI according to IRONMAN [ 37 ]|(b) Dose regimen for FDI according to IRONMAN [ 37 ]|(b) Dose regimen for FDI according to IRONMAN [ 37 ]| |g/dL|mmol/L|Below 50kg|50 to 70kg|70kg and above| |10|6.2|20mg/kg|1000mg|20mg/kg–max. 1.5g| |≥ 10|≥ 6.2–8.7|20mg/kg|20mg/kg|20mg/kg–max. 2g|

A single FCM administration should not exceed: – 15mg iron/kg body weight (for administration by IV injection) or 20mg iron/kg body weight (for administration by IV infusion) – 1000mg of iron

The maximum recommended cumulative dose of FCM is 1000mg of iron (20mL) per week. A single infusion of FDI or the total dose per week should not exceed a dose of 20mg iron/kg body weight

The IRONMAN trial ( $(n\!=\!1137)$ ) addressed the longterm effects of IV FDI, with a median follow-up period of 2.7 years. This investigator-initiated, prospective, open-label trial enrolled patients with a left ventricular ejection fraction (LVEF) $\leq45\%$ and either TSAT<

$20\%$ or serum ferritin $<\!100\,\upmu\mathrm{g/L}$ . The IRONMAN trial, which employed a blinded-endpoint design, primarily enrolled ambulatory patients, with $14\%$ of participants being recruited during a hospitalization for HF and $18\%$ having experienced an HF hospitalization in the preceding 6 months. Patients with hemoglobin levels $>\!13\,\mathbf{g}/\mathrm{{d}L}$ (for women) $\mathrm{and}\!>\!14\,\mathbf{g}/\mathrm{d}\mathrm{L}$ (for men) were excluded from the study. The primary endpoint of the trial was a composite of total (first and recurrent) HF hospitalizations and CV death. The RR for this endpoint was 0.82 $\mathbf{\backslash}95\%$ CI 0.66–1.02; $p\!=\!0.070)$ ) and similar to the sensitivity analysis of AFFIRM-AHF a prespecified sensitivity analysis accounting for the COVID-19 pandemic demonstrated a statistically significant benefit (RR 0.76, $95\%$ CI 0.58–1.00; $p\!=\!0.047)$ ). Additionally, IV iron appeared to improve QOL, with patients with TSAT $<20\%$ deriving the greatest benefit. Moreover, the IRONMAN trial provided evidence that IV iron supplementation with FDI has a reassuring long-term safety profile in HF patients [ 37 , 51 ].

The HEART-FID trial enrolled 3065 patients with HF who had either been hospitalized for HF within the previous 12 months or had elevated NT-proBNP levels $(>\!600\,\mathrm{ng/L}$ in those with sinus rhythm or ${>}1000\,\mathrm{ng/L}$ in those with atrial fibrillation). The ID was defined as a serum ferritin lev $\mathrm{el\!<\!100\,ng/m L}$ or between 100 and $299\,\mathrm{ng}/\mathrm{mL}$ plus a $\mathrm{TSAT}\!<\!20\%$ . The FCM was admin

istered every 6 months, with dosing based on body weight and laboratory results. Patients weighing less than $50\,\mathrm{kg}$ received 2 doses of $15\,\mathrm{mg/kg}$ body weight, while those weighing $50\,\mathrm{kg}$ or more received two doses of $750\,\mathrm{mg},$ , with the doses separated by a 7-day interval. A total of 3014 patients were included in the trial. The primary endpoint was a hierarchical composite of all-cause mortality, HF hospitalizations over 12 months and the 6MWD at 6 months. This primary endpoint was marginally but not statistically improved $(p\!=\!0.019)$ missing the $p$ -value set at $<\!0.01$ . Secondary endpoints included CV death and HF hospitalizations which differed nonsignificantly [ 48 ].

In a meta-analysis by Graham et al. including 10 trials with 3373 patients with CHF and acute heart failure (AHF) and $\mathrm{LVEP}\leq45\%$ , IV iron reduced the composite of total HF hospitalizations and CV death (RR 0.75, $95\%$ CI 0.61–0.93; $P\!<\!0.01)$ ) and time to first HF hospitalization or CV death (odds ratio, OR 0.72, $95\%$ CI 0.53–0.99; $p\!=\!0.04)$ ). There was no effect on CV (OR 0.86, $95\%$ CI 0.70–1.05; $p\!=\!0.14)$ ) or all-cause mortality (OR 0.93, $95\%$ CI 0.78–1.12; $p\!=\!0.47)$ ).

The IRON-CRT study examined the impact of IV FCM on heart remodelling and contractility in patients with ID and $\mathrm{LVEF}\!<\!45\%$ . Out of 75 patients, those on FCM showed a significant LVEF improvement $(+4.22\%)$ versus standard of care $(-0.23\%$ , primary endpoint) after 3 months. A reduction in left ventricular end-systolic volume (LVESV) but not in end-diastolic volume (LVEDV) was observed. The use of FCM also improved cardiac performance which was indicated by a better force-frequency relationship, moving from a negative to a positive slope in the cardiac contractility index (systolic blood pressure/ LVESV index). Functional status and exercise capacity also improved with FCM [ 52 ].

In the most recent FAIR-HFpEF trial involving patients with ID and HF with preserved ejection fraction (HFpEF), IV FCM improved 6MWD and was associated with fewer serious adverse events [ 49 ]; however, the trial was stopped because of slow recruitment after 39 patients and was therefore underpowered to assess effects on symptoms or QOL. Further research in a larger cohort is needed to confirm the benefits of IV iron in this population.

Adverse effects and complications of IV iron treatment

For decades, IV iron was regarded as dangerous, primarily due to the risk of anaphylaxis, a rare but serious

reaction associated with high molecular weight iron dextran formulations, first approved in 1977, which are no longer in use [ 53 ]. In recent years, the number of available IV iron agents has expanded, with the introduction of sodium ferric gluconate (1999) and iron sucrose (2000), followed by ferumoxytol (2009) and more recently FCM and FDI. Newer formulations utilize carbohydrate cores that tightly bind elemental iron, reducing its release into the circulation. This advancement enables complete iron replacement within a single 15–60-min session. Characteristics of the third generation IV iron formulations are detailed in Table 5 , [ 54 ].

Hypersensitivity reactions to IV iron are rare and most commonly occur within the first 10min of infusion. These reactions are categorized into two main types: the self-limiting Fishbane type reactions, which vary in presentation and severity without anaphylactic symptoms, characterized by transient flushing, truncal myalgia and/or chest tightness that spontaneously resolve within minutes. This reaction type is thought to be triggered by labile or free iron and has been observed with all IV iron formulations and it typically resolves without intervention once the IV iron infusion is stopped and does not usually recur upon rechallenge. In contrast, anaphylactic reactions, marked by the acute onset of skin and/or mucosal symptoms, gastrointestinal distress, respiratory involvement and/or hypotension, require immediate and appropriate intervention [ 55 ].

There is an ongoing debate regarding the potential for exacerbating bacterial infections, as iron is a critical nutrient for bacterial growth [ 56 ]; however, neither the AFFIRM study with FCM [ 50 ] nor the IRONMAN study [ 37 ] with FDI showed any signs of an increase in infection rates.

In two meta-analyses of randomized clinical trials various IV iron formulations were compared with oral and intramuscular iron, placebo or no iron. Both analyses demonstrated that IV iron has a comparable safety profile to placebo, with no increased risk of serious adverse effects (SAE) or infections. Gastrointestinal events were less frequent with IV iron compared to oral iron. Although serious infusion reactions were extremely rare, they did occur (35 out of 9223 patients) [ 57 , 58 ]. Remarkably, a subgroup analysis indicated a reduction in SAEs when IV iron was used in HF compared to oral supplementation [ 57 ].

In a meta-analysis by Avani et al. serious infusion reactions were particularly increased with ferric gluconate compared to placebo, oral, intramuscular

Table 5 Third generation IV iron formulations

|Agent Carbohydrate Molecular weight, Da Concentration of elemental iron (mg/mL) Maximum single dose (mg) Maximum dose/week (mg) Ferric carboxymaltose (FCM) Carboxymaltose 150,000 50 1000 1000|Agent Carbohydrate Molecular weight, Da Concentration of elemental iron (mg/mL) Maximum single dose (mg) Maximum dose/week (mg) Ferric carboxymaltose (FCM) Carboxymaltose 150,000 50 1000 1000|Agent Carbohydrate Molecular weight, Da Concentration of elemental iron (mg/mL) Maximum single dose (mg) Maximum dose/week (mg) Ferric carboxymaltose (FCM) Carboxymaltose 150,000 50 1000 1000|Agent Carbohydrate Molecular weight, Da Concentration of elemental iron (mg/mL) Maximum single dose (mg) Maximum dose/week (mg) Ferric carboxymaltose (FCM) Carboxymaltose 150,000 50 1000 1000|Agent Carbohydrate Molecular weight, Da Concentration of elemental iron (mg/mL) Maximum single dose (mg) Maximum dose/week (mg) Ferric carboxymaltose (FCM) Carboxymaltose 150,000 50 1000 1000|Agent Carbohydrate Molecular weight, Da Concentration of elemental iron (mg/mL) Maximum single dose (mg) Maximum dose/week (mg) Ferric carboxymaltose (FCM) Carboxymaltose 150,000 50 1000 1000| |---|---|---|---|---|---| |Ferric derisomaltose (FDI)|Isomaltoside|150,000|100|2000|2000|

Newer iron formulation recommended by current ESC guidelines with carbohydrate cores. These formulations bind elemental iron more tightly and potentially allow complete iron replacement within 15min in one visit

and no iron (RR 5.32; $95\%$ CI 1.49–18.99) [ 57 ]. In this analysis other iron preparations were not associated with a statistically significant increased risk of severe infusion reactions (iron dextran: RR 3.1; $95\%$ CI 0.86–11.22; ferumoxytol: RR 2.26; $95\%$ CI 0.19–26.22; iron sucrose: RR 1.75; $95\%$ CI 0.69–4.43; FCM: RR 1.47; $95\%$ CI 0.40–5.39; FDI: RR 1.00; $95\%$ CI 0.99–1.01).

The two IV iron formulations, FCM and FDI, which were tested in HF and approved for the administration of a sufficient single dose to correct a substantial ID were directly compared for infusion reactions in four analyses: two single-center cohort studies including 1332 and 231 patients showed a lower risk for hypersensitivity of FCM compared to FDI [ 59 , 60 ]. In contrast, an analysis which included 21 prospective trials with more than 8000 patients found a decreased risk of serious or severe hypersensitivity reactions with FDI compared to FCM [ 61 ]; however, the overall rate of hypersensitivity reactions is low and severe hypersensitivity is very rare for either formulation used in HF [ 62 ].

Hypophosphatemia (HPP) is a known adverse effect of iron infusions, particularly with FCM. It is essential for clinicians to recognize the signs of HPP associated with iron infusion, which is characterized by hyperphosphaturic hypophosphatemia, low 1,25-dihydroxyvitamin D2, hypocalcemia and secondary hyperparathyroidism.

The clinical significance of FCM-induced HPP in HFrEF is currently under debate. A substudy of the HEART-FID study examined serum phosphate, 1,25- dihydroxyvitamin D2 and parathorme (PTH) after FCM infusion. This substudy measured changes in serum phosphate, vitamin D metabolites, and PTH over 6 months. Among 133 patients (62 FCM, 71 placebo), phosphate levels dropped in $57.6\%$ of FCM patients versus $10.3\%$ in the placebo group, with a nadir at day 21 and moderate to severe HPP in $51\%$ . Reductions in 1,25-dihydroxyvitamin D and increases in PTH were observed but levels returned to baseline by day 91. No serious adverse events were reported in this short follow-up [ 63 ].

In contrast, Frezier et al. reported on a cohort of 16 women treated for ID anemia at a single-center hematology clinic, receiving a twice weekly dose of FCM. The study observed significant renal phosphate wasting, leading to hypophosphatemia in $87.5\%$ of the patients, which persisted for over 5 weeks. Similarly, Stöhr et al. reported that $60.8\%$ (14 out of 24) of patients with HFrEF developed significant (transient) HPP following high-dose FCM administration. This finding suggests worse laboratory derangements with multiple infusions or high dosages and also raises concerns about potential long-term effects on bone mineralization specifically in older woman with an even higher risk of osteoporosis [ 64 , 65 ].

Comparative clinical studies indicated that serum phosphate levels decrease more frequently following FCM infusion compared to FDI [ 60 ]. Schafer

et al. analyzed data from the PHOSPHARE-IDA trials, which included 245 patients with ID anemia who were treated with either FCM or FDI. The study concluded that FCM was associated with a significantly higher risk of hypophosphatemia compared to FDI (OR: 38.37, $P\!<\!0.001)$ ), with $40\%$ of patients in the FCM group demonstrating persistent hypophosphatemia by day 35 [ 66 ].

A pooled analysis of 45 clinical trials with FCM showed that while FCM induces a temporary decrease in serum phosphate levels, this effect generally resolves within 4–12 weeks [ 67 ]. The proportion of patients with moderate $(1{-}{>}2\,\mathrm{mg/dL})$ and severe $(<\!1\,\mathrm{mg/dL})$ HPP was highest in gastroenterology $(47.1\%)$ and neurology $(39\%)$ patients and lower in cardiology $(9.9\%)$ , non-dialysis-dependent chronic kidney disease $(12.3\%)$ and hemodialysis patients $(0\%)$ . Of 49 patients with severe HPP, $55.1\%$ were in gastroenterology studies and $22.4\%$ in women’s health studies, highlighting that the primary risk factors for severe HPP are treatment area (gastroenterology) and a cumulative (single or repeated) FCM dose of $_{>1000\,\mathrm{mg}}$ within the first 4 weeks of treatment. Notably, the maximum single dose did not correlate with a severe HPP risk and no patient with a serum $\mathrm{{PO_{4}}^{3-}}$ level $<\!1\,\mathrm{mg/dL}$ had an adjudicated serious adverse event.

Regarding HF, it has to be mentioned that repeated doses are rare and HF is a condition with a trend to higher levels of serum phosphate in advanced stages [ 68 ].

Symptomatic HPP may present as fatigue, myalgia, or bone pain, with cases of hypophosphatemic osteomalacia reported in patients with pre-existing risk factors who received high cumulative doses or prolonged FCM treatment [ 69 – 71 ]. Monitoring serum $\mathrm{{P}O_{4}}^{3-}$ levels in patients receiving repeated doses of IV FCM is therefore prudent [ 67 ].

The efficacy of vitamin D supplementation prior to administering FCM remains uncertain. We agree that FCM-induced severe HPP should be treated with IV phosphate supplementation, although the evidence remains sparse [ 72 ]. Ultimately, in patients with confirmed occurrence of FCM-induced HPP, switching to FDI for future administrations appears advisable [ 73 ].

Dosage of IV iron treatment and follow-up evaluation

Serum iron levels and TSAT quickly increase after IV iron supplementation but the clinical significance of these short-term changes is unclear. Oral iron also raises serum iron and TSAT without clinical benefits, likely due to slow intracellular iron increases. In anemic patients the first physiological response to iron supplementation in erythroblasts is a rise in reticulocyte hemoglobin, indicating enhanced hemoglobin synthesis in new red blood cells [ 74 ]. This rise occurs within $_{24-48\,\mathrm{h}}$ following IV iron administration,

 Fig. 2 Recommended management of iron deficiency in heart failure. EF Ejection Fraction, FCM Ferric Carboxymaltose, FID Ferric Isomaltose, Hb Hemoglobin, HF Heart Failure, IV Intravenous, NYHA New York Heart Association, TSAT Transferrin Saturation

whereas hemoglobin increase takes weeks and may be modest in nonanemic patients [ 75 ]; however, it is uncertain if an erythroid response indicates cytosolic iron repletion in cardiomyocytes. An instant increase in the phosphocreatine/ATP ratio by magnetic resonance spectroscopy after IV iron suggests alleviation of cardiomyocyte ID but such measurements are not yet performed [ 39 ].

The most widely used parameter for determining iron status after IV iron treatment is an increase in serum ferritin. Ferritin levels rise significantly as the body produces ferritin to prevent oxidative damage from excess iron [ 76 ]. In the IRONMAN study the ferritin levels increased to over $500\,\upmu\mathrm{g/L}$ after 4 weeks, while the AFFIRM-AHF study showed an increase to about $350\,\upmu\mathrm{g/L}$ . Excessive ferritin levels above $400\,\upmu\mathrm{g/L}$ may indicate short-term iron overload, which is associated with iron accumulation in the liver and cell damage. Vera-Aviles et al. recently demonstrated that non-transferrin-bound iron, after IV iron supplementation, is rapidly delivered to the myocardium without the involvement of reticuloendothelial macrophages. Due to the heart’s limited iron storage capacity, this iron remains labile for weeks, raising concerns about the potential for cumulative iron accumulation with long-term dosing [ 77 ].

It should also be noted that sodium-glucose transporter 2 (SGLT2) inhibitors and neprilysin inhibitors reduce ferritin but they can mobilize iron from stores to cover the demand. Thus, ferritin levels may not reliably indicate iron status in these cases [ 78 , 79 ].

Because of these diagnostic uncertainties the dosing of iron supplementation in HF should be based on clinical outcome data derived from RCT rather than solely on biochemical measurements. Functional ID may persist even after iron supplementation, raising the possibility that HF patients could need ongoing iron treatment, even if iron levels appear adequate. As the dosing regimens in the various studies, especially for FCM, varied widely, it seems difficult to establish clear standards. For FDI, the recommendation

is based on the IRONMAN dosing scheme. Table 4 provides an overview of the recommended dosages.

Regardless of the presence of HF an etiological assessment and red blood cell transfusion are indicated in cases of severe anemia. In patients with symptomatic HFrEF and hemoglobin (Hb) $<\!150\,\mathrm{g/L}$ , it is recommended that the iron status should be assessed according to current guidelines (Fig. 2 ; [ 26 ]).

If ID is confirmed, inpatients should receive iron replacement during the hospital stay based on the results of the AFFIRM-AHF trial. For outpatients, iron supplementation should be planned in a timely manner after confirmation.

After IV iron administration the iron status should be reassessed in 3–6 months. If the results are normal, routine annual checks are recommended.

Current recommendations

The 2021 European Society of Cardiology (ESC) guidelines on HF highlight the significance of ID and provide recommendations for its diagnosis and treatment (Table 6 ). The focused update of 2023 [ 80 ] recommends IV iron supplementation in symptomatic patients with HFrEF and HFmrEF and ID to alleviate HF symptoms and improve QOL.

Given the discussion above, simplifying the diagnostic criteria to a $\mathrm{TSAT}\!<\!20\%$ , may be considered (Table 2 ); however, this represents a well-argued post hoc expert opinion not covered by the ESC guidelines. The ID remains underrecognized and undertreated in clinical practice, partly due to a lack of practical guidance for clinicians. Figure 2 shows a potential management regimen for the screening and treatment of iron insufficiency in HF.

The supplementation FCM or FDI should be considered in symptomatic patients with HFrEF, HFmrEF and ID to reduce the risk of hospitalization. Considering its lower association with hypophosphatemia, FDI may be preferred in patients at risk for hypophosphatemia and osteoporosis, when repeated infusions

Table 6 Recommendations for the treatment of other comorbidities in patients with HF considering the ESC guidelines 2021 and the update 2023 [ 26 , 80 ]

|Recommendations ID|class| level ofevi- dence | |---|---|---| |||| | IV iron supplementation is recommended in symptomatic patients with HFrEF and HFmrEF and ID to alleviate HF symptoms and improve QOL [80] ||| |||| | It is recommended that all patients with HF are periodi- cally screened for anemia and ID with a full blood count, serum ferritin concentration, and TSAT [[261 ||| |||| | IV iron supplementation with FCM or FDI should be con- sidered in symptomatic patients with HFrEF and HFmrEF, and ID, to reduce the risk of HF hospitalization1801 |ia|| |“Treatment of anemia in HF with erythropoietin stimulat-||| |ing agents is not recommended in the absence of other||| |indications for this therapy* [26]||| |ID HFrEF etc.||| | Oral iron therapy is not effective in replenishing iron stores and has not improved performance in patients with HFrEF and ID. It is therefore not ||| |recommended for the treatment of ID in patients with HF||| |FCM Ferric Carboxymaltose, FDI Ferric Derisomaltose, HF Heart Failure,||| |HFmrEF Heart Failure with mildly reduced Ejection Fraction, HFpEF Heart||| |Failure with preserved Ejection Fraction, HFrEF Heart Failure with reduced||| |Ejection Fraction, ID iron deficiency, IVintravenous, QOL Quality Of Life,||| |TSAT Transferrin Saturation|||

are required, although adverse outcomes in HF patients due to hypophosphatemia using FCM remain ill-defined.

Given the limited data, current guidelines do not provide a specific recommendation for IV iron supplementation in HFpEF.

Outlook for the future

The rapid increase in evidence has led to an adaptation of the guidelines. Since 2021 there are new recommendations for screening and diagnosis of ID [ 80 ]. Treatment is recommended to improve functional status and QOL. Data on the efficacy of IV iron supplementation in HFpEF patients are expected in the next years.

Other iron formulations and delivery methods are currently under review; however, none have yet achieved sufficient evidence for recognition or endorsement. There is a critical need to refine current approaches by developing more precise diagnostic criteria for tissue-specific ID and by targeting iron homeostasis pathways more effectively [ 81 , 82 ].

Take home messages

' ID in HF is common and associated with worse symptoms, reduced exercise capacity, higher hospitalization rates and increased mortality. ' Supplementation with FCM or FDI is recommended in symptomatic patients with HFrEF and HFmrEF and ID to alleviate HF symptoms and improve QOL and should be considered to reduce the risk of HF

hospitalization. Data are needed to support IV iron efficacy in HFpEF. ' Current gu ndicate iron supplementation in HF with EF <45% and ID defined as serum ferrit $\mathrm{{in}\!<\!100\,\upmu\mathrm{{g}/L}}$ or $\scriptstyle100-299\,\upmu\mathrm{g/L}$ with $\mathrm{TSAT}\!<\!20\%$ . The potential simplification of diagnostic criteria to TSAT< 20% is currently being discussed. ' Current guidelines recommend that all HFrEF or HFmrEF patients, regardless of glomerular filtration rate or hemoglobin level, should be screened for ID. It is recommended to screen for ID in HF patients at least annually, with particular attention to those classified as NYHA classes II–IV. ' IV iron formulations are effective in HF patients leading to a rapid correction of iron stores, while oral iron is poorly absorbed and has shown no benefit. FCM and FDI are approved for the administration of a single dose sufficient to correct ID. ' Follow-up: reassess iron parameters (serum ferritin and TSAT) 3–6 months post-infusion. Repeat dosing may be necessary if ID persists or reoccurs. Reassessment of iron status is recommended every 6–12 months in patients initially presenting without ID. ' Infusion reactions with FCM and FDI are rare. Hypophosphatemia occurs more frequently with FCM and should be monitored. ' Integration of testing for ID and IV iron supplementation into HF management programs is recommended.

Further information Two studies have been published after the consensus paper went to press and are worth mentioning here due to their importance.

Themulticentre, randomisedFAIR-HF2studyinvestigatedthe effect of FCM (up to 2000 mg as an initial bolus followed by $500\,\mathrm{mg}$ every 4 months) in 1105 patients with chronic heart failure defined as having a ventricular ejection fraction of $\leq\!45\%$ and iron deficiency (serum ferritin level $<\!100\,\mathrm{ng/ml;}$ ; or ifTSATwas $<\!20\%$ ,aserumferritinlevelbetween100ng/mland $299\,\mathrm{ng/ml})$ [ 83 ]. In this study FCM did not significantly reduce the time to first heart failure hospitalisation or cardiovascular death in the overall cohort or in patients with a $\mathrm{TSAT\!<\!20\%}$ or reduce the total number of heart failure hospitalisation compared to placebo.

This study does not support the above postulated simplifi- cation of the diagnostic criteria for iron deficiency in heart failure, a $\mathrm{TSAT\!<\!20\%}$ . However, due to the fact that the study was underpowered $(34\%$ treatment discontinuation in the FCM group and $38\%$ in the placebo group, subgroup analysis), this statement must be taken with caution and therefore does not necessarily call into question the above postulate.

Anequallyrecentmeta-analysisofintravenousirontherapyin patients with heart failure and iron deficiency from six studies (FAIR-HF, CONFIRM-HF, AFFIRM-AHF, IRONMAN, HEARTFID, and FAIR-HF2) involving 7175 patients, showed that patients assigned to IV iron had lower rates of the composite endpoint of recurrent HF hospitalisations and cardiovascular mortality compared to those assigned to placebo at 12 months (RR 0.72 $[95\%$ CI 0.55–0.89]) and for the entire duration of follow-up (RR 0.81 $[95\%$ CI 0.63–0.97]) [ 83 ]. Notably,

each component of the primary endpoint contributed to the beneficial effect of IV iron at both 12 months and over the entire follow-up period.

Funding Open access funding provided by University of Innsbruck and Medical University of Innsbruck.

Conflict of interest M. Messner declares that there is no financial relationship with the organization that sponsored the research and that there is no conflict of interest with respect to the manuscript.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

References

1. vonHaehlingS,GremmlerU,KrummM,MibachF,SchonN, Taggeselle J, Dahm JB, Angermann CE. Prevalence and clinical impact of iron deficiency and anaemia among outpatients with chronic heart failure: the PrEP registry. ClinResCardiol. 2017;106:436–43. 2. Martens P, Nijst P, Verbrugge FH, Smeets K, Dupont M, Mullens W. Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preservedejectionfraction. ActaCardiol. 2018;73:115–23. 3. Dunn LL, Rahmanto YS, Richardson DR. Iron uptake and metabolism in the new millennium. Trends Cell Biol. 2007;17:93–100. 4. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, Borodulin-Nadzieja L, Banasiak W, Polonski L, Filippatos G, McMurray JJ, Anker SD, Ponikowski P. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J. 2010;31:1872–80. 5. Klip IT, Comin-Colet J, Voors AA, PonikowskiP, Enjuanes C, Banasiak W, Lok DJ, Rosentryt P, Torrens A, Polonski L, van Veldhuisen DJ, van der Meer P, Jankowska EA. Iron deficiency in chronic heartfailure: an international pooled analysis. AmHeartJ.2013;165:575–582.e3. 6. Hoes MF, Grote Beverborg N, Kijlstra JD, Kuipers J, Swinkels DW, Giepmans BNG, Rodenburg RJ, van Veldhuisen DJ, de Boer RA, van der Meer P. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail. 2018;20:910–9. 7. Chen Y, Guo X, Zeng Y, Mo X, Hong S, He H, Li J, Fatima S, LiuQ.Oxidativestressinducesmitochondrialironoverload andferroptoticcelldeath. SciRep. 2023;13:15515. 8. Lanser L, Fuchs D, Kurz K, Weiss G. Physiology and inflammation driven pathophysiology of iron homeostasismechanistic insights into anemia of inflammation and its treatment. Nutrients. 2021; https://doi.org/10.3390/ nu13113732 . 9. CamaschellaC.Irondeficiency. Blood. 2019;133:30–9. 10. Layrisse M, Garcia-Casal MN, Solano L, Baron MA, Arguello F, Llovera D, Ramirez J, Leets I, Tropper E. Iron bioavailability in humans from breakfasts enriched with iron bis-glycine chelate, phytates and polyphenols. J Nutr. 2000;130:2195–9. 11. LudwiczekS,TheurlI,MuckenthalerMU,JakabM,MairSM, Theurl M, Kiss J, Paulmichl M, Hentze MW, Ritter M, Weiss G. $\mathrm{Ca2+}$ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med. 2007;13:448–54. 12. Ohno Y, Hanawa H, Jiao S, Hayashi Y, Yoshida K, Suzuki T, Kashimura T, Obata H, Tanaka K, WatanabeT, Minamino T. Liver congestion in heartfailurecontributes to inappropriately increased serum hepcidin despite anemia. Tohoku J ExpMed. 2015;235:69–79. 13. Martens P, Minten L, Dupont M, Mullens W. Prevalence of underlying gastrointestinal malignancies in iron-deficient heartfailure. ESCHeartFail. 2019;6:37–44. 14. Lourenco BH, Vieira LP, Macedo A, Nakasato M, Marucci MdeF,BocchiEA.Nutritionalstatusandadequacyofenergy andnutrientintakesamongheartfailurepatients. ArqBras Cardiol. 2009;93:541–8. 15. Hughes CM, Woodside JV, McGartland C, Roberts MJ, Nicholls DP, McKeown PP. Nutritional intake and oxidative stress in chronic heart failure. Nutr Metab Cardiovasc Dis. 2012;22:376–82. 16. Pasricha SR, Tye-Din J, Muckenthaler MU, Swinkels DW. Irondeficiency. Lancet. 2021;397:233–48. 17. Daher R, Manceau H, Karim Z. Iron metabolism and the roleof theiron-regulating hormonehepcidin in health and disease. PresseMed. 2017;46:e272–e8. 18. Lanser L, Fuchs D, Scharnagl H, Grammer T, Kleber ME, Marz W, Weiss G, Kurz K. Anemia of chronic disease in patients with cardiovascular disease. Front Cardiovasc Med. 2021;8:666638. 19. El-MenyarAA.Cytokinesandmyocardialdysfunction: state oftheart. JCardFail. 2008;14:61–74. 20. Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, von Haehling S, Macdougall IC, Weiss G, McMurray JJ, Anker SD, GheorghiadeM, Ponikowski P. Iron status in patients with chronic heart failure. Eur Heart J. 2013;34:827–34. 21. CekicC,IpekS,AslanF,AkpinarZ,ArabulM,TopalF,Saritas Yüksel E, Alper E, Unsal B. The effect of intravenous iron treatment on quality of life in inflammatory bowel disease patientswithnonanemicirondeficiency. GastroenterolRes Pract. 2015;2015:582163. 22. Fletcher A, Forbes A, Svenson N, Wayne Thomas D, Paper ABSf HG. Guideline for the laboratory diagnosis of iron deficiencyinadults(excludingpregnancy)andchildren. Br JHaematol. 2022;196:523–9. 23. Packer M, Anker SD, Butler J, Cleland JGF, Kalra PR, Mentz RJ, Ponikowski P, Talha KM. Redefining iron defi- ciency in patients with chronic heart failure. Circulation. 2024;150:151–61. 24. SkikneBS,FlowersCH,CookJD.Serumtransferrinreceptor: a quantitative measure of tissue iron deficiency. Blood. 1990;75:1870–6. 25. Maeder MT, Khammy O, dos Remedios C, Kaye DM. Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failure. J Am Coll Cardiol. 2011;58:474–80. 26. McDonagh TA, Metra M, Adamo M, Gardner RS, BaumbachA,BohmM,BurriH,ButlerJ,CelutkieneJ,ChioncelO, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, MindhamR,MunerettoC,PiepoliMF,PriceS,RosanoGMC, RuschitzkaF,SkibelundAK,GroupESCSD.2021ESCguidelines for the diagnosis and treatment of acute and chronic heartfailure. EurHeartJ.2021;42:3599–726. 27. Charles-Edwards G, Amaral N, Sleigh A, Ayis S, Catibog N, McDonagh T, Monaghan M, Amin-Youssef G, Kemp GJ, ShahAM,OkonkoDO.Effectofironisomaltosideonskeletal muscleenergeticsinpatientswithchronicheartfailureand irondeficiency. Circulation. 2019;139:2386–98. 28. ZhangH,JamiesonKL,GrenierJ,NikhanjA,TangZ,WangF, WangS,SeidmanJG,SeidmanCE,ThompsonR,SeubertJM, Oudit GY. Myocardial iron deficiency and mitochondrial dysfunction in advanced heart failure in humans. JAHA. 2022;11:e22853. 29. Correction to: Imbalance of Iron Availability and Demand in Patients With Acute and Chronic Heart Failure. J Am HeartAssoc2024;13:e9685. 30. HirschVG,TongersJ,BodeJ,BerlinerD,WidderJD,EscherF, Mutsenko V, Chung B, Rostami F, Guba-Quint A, Giannitsis E, Schultheiss HP, Vogt C, Bauersachs J, Wollert KC, KempfT.Cardiacironconcentrationinrelationtosystemic iron status and disease severity in non-ischaemic heart failure with reduced ejection fraction. Eur J Heart Fail. 2020;22:2038–46. 31. Barsan L, Stanciu A, Stancu S, Capusa C, Bratescu L, Mandache E, Radu E, Mircescu G. Bone marrow iron distribution, hepcidin, andferroportin expression in renal anemia. Hematology. 2015;20:543–52. 32. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpetforironmetabolism. Cell. 2017;168:344–61. 33. Jankowska EA, Kasztura M, Sokolski M, Bronisz M, NawrockaS,Oleskowska-FlorekW,ZymlinskiR,BiegusJ,Siwolowski P, Banasiak W, Anker SD, Filippatos G, ClelandJG, Ponikowski P. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episodeofacuteheartfailure. EurHeartJ.2014;35:2468–76. 34. Kurz K, Lanser L, Seifert M, Kocher F, Polzl G, Weiss G. Anaemia, iron status, and gender predict the outcome in patients with chronic heart failure. ESC Heart Fail. 2020;7:1880–90. 35. Papadopoulou C, Reinhold J, Gruner-Hegge N, Kydd A, Bhagra S, Parameshwar KJ, Lewis C, Martinez L, Pettit SJ. Prognostic value of three iron deficiency definitions in patients with advanced heart failure. Eur J Heart Fail. 2023;25:2067–74. 36. Martens P, Tang WHW. Defining iron deficiency in heart failure: importance of transferrin saturation. Circ Heart Fail. 2024;17:e11440. 37. Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, Ahmed FZ, Al-Mohammad A, Cowburn PJ, FoleyPWX,GrahamFJ,JappAG,LaneRE,LangNN,LudmanAJ, MacdougallIC,PellicoriP,RayR,RobertsonM,SeedA,FordI, Group IS. Intravenous ferric derisomaltosein patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, openlabel,blinded-endpointtrial. Lancet. 2022;400:2199–209. 38. Graham FJ, Pellicori P, Kalra PR, Ford I, Bruzzese D, ClelandJGF.Intravenousironinpatientswithheartfailureand irondeficiency: anupdatedmeta-analysis. EurJHeartFail. 2023;25:528–37. 39. PackerM,AnkerSD,ButlerJ,ClelandJGF,KalraPR,MentzRJ, PonikowskiP,TalhaKM.Criticalre-evaluationoftheidentificationofirondeficiencystatesandeffectiveironrepletion strategies in patients with chronic heartfailure. Eur J Heart Fail. 2024;26:1298–312. 40. Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E, Network NHFCR. Effect of oral iron repletion on exercise capacityinpatientswithheartfailurewithreducedejection fractionandirondeficiency: theIRONOUTHFrandomized clinicaltrial. JAMA.2017;317:1958–66. 41. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O’Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ, Committees R-H, Investigators R-H. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368:1210–9. 42. Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Mori C, von Eisenhart RotheB,PocockS,Poole-WilsonPA,PonikowskiP.Rationale and design of Ferinject assessment in patients with IRon deficiencyandchronicheartfailure(FAIR-HF)study:arandomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia. EurJHeartFail. 2009;11:1084–91. 43. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P, Investigators F-HT. Ferric carboxymaltose in patients with heart failure andirondeficiency. NEnglJMed. 2009;361:2436–48. 44. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh TA, Parkhomenko A, Tavazzi L, LevesqueV, Mori C, RoubertB, Filippatos G, Ruschitzka F, Anker SD. Rationaleanddesign of theCONFIRMHFstudy: adouble-blind,randomized,placebo-controlled studytoassesstheeffectsofintravenousferriccarboxymaltose on functional capacity in patients with chronic heart failureandirondeficiency. ESCHeartFail. 2014;1:52–8. 45. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, RuschitzkaF,AnkerSD,InvestigatorsC-H.Beneficialeffects of long-term intravenous iron therapy with ferric carboxymaltoseinpatientswithsymptomaticheartfailureandiron deficiencydagger. EurHeartJ.2015;36:657–68. 46. Weinberg ED. Iron availability and infection. Biochim Biophys Acta. 2009;1790(7):600–5. https://doi.org/10. 1016/j.bbagen.2008.07.002 . 47. van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Bohm M, Doletsky A, Voors AA, Macdougall IC, Anker SD, RoubertB,ZakinL,Cohen-SolalA,InvestigatorsE-H.Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failureand iron deficiency. Circulation. 2017;136:1374–83. 48. Mentz RJ, Garg J, Rockhold FW, Butler J, De Pasquale CG, Ezekowitz JA, Lewis GD, O’Meara E, Ponikowski P, Troughton RW, Wong YW, She L, Harrington J, AdamczykR,BlackmanN,HernandezAF,InvestigatorsH-F.Ferric carboxymaltoseinheartfailurewithirondeficiency. NEngl JMed. 2023;389:975–86. 49. von Haehling S, Doehner W, Evertz R, Garfias-Veitl T, DeradC,DiekM,KarakasM,BirkemeyerR,FillippatosG,Lainscak M, Butler J, Ponikowski P, Bohm M, Friede T, Anker SD. Ferriccarboxymaltoseandexercisecapacityinheartfailure with preserved ejection fraction and iron deficiency: the FAIR-HFpEFtrial. EurHeartJ.2024;45:3789–800. 50. Ponikowski P, Kirwan BA, Anker SD, McDonagh T, DorobantuM,DrozdzJ,FabienV,FilippatosG,GohringUM, Keren A, Khintibidze I, Kragten H, Martinez FA, Metra M, MilicicD,NicolauJC,OhlssonM,ParkhomenkoA,PascualFigal DA, Ruschitzka F, Sim D, Skouri H, van der Meer P, Lewis BS, Comin-Colet J, von Haehling S, Cohen-Solal A, Danchin N, Doehner W, Dargie HJ, Motro M, Butler J, Friede T, Jensen KH, Pocock S, Jankowska EA. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlledtrial. Lancet. 2020;396:1895–904. 51. Ray R, Ford I, Cleland JGF, Graham F, Ahmed FZ, AlMohammad A, Cowburn PJ, Critoph C, Kalra PA, Lane RE, Ludman A, Pellicori P, Petrie MC, Robertson M, Seed A, Squire I, Kalra PR. The impact of ferric derisomaltose on cardiovascular and noncardiovascular events in patients withanemia,irondeficiency,andheartfailurewithreduced ejectionfraction. JCardFail. 2024;30:682–90. 52. Martens P, Dupont M, Dauw J, Nijst P, Herbots L, Dendale P, VandervoortP,BruckersL,TangWHW,MullensW.Theeffect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapytheIRON-CRTtrial. EurHeartJ.2021;42:4905–14. 53. Auerbach M, Macdougall IC. Safety of intravenous iron formulations: facts and folklore. Blood Transfus. 2014;12:296–300. 54. BazeleyJW,WishJB.Recentandemergingtherapiesforiron deficiency in anemia of CKD: a review. Am J Kidney Dis. 2022;79:868–76. 55. LimW,AfifW,KnowlesS,LimG,LinY,MothersillC,NistorI, Rehman F, Song C, Xenodemetropoulos T. Canadian expert consensus: management of hypersensitivity reactions to intravenousironinadults. VoxSang. 2019;114:363–73. 56. Centanni N, Hammond J, Carver J, Craig W, Nichols S. Intravenous iron in patients hospitalized with bacterial infections: utilization and outcomes. J Maine Med Cent. 2024; https://doi.org/10.46804/2641-2225.1176 . 57. Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015;90:12–23. 58. Rognoni C, Venturini S, Meregaglia M, Marmifero M, Tarricone R. Efficacy and safety of ferric carboxymaltose and other formulations in iron-deficient patients: a systematic review and network meta-analysis of randomised controlledtrials. ClinDrugInvestig. 2016;36:177–94. 59. Mulder MB, van den Hoek HL, Birnie E, van Tilburg AJP, Westerman EM. Comparison of hypersensitivity reactions ofintravenousiron: ironisomaltoside-1000(Monofer((R))) versusferriccarboxy-maltose(Ferinject((R))).Asinglecenter,cohortstudy. BrJClinPharmacol. 2019;85:385–92. 60. Bager P, Hvas CL, Dahlerup JF. Drug-specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions. Br J Clin Pharmacol. 2017;83:1118–25. 61. Pollock RF, Biggar P. Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltoseinthetreatmentofirondeficiencyanemia. ExpertRevHematol. 2020;13:187–95. 62. Wolf M, Rubin J, Achebe M, Econs MJ, Peacock M, Imel EA, Thomsen LL, Carpenter TO, Weber T, Brandenburg V, Zoller H. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: tworandomizedclinicaltrials. JAMA.2020;323:432–43. 63. Nouhravesh N, Garg J, Rockhold FW, De Pasquale CG, O’Meara E, Lewis GD, Butler J, Harrington J, Ezekowitz JA, Ponikowski P, Troughton RW, Wong YW, Blackman N, NumanS,AdamczykR,HernandezAF,MentzRJ.Characterization of serum phosphate levels over time with intravenous ferriccarboxymaltoseversusplaceboastreatmentforheart failure with reduced ejection fraction and iron deficiency: anexploratoryprospectivesubstudyfromHEART-FID.Eur JHeartFail. 2024; https://doi.org/10.1002/ejhf.3348 . 64. Frazier R, Hodakowski A, Cai X, Lee J, Zakarija A, Stein B, David V, Wolf M, Isakova T, Mehta R. Effects of ferric carboxymaltose on markers of mineral and bone metabolism: a single-center prospective observational study of women withirondeficiency. Bone. 2020;141:115559. 65. Stohr R, Sandstede L, Heine GH, Marx N, Brandenburg V. High-dose ferric carboxymaltose in patients with HFrEF induces significant hypophosphatemia. J Am Coll Cardiol. 2018;71:2270–1. 66. Schaefer B, Zoller H, Wolf M. Risk factors for and effects of persistent and severe hypophosphatemia following ferric carboxymaltose. J Clin Endocrinol Metab. 2022;107:1009–19. 67. Rosano G, Schiefke I, Gohring UM, Fabien V, Bonassi S, Stein J. A pooled analysis of serum phosphate measurements and potential hypophosphataemia events in 45 interventionaltrialswithferriccarboxymaltose. JClinMed. 2020; https://doi.org/10.3390/jcm9113587 . 68. PlischkeM,NeuholdS,AdlbrechtC,BieleszB,ShayganfarS, Bieglmayer C, Szekeres T, Horl WH, Strunk G, Vavken P, Pacher R, Hulsmann M. Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure. Eur J Clin Invest. 2012;42:649–56. 69. Schaefer B, Glodny B, Zoller H. Blood and bone loser. Gastroenterology. 2017;152:e5–e6. 70. Klein K, Asaad S, Econs M, Rubin JE. Severe FGF23-based hypophosphataemic osteomalacia due to ferric carboxymaltose administration. BMJ Case Rep. 2018; https://doi. org/10.1136/bcr-2017-222851 . 71. Fang W, McMahon LP, Bloom S, Garg M. Symptomatic severehypophosphatemiaafterintravenousferriccarboxymaltose. JGHOpen. 2019;3:438–40. 72. ZollerH,WagnerS,SchaeferB.Whatiswrongindoinggood? BrJHaematol. 2023;202:1089–90. 73. Zoller H, Wolf M, Blumenstein I, Primas C, Lindgren S, Thomsen LL, Reinisch W, Iqbal T. Hypophosphataemia followingferricderisomaltoseandferriccarboxymaltosein patientswithirondeficiencyanaemiaduetoinflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial. Gut. 2023;72:644–53. 74. Auerbach M, Staffa SJ, Brugnara C. Using reticulocyte hemoglobin equivalent as a marker for iron deficiency and responsiveness to iron therapy. Mayo Clin Proc. 2021;96:1510–9. 75. Filippatos G, Ponikowski P, Farmakis D, Anker SD, Butler J, Fabien V, Kirwan BA, Macdougall IC, Metra M, Rosano G, Ruschitzka F, van der Meer P, Wachter S, Jankowska EA, Investigators A-A. Association between hemoglobin levels and efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency: an AFFIRM-AHF subgroup analysis. Circulation. 2023;147:1640–53. 76. Tran TN, Eubanks SK, Schaffer KJ, Zhou CY, Linder MC. Secretionofferritinbyrathepatomacellsanditsregulationby inflammatorycytokinesandiron. Blood. 1997;90:4979–86. 77. Vera-Aviles M, Kabir SN, Shah A, Polzella P, LimDY, Buckley P,BallC,SwinkelsD,MatlungH,BlansC,HoldshipP,Nugent J,AndersonE,DesboroughM,PiechnikS,FerreiraV,LakhalLittleton S. Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway. EurHeartJ.2024;. 78. Packer M. How can sodium-glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron

deficient? Implications for understanding iron homeostasisinheartfailure. EurJHeartFail. 2022;24:2287–96.

79. Docherty KF, Welsh P, Verma S, De Boer RA, O’Meara E, Bengtsson O, Kober L, Kosiborod MN, Hammarstedt A, Langkilde AM, Lindholm D, Little DJ, Sjostrand M, Martinez FA, Ponikowski P, Sabatine MS, MorrowDA, Schou M, Solomon SD, Sattar N, Jhund PS, McMurray JJV, Investigators D-H. Iron deficiency in heart failure and effect of dapagliflozin: findings from DAPA-HF. Circulation. 2022;146:980–94.

80. Authors/Task Force M, McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, JankowskaEA,LainscakM,LamCSP,LyonAR,McMurrayJJV, MebazaaA,MindhamR,MunerettoC,FrancescoPiepoliM, Price S, Rosano GMC, Ruschitzka F, Skibelund AK, Group ESCSD. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and

treatmentofacuteandchronicheartfailureoftheEuropean society of cardiology (ESC) with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail. 2024;26:5–17. 81. Lakhal-LittletonS,ClelandJGF.Irondeficiencyandsupplementationinheartfailure. NatRevCardiol. 2024;21:463–86. 82. von Haehling S, Sato R, Anker SD. Is myocardial accumulation of non-transferrin-boundiron clinically relevant? Eur HeartJ.2024; https://doi.org/10.1093/eurheartj/ehae560 . 83. Anker SD, Friede T, Butler J, et al. Intravenous ferric carboxymaltose in heart failure with iron deficiency: the FAIR-HF2 DZHK05 randomized clinical trial. JAMA. 2025; https://doi.org/10.1001/jama.2025.3833 . 84. AnkerSD,KarakasM,MentzRJ,etal. Systematicreviewand meta-analysis of intravenous iron therapy for patients with heart failure and iron deficiency. Nat Med. 2025; https:// doi.org/10.1038/s41591-025-03671-1 .

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