JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 83, NO.

25, 2024

ª 2024 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Intravenous Iron Repletion for Patients

With Heart Failure and Iron Deficiency
JACC State-of-the-Art Review

Baljash Cheema, MD, MSCI, MSAI,a,b Anuj Chokshi, MD,c Olusola Orimoloye, MD, MPH,c Hossein Ardehali, MD, PHDb

ABSTRACT

Iron deficiency and heart failure frequently co-occur, sparking clinical research into the role of iron repletion in this
condition over the last 20 years. Although early nonrandomized studies and subsequent moderate-sized randomized
controlled trials showed an improvement in symptoms and functional metrics with the use of intravenous iron, 3 recent
larger trials powered to detect a difference in hard cardiovascular outcomes failed to meet their primary endpoints.
Additionally, there are potential concerns related to side effects from intravenous iron, both in the short and long term.
This review discusses the basics of iron biology and regulation, the diagnostic criteria for iron deficiency and the clinical
evidence for intravenous iron in heart failure, safety concerns, and alternative therapies. We also make practical
suggestions for the management of patients with iron deficiency and heart failure and outline key areas in need of future
research. (J Am Coll Cardiol 2024;83:2674–2689) © 2024 by the American College of Cardiology Foundation.

I ron deficiency (ID), as defined by the American

Heart Association (AHA) and American College
of Cardiology (ACC) guidelines, occurs with heart
failure (HF) in 40% to 70% of patients. 1-5 Several hy-
Early studies led to subsequent moderate-sized
randomized controlled trials (RCTs), including FAIR-
HF (Ferinject Assessment in Patients With Iron Defi-
ciency and Chronic Heart Failure), CONFIRM-HF
potheses exist for this association, including dietary (Ferric Carboxymaltose Evaluation on Performance
deficiencies, impaired iron absorption caused by gut in Patients With Iron Deficiency in Combination With
edema or concomitant proton pump inhibitor use, or Chronic Heart Failure), and EFFECT-HF (Effect of
increased blood loss caused by the use of antiplatelet Ferric Carboxymaltose on Exercise Capacity in Pa-
agents and anticoagulants, although none of these tients With Heart Failure and Iron Deficiency), which
theories is strongly supported by scientific investiga- collectively showed an improvement in functional
tions. 1,6-10 Epidemiologic studies link ID in patients capacity, patient-reported symptoms, and quality-of-
with HF to reduced exercise capacity, worse quality- life metrics with intravenous (IV) iron in patients with
of-life metrics, reduced peak oxygen consumption, ID and HF with reduced ejection fraction (HFrEF).16-21
recurrent hospitalizations for HF, cardiovascular Subsequent meta-analyses strengthened these claims
mortality, and all-cause mortality.2,3,11-15 As such, and additionally suggested an improvement in com-
iron repletion for ID in HF has been an active area bined endpoints of all-cause mortality, cardiovascular
of research over the last 20 years and counting. mortality, and hospitalization for worsening HF.22,23

Listen to this manuscript’s

audio summary by
Editor-in-Chief
Dr Valentin Fuster on From the aBluhm Cardiovascular Institute, Center for Artificial Intelligence, Northwestern Medicine, Chicago, Illinois, USA;
www.jacc.org/journal/jacc. b
Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; and the cMcGaw Medical Center, Northwestern
University, Feinberg School of Medicine, Chicago, Illinois, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received January 23, 2024; revised manuscript received March 13, 2024, accepted March 15, 2024.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2024.03.431

JACC VOL. 83, NO. 25, 2024 Cheema et al 2675
JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

and alternatives to treatment with IV iron. ABBREVIATIONS

HIGHLIGHTS AND ACRONYMS
This review provides a guide for the diagnosis
 Iron deficiency and heart failure and treatment of ID in HF and covers the
6MWTD = 6-minute walk test
frequently occur concurrently and are basics of iron biology and regulation as well distance
associated with adverse cardiovascular as the diagnostic criteria for ID in HF, high-
ACC = American College of
outcomes. lighting areas of ambiguity. It then moves to a Cardiology
discussion of clinical trials in this space AHA = American Heart
 Early trials of intravenous iron repletion
before addressing safety concerns with IV Association
in patients with heart failure found im-
iron and the rationale and evidence for EF = ejection fraction
provements in symptoms and functional
alternative therapies. It concludes with a ESC = European Society of
capacity, but subsequent large trials
summary of key unanswered questions to Cardiology
failed to confirm objective consistent
spark future inquiry and practical sugges- FCM = ferric carboxymaltose
benefit.
tions for clinical management of patients FGF = fibroblast growth factor

 Side effects of and alternatives to intra- with ID and HF. The main points are sum- FPN1 = ferroportin 1

venous iron repletion warrant careful marized in the Central Illustration. GI = gastrointestinal
consideration. Hb = hemoglobin
BIOLOGY AND REGULATION OF IRON
HF = heart failure

At present, the AHA/ACC HF guidelines give a Class Iron is the most abundant element by mass HFrEF = heart failure with
reduced ejection fraction
2a, Level of Evidence (LOE): B-R recommendation to on Earth, and the average human body con-
tains roughly 3.5 to 4.5 g of it.33,34 Mamma- ID = iron deficiency
treat ID in patients with HFrEF with IV iron to improve
2þ IRP = iron regulatory proteins
functional status and quality of life, while the Euro- lian cells rely on iron in the reduced Fe
pean Society of Cardiology (ESC) gives a Class I, LOE: A state, ferrous iron, which is less abundant in IV = intravenous

recommendation for the same while giving an addi- nature than the oxidized Fe 3þ state, ferric LOE = level of evidence

tional Class IIa, LOE: A recommendation to treat ID in iron.35 Iron easily accepts or donates elec- MLHFQ = Minnesota Living
HFrEF with IV iron to reduce risk of HF hospitaliza- trons, making it an essential micronutrient With Heart Failure
Questionnaire
tion.22-26 for various cellular reactions, including those
PGA = Patient Global
Despite the positive signal in smaller studies, involved in metabolism and energy produc-
Assessment
AFFIRM-AHF (Study to Compare Ferric Carbox- tion. 36 It is indispensable to the function of
RCT = randomized controlled
ymaltose With Placebo in Patients With Acute heme-containing proteins, which facilitate trial
Heart Failure and Iron Deficiency), IRONMAN the generation of energy in the form of
sTFR = soluble transferrin
(Intravenous Iron Treatment in Patients With adenosine triphosphate through the electron receptor

Heart Failure and Iron Deficiency), and HEART-FID transport chain. Heme is also an essential TFR1 = transferrin receptor 1
(Randomized Placebo-Controlled Trial of Ferric Car- component of hemoglobin (Hb) and TSAT = transferrin saturation
boxymaltose as Treatment for Heart Failure With myoglobin, which transport and store oxy-
Iron Deficiency), 3 recently completed large RCTs gen, respectively. 34
powered to detect a reduction in major adverse Iron is predominantly found in the intracellular
cardiovascular events, did not meet their primary space, with w60% attached to Hb within red blood
endpoints.27-29 The results of these studies have cells and w25% attached to ferritin within hepato-
raised several questions regarding the accuracy of cytes and macrophages in the liver and spleen.1,37
the diagnostic criteria and management of ID in the Intracellular iron is mainly stored as ferritin, either
HF population.9,10,27-31 These issues are of critical in the cytoplasm or within the mitochondria. Addi-
importance because IV iron has potential side effects tionally, all cell types contain a small amount of iron
caused by the delivery of a nonphysiologic load of in the form of iron-sulfur cluster–containing proteins,
iron directly into the bloodstream, bypassing the which are critical to a number of cellular processes,
intrinsic regulatory system highly conserved across particularly in cell types with high metabolic work-
mammalian species to avoid tissue damage from load, including cardiomyocytes. 9,10,34,38
9,10
exposure to free iron. All the while, the market A small amount of iron exists as free iron within
share of IV iron therapy is growing yearly, with es- the cellular labile iron pool. 1,31 This pool of free iron is
timates that IV iron will be a $4 billion industry by tightly regulated because unbound iron is highly
2028.32 reactive and interacts with the normal aerobic
Therefore, clinicians must understand the diag- metabolite hydrogen peroxide to form hydroxyl rad-
nostic nuances to correctly identify ID in patients icals, which are the most damaging form of reactive
with HF and be able to rationalize the risks, benefits, oxygen species. 10,39 Only about 0.1% of total body
2676 Cheema et al JACC VOL. 83, NO. 25, 2024

Iron Repletion for Heart Failure JUNE 25, 2024:2674–2689

C E N T R A L IL L U ST R A T I O N Intravenous Iron for Iron Deficiency and Heart Failure

Cheema B, et al. J Am Coll Cardiol. 2024;83(25):2674–2689.

(A) The rationale for, clinical trial outcomes for, and risks associated with intravenous and oral iron therapy in patients with iron deficiency
and heart failure. (B) Importantly, trial data are generated from the inclusion of patients with iron deficiency defined by serum iron indexes,
despite test characteristics that portend a high chance of misclassification. (C) Areas in need of ongoing research. BM ¼ bone marrow;
GI ¼ gastrointestinal; HF ¼ heart failure; ID ¼ iron deficiency; IV ¼ intravenous; PO ¼ per os; TSAT ¼ transferrin saturation.

iron, or 2 to 4 mg, exists in the extracellular space and about 20 to 25 mg of iron, which is subsequently
is mostly attached to transferrin, a transport protein used by the bone marrow for erythropoiesis, the most
in the serum.1,9,37 iron-intensive process in the body (Figure 1). 1,37
Although a typical human diet may contain 10 to
20 mg of iron per day and is a mix of heme-based iron SYSTEMIC AND CELLULAR IRON HOMEOSTASIS. There is
and nonheme iron, only about 1 to 2 mg of iron is no known pathway for iron excretion from the human
absorbed through the duodenum and proximal body, with the only loss of iron occurring through
jejunum daily. 1,37,40 Roughly the same amount is lost desquamation or blood loss. Iron homeostasis,
through desquamation of epithelial cells in the normal therefore, is highly dependent on intake, uptake, and
resting state. The majority of daily iron turnover in the storage. Iron absorption into the gut mucosa occurs
body comes from recycling iron from senescent red for heme-bound iron via the heme transporter and for
blood cells by scavenger macrophages, generating non-heme-bound iron after reduction of ferric to
JACC VOL. 83, NO. 25, 2024 Cheema et al 2677
JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

F I G U R E 1 Tissue Distribution and Metabolism of Iron

A typical Western diet contains 10 to 20 mg of iron per daily, with about 5% to 10% absorbed to counteract systemic losses. Absorption
occurs into the duodenal enterocyte, where it can then be released into the systemic circulation. From there, iron can be used for eryth-
ropoiesis in the bone marrow or stored in hepatocytes or macrophages. Hepcidin, produced in the liver, inhibits the release of iron from cells
into the systemic circulation. The majority of daily iron flux is from scavenger macrophages recycling iron from senescent red blood cells. The
relative amount of iron in different cell and tissue types is provided. Fe ¼ iron; RBC ¼ red blood cell; Tf ¼ transferrin.

ferrous iron through the divalent metal transporter 1 lysosomes, resulting in intracellular iron sequestra-
(DMT1). Iron influx into cells from transferrin-bound tion and a reduction in the ability of iron to leave the
serum iron occurs mainly through binding to trans- gut mucosa or cells of the reticuloendothelial cell
ferrin receptor 1 (TFR1), a transmembrane glycopro- system.37 Hepcidin is increased in response to
tein, with subsequent receptor-mediated endocytosis increased intracellular iron, serum iron, and endog-
and iron release. There are additional pathways for enous or exogenous erythropoietin as well as in states
iron influx unique to distinct tissue types. 10,41 The of chronic inflammation or infection. Because iron is a
only known pathway for cellular efflux is through key micronutrient to microorganism growth,
transmembrane protein ferroportin 1 (FPN1), which increased hepcidin production during infection and
allows iron to enter the serum, where it is subse- the subsequent reduction in serum iron is thought to
quently bound to transferrin and can make its way to serve as a protective mechanism from microbial
target tissues or enter macrophages and hepatocytes growth.37 Higher hepcidin is also seen in obesity via
for longer-term storage (Figure 2). leptin-mediated increase, and it is increased in
The key regulator of iron’s movement between conjunction with the development of renal dysfunc-
cells and the serum is hepcidin. Hepcidin is produced tion because it is renally cleared.42
by hepatocytes and was initially discovered in rela- At the cellular level, iron regulatory proteins (IRPs)
tion to its bactericidal properties. Hepcidin exerts its 1 and 2 control the amount of intracellular iron
influence through its interactions with FPN1. When through post-transcriptional regulation of certain
hepcidin binds to FPN1, the complex is internalized proteins in iron homeostasis pathways. Binding of
into the intracellular space and degraded in IRP-1 and IRP-2 to the 3-untranslated region of TFR1
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Iron Repletion for Heart Failure JUNE 25, 2024:2674–2689

F I G U R E 2 Cellular Iron Regulation

Transferrin-bound iron in the serum binds TFR1, where it undergoes endocytosis and is internalized, releasing iron within the acidic envi-
ronment of the lysosome. Iron is subsequently stored as ferritin, tracked to the mitochondria, or it exists as a small labile pool within the
cytoplasm, and the TFR1 complex is distributed back to the cellular membrane. A small amount of non-transferrin-bound iron uptake occurs
via other transmembrane proteins, most notably DMT1. Iron export is solely mediated by ferroportin 1, whose activity is regulated by
hepcidin. DMT ¼ divalent metal transporter; Fe ¼ iron; FPN1 ¼ ferroportin 1; TF ¼ transferrin; TFR1 ¼ transferrin receptor 1.

stabilizes the transcript and increases protein trans- to iron at the cellular and tissue level in the face of
lation, whereas their binding to the 5-untranslated replete iron stores, known as functional ID. Absolute
region of FPN1 and ferritin prevents translation.43 ID is caused by nutritional deficiencies or blood loss,
These regulatory functions of IRPs collectively whereas functional ID occurs because of sequestered
result in more iron uptake, less iron export, and more iron stores in hepatocytes or macrophages because of
iron release from intracellular iron stores. We have the action of hepcidin. Both subtypes of ID result in
demonstrated another pathway in parallel to the IRP low iron availability to the tissues that need it. The
system to maintain sufficient cellular iron during se- gold standard for diagnosing ID is reduced iron
vere ID, termed the iron conservation pathway, as staining on bone marrow biopsy, because erythro-
opposed to the iron acquisition pathway mediated by poiesis in the bone marrow is the bodily process that
the IRP system. In severe ID, the expression of a requires the most iron. However, because of the
messenger RNA–binding protein called tristetraprolin invasive nature of this study, the diagnosis in clinical
is increased, which paradoxically inhibits TFR1 pro- practice is made by serum iron indexes, including
duction but conserves iron inside the cell. 44 In addi- ferritin, iron level, and transferrin saturation
tion, we have shown the NAD (nicotinamide adenine (TSAT).4,5,30,46,47
dinucleotide) þ-dependent deacetylase protein sirtuin In an otherwise healthy individual, low serum
2 also regulates cellular iron through deacetylation of ferritin levels and TSAT are reliable to diagnose ID
the transcription factor nuclear factor erythroid- because they accurately reflect states of inadequate
derived 2–related factor 2. 45 total body iron stores. 1,47 Serum ferritin, however, is
an acute-phase reactant and fluctuates based on
DIAGNOSING ID IN HF states of inflammation in conjunction with hepcidin
levels, thus making it more challenging to rely on it in
ID occurs because of inadequate total body iron disease states with an inflammatory component,
stores, referred to as absolute ID, or restricted access complicating the diagnosis of ID when considering
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JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

functional ID.46 HF has long been thought to be a resolve spontaneously without the administration of
disease with chronic inflammation, associated with exogenous iron.53 In a study of 906 patients with HF,
elevated inflammatory cytokines, including inter- 43% of patients had ID as defined by serum iron
leukin-1, interleukin-6, and tumor necrosis factor- of <13 m g/dL, chosen for its greater diagnostic per-
alpha, although hepcidin levels actually show a pro- formance discussed earlier. 4 In 44% of those patients,
gressive decline along the spectrum of NYHA func- ID resolved at 1 year of follow-up despite only 4% of
tional class.1,8,48-51 them receiving iron repletion. Persistent ID (defined
In various disease states, investigators have as ID present 1 year later) or incident ID at 1 year was
attempted to correct for ferritin fluctuations with associated with higher mortality, whereas resolved ID
inflammation by raising the lower limit of normal to at 1 year was associated with lower mortality. Of note,
as high as 40 ng/mL 30,46,47 to account for functional when using the FAIR-HF criteria instead of serum
ID. The criteria commonly used to define ID in HF and iron in this cohort, a larger portion of patients were
for inclusion in clinical trials were modeled based on said to have ID at baseline (63%), with resolution in
IV iron trials in the chronic kidney disease literature only 21% at 1 year. Further, the correlation between
and used ferritin of <100 ng/mL or ferritin of 100 to persistent ID, resolved ID, or incident ID at 1 year with
299 ng/mL if TSAT was <20%. 30,31,52 This was first mortality was no longer present. 53
done in 2008 in FAIR-HF, subsequently referred to as Collectively, these studies raise the question of
the FAIR-HF criteria in this review, and were carried whether serum iron indexes accurately reflect ID in all
forward in nearly all future clinical trials of IV iron in circumstances and warrant repletion or, instead, may
HFrEF patients with ID. reflect poor health in patients with HF. At a mini-
mum, they support the notion that the FAIR-HF
AREAS OF UNCERTAINTY. The FAIR-HF criteria,
criteria have a weaker association with cardiovascu-
however, were arbitrability adopted before they had
lar outcomes than serum iron or TSAT alone and may
been systematically studied in patients with HF, an
not be the best suited inclusion criteria for clinical
endeavor subsequently taken on by Grote Beverborg
trials. Despite this, the FAIR-HF criteria have been
et al.4 In their study, 42 patients with HF undergoing
consistently used in clinical trials with IV iron in HF
coronary artery bypass surgery in the Netherlands
patients, summarized in the following section and in
had sternal bone marrow aspirates performed to
Table 1.
compare various serum iron indexes vs the gold
standard of decreased iron staining on bone marrow CLINICAL TRIALS OF IV IRON IN HF
aspirate to diagnose ID. They confirmed a high rate of
ID in patients with HF, with decreased iron staining Clinical research into the treatment of ID in HF was a
by bone marrow aspirate seen in 40% of this group. byproduct of earlier work in which anemic patients
Overall, compared to bone marrow iron staining, the with HF were treated with a combination of exoge-
FAIR-HF criteria had a sensitivity of 82.4%, a speci- nous erythropoietin and IV iron. An uncontrolled
ficity of 72.0%, a positive predictive value of 66.7%, study by Silverberg et al54 in 2000 in this patient
and a negative predictive value of 85.7%. Thus, one- population showed improved symptoms, higher EF,
third of patients who were predicted to have ID by and reduced hospitalizations for HF; however, sub-
FAIR-HF criteria in fact had normal bone marrow iron sequent work suggested detrimental effects associ-
stores. Further, the presence of low ferritin with a ated with the use of erythropoiesis-stimulating agents
TSAT of >19.8% was not found to correlate with bone in HF. This was confirmed in the RED-HF (Reduction
marrow iron staining, although it met the FAIR-HF of Events With Darbepoetin Alfa in Heart Failure) RCT,
criteria and would allow for entry into several trials where patients with anemia and HFrEF treated with
of ID in HF. They also showed that TSAT of <19.8% darbepoetin had significantly higher rates of throm-
and serum iron of <13 mg/dL both correlated more boembolic events and ischemic strokes. 55,56
strongly with decreased iron staining on bone marrow IV IRON ALONE FOR ID IN HF WITH ANEMIA. In
aspirate than the FAIR-HF criteria. This group sub- 2006, Bolger et al17 published an uncontrolled pro-
sequently analyzed all-cause mortality in 387 spective study of 16 patients with anemia and symp-
consecutive patients with HF, and although both tomatic HFrEF treated with a 1-g dose of IV iron
TSAT of <19.8% and serum iron of <13 mg/dL were sucrose via daily bolus therapy for 12 days. Hb stores
associated with all-cause mortality after multivari- increased, Minnesota Living With Heart Failure
able adjustment, ferritin level was not.4 Questionnaire (MLHFQ) scores fell, and 6-minute
Additionally, evidence has emerged that serum walk test distance (6MWTD) improved. Improve-
iron indexes in HF fluctuate over time and can even ment in functional measures and symptom scores
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Iron Repletion for Heart Failure JUNE 25, 2024:2674–2689

T A B L E 1 Key Clinical Trials of Intravenous Iron in Heart Failure

First Author/ Primary Key Secondary

Study Year n Inclusion Criteria Intervention Comparator Follow-Up Outcome(s) Outcomes

Toblli et al20 2007 40 HF (LVEF of #35%, NYHA Iron sucrose 200 mg Isotonic saline 6 mo Reduced NT-proBNP, Reduced HF
functional class II-IV), ID weekly for 5 wks increased LVEF, lower hospitalizations and
(ferritin of <100 ng/mL and NYHA functional improved
TSAT of #20%), anemia (Hb class, increased hematologic
of <12.5 g/dL for men 6MWTD indexes, including
and <11.5 g/dL for women), ferritin, TSAT, and
chronic renal failure Hb concentrations
(CrCl of <90 mL/min)
FERRIC-HF18 2008 35 HF (LVEF of <45%, NYHA Iron sucrose weekly No treatment 18 wks Increased absolute pVO2 Improved pVO2/kg, iron
functional class II-III, until ferritin is parameters, NYHA
pVO2/kg of <18 mL/kg/min), >500 ng/mL, functional class,
ID (ferritin of <100 ng/mL or then at weeks 4, PGA score, fatigue
ferritin of 100-300 ng/mL 8, 12, and 16 score, and MLHFQ
with TSAT of <20%) score
FAIR-HF16 2009 459 HF (LVEF of <45% with NYHA FCM 200 mg weekly Normal saline 24 wks Improved PGA score and Improved 6MWTD,
functional III class or LVEF until iron NYHA functional class KCCQ, and EQ-5D
of <40% with NYHA repletion, then visual assessment
functional class II), ID every 4 wks scores
(ferritin of <100 mg/L or
ferritin of 100-299 mg/L if
TSAT of <20%),
Hb of 9.5 to 13.5 g/dL
CONFIRM- 2015 304 HF (LVEF of #45%, elevated FCM 500-2,000 mg Normal saline 52 wks Improved 6MWTD Improved PGA, KCCQ,
HF19 natriuretic peptides, during the and EQ-5D scores;
NYHA functional class II-III), ID treatment phase, improved NYHA
(ferritin of <100 ng/mL or then 500-mg functional class;
ferritin of 100-300 ng/mL if maintenance dose reduced fatigue
TSAT of <20%), Hb of injections at score; and reduced
<15 g/dL weeks 12, 24, and rate of HF
36 if ID remained hospitalizations
EFFECT- 2017 172 HF (LVEF of #45%, NYHA FCM 500-1,000 mg Standard of 24 wks No significant difference Improved in NYHA
HF21 functional class II-III, at week 0 and care in pVO2 functional class and
elevated natriuretic week 6, then at PGA scores
peptides, pVO2 of week 12 if still
10-20 mL/kg/min), ID iron deficient
(ferritin of <100 ng/mL or
ferritin of 100-300 ng/mL if
TSAT of <20%)
AFFIRM- 2020 1,132 Acute HF (hospitalization FCM as outpatient at Placebo 52 wks No change in composite No change in composite
AHF27 requiring IV diuretics, LVEF week 0 and week of total HF of total CV
of <50%, elevated 6, then at week 12 hospitalizations and hospitalizations and
natriuretic peptides), ID and week 24 if still CV death at 52 wks CV death or CV
(ferritin of <100 mg/L or iron deficient or if death alone
ferritin of 100-299 mg/L if Hb is 8-15 g/dL Reduction in total HF
TSAT of <20%) hospitalizations and
the composite of
first HF
hospitalization or
CV death
IRONMAN28 2022 1,137 HF (LVEF of #45% and elevated Ferric derisomaltose Usual care 2.7 y No change in composite Reduction in combined
natriuretic peptides, or at days 0 and 28, of recurrent HF endpoint of
hospitalization for HF within then every 4 mo if hospitalizations and cardiovascular
6 mo), ID (ferritin ID CV death death or hospital
of <100 ng/mL or TSAT admission for
of <20%) stroke, myocardial
infarction, or HF
No change in any other
hard cardiovascular
outcome
HEART- 2023 3,065 HF (LVEF of #40% and either FCM weekly  2 wks, Placebo 1.9 y No change in hierarchical No change in composite
FID29 HF within the previous then every 6 mo composite endpoint endpoint of
12 mo or an elevated based on Hb and of death within 12 mo, cardiovascular
natriuretic peptide level), presence of ID hospitalization for HF death or HF
ID (ferritin of <100 ng/mL or within 12 mo, or hospitalization
ferritin of 100-300 ng/mL if change in 6MWTD No change in any other
TSAT of <20%), Hb of from baseline to 6 mo secondary outcome
9-13.5 g/dL in women or
<15 g/dL in men

6MWTD ¼ 6-minute walk test distance; AFFIRM-AHF ¼ Study to Compare FCM With Placebo in Patients With Acute Herat Failure and Iron Deficiency; CONFIRM-HF ¼ Ferric Carboxymaltose Evaluation on
Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure; CrCl ¼ creatinine clearance; CV ¼ cardiovascular; EFFECT-HF ¼ Effect of Ferric Carboxymaltose on Exercise Capacity in
Patients With Heart Failure and Iron Deficiency; EQ-5D ¼ European Quality of Life-5 Dimensions Visual Analog Scale; FAIR-HF ¼ Ferinject Assessment in Patients With Iron Deficiency and Chronic
Heart Failure; FCM ¼ ferric carboxymaltose; FERRIC-HF ¼ Ferric Iron Sucrose in Heart Failure; Hb ¼ hemoglobin; HEART-FID ¼ Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure
With Iron Deficiency; HF ¼ chronic heart failure; ID ¼ iron deficiency; IRONMAN ¼ Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency; IV ¼ intravenous; KCCQ, Kansas City
Cardiomyopathy Questionnaire; LVEF ¼ left ventricular ejection fraction; MLHFQ ¼ Minnesota Living With Heart Failure Questionnaire; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; PGA ¼ Patient
Global Assessment; pVO2 ¼ peak oxygen uptake; TSAT ¼ transferrin saturation.
JACC VOL. 83, NO. 25, 2024 Cheema et al 2681
JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

closely tracked with increased Hb, and increased Hb FAIR-HF was a double-blind, placebo-controlled,
closely tracked with serum iron and iron saturation. randomized trial of 459 ambulatory patients with
In 2008, Usmanov et al57 published an uncontrolled HFrEF (EF of #40% and NYHA functional class II or
prospective study of 32 patients with HF and Hb EF of #45% and NYHA functional class III), ID, and Hb
of <11 g/dL treated with 100 mg IV iron sucrose dosed between 9.5 and 13.5 g/dL who were randomized 2:1
3 times/week and showed an improvement in Hb and to FCM or saline. 16 The treatment arm received
NYHA functional class in those with baseline class III weekly FCM in 200-mg boluses until iron stores were
or less symptoms. replete, followed by entry into a maintenance phase
In 2007, Toblli et al 20 conducted the first RCT of IV of monthly injections. Those in the treatment arm
iron and HFrEF in anemia. This was a double-blinded had an improvement in self-reported Patient Global
trial of weekly 200-mg IV iron sucrose vs saline in 40 Assessment (PGA) and NYHA functional class at week
patients (20 in each arm) with anemia, ID as defined 24, with 47% ending the trial as NYHA functional
by TSAT of <20% and ferritin of <20 ng/mL, HFrEF class I or II compared to 30% in the placebo group.
with EF of <35%, and chronic kidney disease. The There was a significant improvement in several of the
treatment arm had improvements in Hb lower trial’s secondary endpoints, as early as week 4,
C-reactive protein level, higher EF, higher MLHFQ collectively suggesting an improvement in quality of
score, and greater 6MWTD. Further, no patients were life and exercise capacity in the treatment arm. There
hospitalized for HF in the treatment arm, with 5 was no difference in death, adverse events, or serious
hospitalizations for HF in the placebo arm. adverse events in either trial arm. 16
IV IRON FOR ID IN HF WITHOUT ANEMIA: EARLY It is important to note that in this trial, the median
WORK. Positive findings in these early studies length of time before iron stores were replete was
prompted research into IV iron for HF in the absence 6 weeks, but a number of secondary outcomes were
of anemia, and in 2008, Okonko et al18 published the significantly improved by week 4, raising the ques-
findings from FERRIC-HF (Ferric Iron Sucrose in tion of the exact etiology of symptomatic improve-
Heart Failure). This was a trial of IV iron for ID in ment given ongoing ID. Additionally, this was a study
HFrEF and used an objective measure of cardiovas- of mostly White patients (99%) with ischemic car-
cular performance in peak V O 2 measured by cardio- diomyopathy (80%), with 82% in NYHA functional
pulmonary stress testing as the primary endpoint. It class III and 56% reporting angina, limiting its
was a randomized, observer-blinded trial of 35 pa- generalizability. The follow-up period was only
tients with EF of #45%, NYHA functional class II or 6 months, which raises the question of whether safety
III, and peak VO 2/kg of #18 mL/kg/min, with ID signals may have been seen with a longer time course.
defined by ferritin of <100 ng/mL or between 100 and Last, at least 1 physician was unblinded at each site
300 ng/mL with a TSAT of <20%. The treatment arm because the study drug was distinctly different in
received 200 mg IV iron sucrose weekly until ferritin appearance compared to the normal saline used in the
was >500 ng/mL, then 200 mg monthly for 16 weeks placebo arm.16 After release of FAIR-HF results, IV
total. The treatment arm had an increase in peak VO 2 FCM for ID first entered HF guidelines from the ESC in
by 2.2 mL/kg/min (P ¼ 0.01). In those with anemia, 2012 58 and appeared in the Australian and New Zea-
peak V O2 increased by 3.9 mL/kg/min (P ¼ 0.01). land joint guidelines published in 2011.59
IV IRON FOR ID IN HF WITHOUT ANEMIA: The next trial was CONFIRM-HF, in which 304
MODERATE-SIZED RCTs FOR FUNCTIONAL OUTCOMES. ambulatory HFrEF patients (EF of #45%, NYHA
These study results led to 3 moderate-sized random- functional class II or III, and elevated natriuretic
ized clinical trials aimed at substantiating the func- peptides) with ID were randomized 1:1 to FCM or
tional and subjective improvements with IV iron placebo.19 The treatment arm received FCM once at
treatment in patients with ID and HFrEF without baseline and again at week 6, for a total dose of 500 to
anemia. These trials were the first investigations into 2,000 mg based on a dosing schedule related to body
the use of ferric carboxymaltose (FCM), a form of IV weight and Hb level. A maintenance phase followed,
iron that allows for a larger dose to be delivered in with 3 500-mg injections at weeks 12, 24, and 36 if ID
one sitting and has greater bioavailability. Each trial was still present, and the trial duration was 52 weeks.
was funded by Vifor Pharma Ltd, the producer of Compared to FAIR-HF, the FCM doses were larger and
FCM. Additionally, these trials each used the same more spread out, and the follow-up period was
definition of ID (ferritin of <100 ng/mL or between longer. This study showed a net difference in 6MWTD
100 and 299 ng/mL with TSAT of <20%), as previously of 33  11 m (P ¼ 0.002) between the treatment arm
discussed. This is the definition of ID used in each of and placebo arm, and many of the secondary end-
the following clinical trials unless otherwise stated. points were positive from week 24 onward.
2682 Cheema et al JACC VOL. 83, NO. 25, 2024

Iron Repletion for Heart Failure JUNE 25, 2024:2674–2689

Additionally, there was a significant reduction in literature by assessing for an improvement in hard
hospitalization for HF in the treatment arm, with no clinical outcomes, including hospitalizations for HF,
difference in the rate of death or adverse events cardiovascular death, and all-cause mortality. Addi-
between the trial arms. tionally, they explored the use of IV iron in acute HF
Similar to FAIR-HF, this was a mostly White trial and evaluated alternative forms of IV iron than FCM
population (99%) with ischemic cardiomyopathy or iron sucrose.
(83%) and 65% of patients reporting angina. At least 1 AFFIRM-AHF was a large, multicenter, double-
physician at each site was unblinded because of the blind, placebo-controlled trial of patients hospital-
nature of the study drug. Although there was a net ized for acute HF (elevated natriuretic peptides and
difference of 33 m in 6MWTD in each group, the actual had received IV diuretics) with EF of <50% and ID,
increase in the treatment arm was 18  8 m from a randomized 1:1 before discharge to FCM for up to
baseline of 288  98 m, with a decline in total distance 24 weeks as outpatient therapy dosed in relation to
in the placebo group accounting for the greater mar- their degree of ID or placebo.27 The study’s primary
19
ginal difference. Although there is no standard endpoint was a composite of hospitalizations for HF
measure for a clinically meaningful increase in and cardiovascular death at 52 weeks, and key sec-
6MWTD, it has been suggested that an improvement ondary outcomes included cardiovascular death, total
of 30 to 50 m is significant for those who start with a HF hospitalizations, time to first hospitalization for
lower baseline of around 100 m and that an improve- HF or cardiovascular death, and combinations of
ment of 100 m is significant if one’s baseline is closer these measures. A total of 1,132 patients were ran-
to 300 m. 60 After publication of CONFIRM-HF, the domized, with 1,108 included in the final analysis (558
AHA/ACC added treatment recommendations for ID in treatment arm, 550 placebo arm). The trial’s primary
HFrEF with IV iron to their HF guidelines, and the ESC composite endpoint was neutral (RR: 0.79; 95% CI:
continued to recommend the therapy in its latest 0.62-1.01; P ¼ 0.059). There was no significant dif-
guideline iteration at the time. 61,62 ference in the combined endpoint of total cardiovas-
The last of these 3 trials was EFFECT-HF (Effect of cular hospitalizations and cardiovascular death or
Ferric Carboxymaltose on Exercise Capacity in Pa- cardiovascular death alone. There was a reduction in
tients With Heart Failure and Iron Deficiency), an total HF hospitalizations (RR: 0.74; 95% CI: 0.58-0.94;
open-label, randomized trial of 174 patients with P ¼ 0.013) and the combined secondary endpoint of
HFrEF (EF of #45%, NYHA functional class II or III, first HF hospitalization or cardiovascular death (HR:
elevated natriuretic peptides) and ID.21 Participants 0.80; 95% CI: 0.66-0.98; P ¼ 0.030). Of note, this trial
were randomized 1:1 to FCM or standard of care, with faced challenges because of the COVID-19 pandemic,
no placebo arm. The treatment arm received the same and in a sensitivity analysis limiting the data to the
dosing schedule as in CONFIRM-HF, with initial bolus first occurrence of COVID-19 in each country the trial
dosing until iron stores were replete followed by a was conducted in, there was a greater reduction in
maintenance phase. The primary endpoint was a primary composite endpoint in the treatment arm
change in peak VO2 from baseline to 24 weeks to build (RR: 0.79; 95% CI: 0.65-0.97; P ¼ 0.023). 27 The rate of
on the results of FERRIC-HF. 18 The initial analysis of adverse events in each trial arm was similar.
this study was done by imputing a value of 0 for peak IRONMAN was a prospective, open-label, random-
VO2 in 4 participants who died in the standard-of-care ized clinical trial of patients with HFrEF (EF of #45%,
arm, using the principle of “last observation carried elevated natriuretic peptides or hospitalization for HF
forward,” and the results showed a reduction in peak in last 6 months) and ID as defined by TSAT of <20%
VO2 in the standard-of-care arm but no significant or serum ferritin of <100 ng/mL who were random-
change in the treatment arm. When this controversial ized 1:1 to receive either IV ferric derisomaltose or
imputation strategy was abandoned and deceased usual care. 28 This was the first trial of ferric deriso-
participants were excluded, there was no significant maltose, a therapy that can be provided as a high-
change in peak VO2 in the treatment arm. Last, there dose, rapid infusion, and the definition of ID in this
were 37 hospitalizations among the 88 participants in trial breaks from the established norm of the FAIR-HF
the treatment arm compared to 21 among the 86 criteria by removing the provision by which ferritin of
participants in the standard-of-care arm, none 100 to 299 ng/mL was acceptable if TSAT was <20%.
deemed to be related to the treatment itself. The treatment arm was dosed at baseline,
IV IRON FOR ID IN HF WITHOUT ANEMIA: LARGE after 1 month, then every 4 months if ferritin
RCTs FOR HARD CARDIOVASCULAR OUTCOMES. was <100 ng/mL or ferritin was <400 ng/mL and
Recently, 3 large clinical trials of IV iron in ID with TSAT was <25%. The median follow-up was 2.7 years,
HFrEF have completed. They add to the existing substantially longer than prior trials. The primary
JACC VOL. 83, NO. 25, 2024 Cheema et al 2683
JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

endpoint was a composite of recurrent hospitalization Q1-Q3: 11-20), raising concerns that the true rate of ID
for HF and cardiovascular death, the same as in in this trial was lower than intended. 63
AFFIRM-AHF, with a similarly prespecified sensitivity A series of meta-analyses have been published
analysis planned in relation to COVID-19. A total of since the results of these trials became public,
1,137 patients were randomized, with 569 in the including a meta-analysis of IV iron trials from
treatment arm and 568 in the usual care arm. The tri- January 2000 through November 2022 that suggested
al’s primary endpoint was neutral (RR: 0.82; 95% CI: IV iron was associated with reduced hospitalizations
0.66-1.02; P ¼ 0.070). There was a reduction in the for HF with an inconclusive effect on mortality. 64 A
secondary endpoint of cardiovascular death or hospi- patient-level meta-analysis by Ponikowski et al65 that
tal admission for stroke, myocardial infarction, or HF included the recent HEART-FID had similar conclu-
(RR: 0.83; 95% CI: 0.69-1.00; P ¼ 0.045). All other sions, suggesting that FCM was associated with a
secondary endpoints were neutral, including all-cause reduction in hospitalizations from HF as well as other
mortality, which occurred in 32% and 34% of the cardiovascular causes with no effect on mortality. A
treatment and usual care arms, respectively. In a third meta-analysis aggregating 14 trials of IV iron
prespecified sensitivity analysis to adjust for the suggested that IV iron additionally reduces cardio-
COVID-19 pandemic, there was a greater reduction vascular death and HF-related events.66
in the primary endpoint in the treatment arm that
just met statistical significance (RR: 0.76; 95% CI: SAFETY CONCERNS FOR IV IRON AND
0.58-1.00; P ¼ 0.047).28 There was no increase in THE ROLE OF ORAL IRON
adverse events noted in the treatment arm.
HEART-FID is the most recent large clinical trial of POTENTIAL HAZARDS WITH IV IRON. IV iron in-
IV iron in HFrEF to conclude. This was a double-blind fusions deliver iron directly to the bloodstream and
RCT of FCM in patients with HFrEF (EF of #40%, with bypass the typical regulation orchestrated by hepci-
hospitalization for HF in the last 12 months or din’s effects on iron absorption in the gut. This results
elevated natriuretic peptides), ID by the FAIR-HF in a rapid rise in non-transferrin-bound iron in
criteria, and Hb of 9.0 to 13.5 g/dL in women or 9.0 healthy subjects, and there is the potential for dam-
to 15.0 g/dL in men. The trial’s primary endpoint was age to endothelial cells and tissues because elemental
a hierarchical composite of death at 12 months, hos- iron is reactive and produces free radicals. 9,10,67,68 In
pitalizations for HF at 12 months, and the change in humans, IV iron infusion was associated with a
6MWTD from baseline to 6 months, based on the reduction in flow-mediated vasodilation compared to
unmatched win ratio. Treatment arm participants placebo, a direct measure of endothelial cell
received 2 doses of FCM within 7 days and were health.67,69 In animal models of atherosclerosis, pro-
eligible for additional therapy every 6 months based gressive iron overload was associated with worsening
on Hb and serum iron stores. A total of 3,065 patients atherosclerotic disease burden and increased inflam-
were randomized, 1,532 to the treatment arm and mation, whereas dietary restriction of iron in the
1,533 to placebo. Death occurred in 131 (8.6%) patients same model attenuated those effects. 70,71
in the treatment arm and 158 (10.3%) in the placebo Additionally, there is evidence that links IV iron
arm. There were 297 hospitalizations for HF in the with infection, with a recent meta-analysis of 154
treatment arm and 332 in the placebo arm. 6MWTD clinical trials showing a higher risk of infection than
increased by 8 m in the treatment arm and 4 m in the with oral iron therapy or no therapy (RR: 1.16; 95% CI:
placebo arm. The investigators concluded that there 1.03-1.29; i 2 ¼ 36%).72
was no difference in the composite endpoint (un- IV iron has been linked to hypophosphatemia, and
matched win ratio: 1.10; 99% CI: 0.99-1.23; Wilcoxon- elevated levels of fibroblast growth factor (FGF)-23
Mann-Whitney P ¼ 0.02). The rate of adverse events appear to play a causal role.73-75 FGF-23 is involved in
was similar in each trial arm. Of note, this trial was phosphate homeostasis, with elevated FGF-23 blunt-
designed with the goal of providing adequate evi- ing renal phosphonate absorption, contributing to
dence for U.S. Food and Drug Administration low serum phosphate levels, bone resorption, and
approval for a new drug application from 1 clinical eventually osteomalacia. In other patient pop-
trial; hence, a higher degree of evidence was needed, ulations, elevated FGF-23 has been linked to all-cause
and a 99% CI was prespecified. Additionally, the mortality, left ventricular hypertrophy, myocardial
median TSAT in this trial was 23.9%  11.2% at fibrosis, and incident HF. 9 Additionally, the associa-
baseline, substantially higher than that seen in tion between IV iron and elevated FGF-23 appears to
AFFIRM-AHF (15.2%  8.3%) and IRONMAN (15%; be specifically linked to FCM, because roughly 30% of
2684 Cheema et al JACC VOL. 83, NO. 25, 2024

Iron Repletion for Heart Failure JUNE 25, 2024:2674–2689

T A B L E 2 Clinical Trials of Oral Iron in HF

Primary Key Secondary

Study Year n Inclusion Criteria Intervention Comparator Follow-Up Outcome(s) Outcomes

IRON-HF78 2013 23 HF (LVEF of <40%, NYHA 2 intervention arms: Placebo 12 wks No change in p VO2 in —
functional class II-IV), ID Group 1: Iron sucrose either treatment arm
(ferritin of <500 mg/L, 200 mg weekly for This study was
TSAT of <20%), anemia 5 wks terminated early
(Hb of 9-12 g/dL) Group 2: Oral ferrous because of funding
sulfate 200 mg challenges and
3 times daily for 8 wks competing studies.
IRONOUT HF79 2017 225 HF (LVEF of #40%, NYHA Oral iron polysaccharide Placebo 16 wks No change in pVO2 No significant change
functional class II-IV), ID 150 mg twice daily for in 6MWTD,
(ferritin of 15-100 ng/mL or 16 wks NT-proBNP levels,
ferritin of 100-299 ng/mL or KCCQ score
if TSAT of <20%)
IRON580 2022 54 HF (LVEF of <45%, NYHA Ferrous sulfate 200 mg Placebo 12 wks Significant improvement Significant
functional class II-III), ID 3 times daily for in 6MWTD in improvement in
(ferritin of <100 ng/mL or 12 wks treatment arm hematologic
ferritin of 100-300 ng/mL indexes and NYHA
with TSAT of <20%), functional class in
anemia (Hb of <13 for men treatment arm
or <12 for women) No significant changes
in NT-proBNP or
LVEF

IRON5 ¼ The Effect of Short Term Oral Iron Supplementation in Systolic Heart Failure Patients Suffering From Iron Deficiency Anemia; IRON-HF ¼ Iron Supplementation in Heart Failure Patients With Anemia;
IRONOUT HF ¼ Iron Repletion Effects on Oxygen Uptake in Heart Failure; other abbreviations as in Table 1.

the patients in a trial evaluating different forms of IV mechanisms in place to maintain iron homeostasis in
iron for patients with ID and anemia were found to the body. Specifically, when iron stores are low,
have hypophosphatemia in the FCM arm through reduced hepcidin allows for increased absorption
5 weeks, with <1% hypophosphatemia in the from the GI tract before the axis shifts, and higher
comparator ferumoxytol arm.76 Hypophosphatemia hepcidin decreases the rate of iron absorption as
and the resultant consequences on bone health have stores increase. This makes serious toxicity from oral
not been systematically studied as a part of the trials iron exceedingly rare. Further, it is cheap and readily
of IV iron in patients with ID and HFrEF discussed available over the counter. The main side effects are
earlier. gastrointestinal (GI) related and include nausea,
Because cancer cells are highly dependent on iron bloating, constipation, and a metallic aftertaste. The
to grow, there are also concerns that IV iron loading new oral iron preparations (discussed later) have
could contribute to the development and progression fewer associated GI symptoms and may be toler-
of malignancy, which has been seen in a number of ated better.
animal models. 1,77
EVIDENCE OF ORAL IRON REPLETION IN HF WITH ID.
There is also the potential that exogenous IV iron
Studies of oral iron to treat ID in HF patients have
administration could contribute to ferroptosis, a
been limited and are collectively summarized
nonapoptotic form of cell death directly linked to
in Table 2.
iron, which has previously been associated with
There have been no completed studies comparing
forms of cardiovascular disease, including ischemic/
oral iron to IV iron in patients with ID and HF. IRON-HF
reperfusion injury and doxorubicin-mediated
(Iron Supplementation in Heart Failure Patients With
cardiomyopathy.9,10
Anemia) was meant to address this question, specif-
Further, each of these risks must be considered in
ically in patients with anemia as well HF and ID, but it
the short term as well as the long term, with patients
was terminated early because of challenges with
potentially receiving IV iron repeatedly over the
funding and competing studies.78 A total of 23 patients
course of their lifetimes. Although the current trials
completed the study, and 18 patients had primary
have not shown increased risk with IV iron, there are
endpoint data available. (The target enrollment was
inadequate long-term data on the consequences of
119 patients.) In this limited follow-up, there was a
repeated IV iron infusions.
suggestion of improved peak V O2 in the IV iron arm
ORAL IRON THERAPY FOR ID AND HF. Oral iron with no change in the oral therapy arm at 90 days.78
replacement for ID in HF has significant appeal IRONOUT HF (Iron Repletion Effects on Oxygen
because the route of delivery of iron uses the Uptake in Heart Failure) was a phase 2, double-blind,
JACC VOL. 83, NO. 25, 2024 Cheema et al 2685
JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

placebo-controlled randomized clinical study of pa- serum and is measurable. In a study of 65 patients
tients with HFrEF (EF of <40%) and ID by FAIR-HF with stable coronary artery disease undergoing car-
criteria with 225 randomized to oral iron poly- diac surgery, sTFR had a significantly higher correla-
saccharide 150 mg twice daily (n ¼ 111) vs placebo tion with the gold standard of bone marrow iron
(n ¼ 114).79 A total of 203 patients completed the staining than ferritin, TSAT, or serum iron.81 Addi-
study, and the follow-up was 16 weeks. There was no tional work in the rheumatoid arthritis literature
significant difference in VO 2max or 6MWTD between supports the sTFR-to-ferritin ratio in a patient popu-
the treatment and placebo arms, although there was lation with chronic inflammation.82 Further, in a
an improvement in serum iron, TSAT, and soluble study of patients hospitalized for acute HF, concom-
transferrin receptor (sTFR) in the treatment arm. itant low serum hepcidin and high sTFR were asso-
With a follow-up period of 16 weeks, the trial duration ciated with mortality, whereas those with normal
may have been too short to detect an improvement in hepcidin and sTFR levels were not at risk, nor were
outcomes in the treatment arm. Of note, the patients patients with ID according to the FAIR-HF criteria. 83
with the lowest hepcidin levels in this study saw the
TARGET FOR THERAPY OR DISEASE MARKER? It
greatest increase in serum iron indexes, in line with
remains unclear to what extent serum iron indexes
the mechanism by which oral iron absorption is
reflect a true target for therapeutic intervention as
regulated.
opposed to a marker of disease severity in patients
In a small study conducted in the outpatient setting
with HF. This is evidenced by work highlighted
in Indonesia (IRON5 [The Effect of Short Term Oral
earlier that showed that serum iron indexes fluctuate
Iron Supplementation in Systolic Heart Failure Pa-
over the course of a year in patients with chronic HF,
tients Suffering From Iron Deficiency Anemia]), adult
regardless of iron repletion. 53
patients with HF (EF of <45%; NYHA functional class II
Additionally, in DAPA-HF (Study to Evaluate the
or III), anemia (Hb of <13 g/dL for men and <12 g/dL for
Effect of Dapagliflozin on the Incidence of Worsening
women), ID by the FAIR-HF criteria, and estimated
Heart Failure or Cardiovascular Death in Patients With
glomerular filtration rate of >30 mL/min/1.73 m 2 were
Chronic Heart Failure), treatment with dapagliflozin
treated with placebo vs ferrous sulfate 200 mg 3 times
resulted in lower values of TSAT, ferritin, hepcidin,
per day for 12 weeks. A total of 54 patients were ran-
and total iron-binding capacity at study conclusion
domized, and 41 completed the study (22 in the treat-
compared to the placebo arm.84 Further, in a post hoc
ment arm, 19 in the placebo arm). The treatment arm
analysis of the DAPA-VO2 (Short-term Effects of Dapa-
saw an increase in 6MWTD, improvement in NYHA
gliflozin on Peak V O2 in HFrEF) clinical trial, patients
functional class, and higher ferritin and TSAT values.
with HFrEF treated with dapagliflozin had an increase
There were no differences in HF hospitalizations, EF,
in peak V O2 in relation to their baseline serum ferritin
or deaths noted in this small study. Importantly, there
and TSAT levels, with those benefiting the most having
was no differences in major or minor GI side effects. 80
the lowest baseline values of ferritin and TSAT.85 Last,
UNANSWERED QUESTIONS in a cardiac magnetic resonance–based substudy of
Myocardial-IRON (Noninvasive Imaging Estimation of
There remain a number of outstanding research Myocardial Iron Repletion Following Administration
questions in need of additional investigation. of Intravenous Iron), investigators saw evidence of
ACCURATE DIAGNOSTICS AND CLINICAL TRIAL INCLUSION improved iron repletion at the level of the myocardium
CRITERIA. It remains controversial how best to di- while simultaneously showing reduced serum iron
agnose ID in patients with HF. In the previously dis- indexes after treatment of HF. 86 Collectively, these
cussed work by Grote Beverborg et al,4 both low findings suggest that ferritin and TSAT fluctuate with
serum iron and reduced TSAT had better test char- the treatment of HF, making it challenging to interpret
acteristics than the commonly used definition of ID their values at any given point in time in the context of
derived from FAIR-HF, complicating the interpreta- a patient’s greater journey with HF and in conjunction
tion of trials of iron therapy in ID and HF using these with the use of medical therapy. 87 Further research is
criteria for inclusion. needed to elucidate if the redistribution of iron in HF is
Several recent investigations have shown the util- truly maladaptive and harmful or if it may reflect a
ity of alternative serum markers of ID, including the compensatory mechanism instead.
use of sTFR. Transferrin receptor transcription is up- NOVEL FORMS OF ORAL IRON AND ALTERNATIVE
regulated in states of iron depletion, and a compo- DOSING STRATEGIES. A recent nonrandomized,
nent of this transmembrane receptor enters the open-label study of oral sucrosomial iron was
2686 Cheema et al JACC VOL. 83, NO. 25, 2024

Iron Repletion for Heart Failure JUNE 25, 2024:2674–2689

T A B L E 3 Guideline Recommendations for ID and HF

Class of Level of
Association Guideline Year IDA Diagnostic Criteria IV Iron Recommendation Recommendation Evidence

ESC25,26 2021, updated 2023 Ferritin of <100 mg/L IV iron supplementation is recommended in I A
or ferritin of symptomatic patients with HFrEF and HFmrEF and
100-299 mg/L if iron deficiency to alleviate HF symptoms and
TSAT of <20% improve QOL.
IV iron supplementation with ferric carboxymaltose or IIa A
ferric derisomaltose should be considered in
symptomatic patients with HFrEF and HFmrEF and
iron deficiency to reduce the risk of HF
hospitalization.
ACC/AHA24 2022 Ferritin of <100 mg/L In patients with HFrEF and iron deficiency with or IIa B-R
or ferritin of without anemia, IV iron replacement is reasonable to
100-299 mg/L if improve functional status and QOL.
TSAT of <20%

ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; ESC ¼ European Society of Cardiology; HFrEF ¼ heart failure with reduced ejection fraction; HFmrEF ¼ heart failure
with midrange ejection fraction; IDA ¼ iron deficiency anemia; QOL ¼ quality of life; other abbreviations as in Table 1.

completed and suggested an improvement in serum slightly more conservative approach. We are more
iron indexes and Hb on par with that of IV iron while likely to use IV iron in patients hospitalized for HF if
maintaining a better GI side effect profile than other serum iron indexes are in line with those most
forms of oral iron.88 Sucrosomial iron is being further indicative of true ID at the bone marrow level, such as
investigated in 2 clinical trials compared to FCM in TSAT of <19.8% and serum iron of <13 mg/dL.4,91 In
patients with ID who have either HF with preserved patients who otherwise meet guideline-based
EF (PREFER-HF [Effects of Iron Therapy in recommendation for IV iron but do not fall within
Heart Failure With Preserved Ejection Fraction and these parameters, we consider oral iron repletion
Iron Deficiency]; NCT03833336) or HFrEF (IVOFER- because it has a documented ability to increase iron
HF; EudraCT 2017-005053-37). Additionally, recent stores with a minimal side effect profile, with the
data have suggested that absorption of oral iron may acknowledgment that clinical trial evidence has not
be improved by lowering the dose or spacing out the yet shown that oral iron repletion improves cardio-
dosing schedule to every other day, potentially vascular outcomes.79 We do not use IV iron in those
89,90
improving GI tolerance at the same time. who could have acute coronary syndrome, given its
association with endothelial cell dysfunction in ani-
MANAGING PATIENTS WITH ID AND HF
mal models. We rely on ferritin to monitor for iron
overload and consider it predictive of bone marrow ID
Addressing ID in patients with HF is an important
when levels are very low. Additionally, should alter-
consideration, and we agree with routine monitoring
native serum iron indexes, such as sTFR or serum
of serum iron indexes in these patients. According to
hepcidin, become available in routine clinical prac-
the most recent HF guidelines from the AHA/ACC,
tice, we acknowledge that they are likely more accu-
patients with HFrEF and ID with or without anemia, IV
rate predictors for true ID than the established
iron replacement is reasonable to improve functional
standard. Last, we keep in mind that iron indexes
status and quality of life (Class IIa, LOE: B-R). 24 Based
may fluctuate solely in relation to HF treatment with
on the ESC HF guidelines from 2021, FCM should be
guideline-direct medical therapy, making sure to
considered for ID, as defined by serum ferritin
repeat iron studies once medical therapy has been
of <100 ng/mL or serum ferritin of 100 to 299 ng/mL
optimized.
with TSAT of <20%, to improve symptoms and reduce
rehospitalizations (Class IIa, LOE: B). 25 An update to CONCLUSIONS
these guidelines in August 2023 added that IV iron
supplementation with FCM or ferric derisomaltose Treating ID in patients with HF is an important clin-
should be considered in symptomatic patients with ical consideration. Although earlier work showed an
HFrEF or HF with midrange EF and ID to reduce the improvement in symptoms and function in trials of IV
risk of HF hospitalization (Class IIa, LOE: A) (Table 3).26 iron in HFrEF, larger trials have failed to show an
Based on our review of the available trial data, our improvement in hard cardiovascular outcomes.
approach is in line with the HF guidelines but takes a Additionally, IV iron has potential side effects that
JACC VOL. 83, NO. 25, 2024 Cheema et al 2687
JUNE 25, 2024:2674–2689 Iron Repletion for Heart Failure

warrant consideration. With this context, our FUNDING SUPPORT AND AUTHOR DISCLOSURES
approach is to limit the use of IV iron to patients who
are intolerant of oral iron, for whom oral iron therapy Dr Cheema has received consulting fees from Caption Health, Inc and
Viz.ai; has served on an Advisory Board for Novo Nordisk; and is an
has previously failed, or who have serum iron indexes
advisor with equity interest in Healthspan, Inc and Zoe Biosciences.
that have been shown to reflect ID most accurately, Dr Ardehali is a consultant for Pharmacosmos. All other authors have
including very low TSAT and serum iron. Oral iron reported that they have no relationships relevant to the contents of

remains appealing for a number of reasons, but this paper to disclose.

additional trials with novel formulations and alter-

ative dosing strategies, enhanced inclusion criteria, ADDRESS FOR CORRESPONDENCE: Dr Hossein
and longer follow-up are needed. Additionally, there Ardehali, Northwestern University Feinberg School of
is a need for ongoing research into the natural fluc- Medicine, SQBRC 8-521, 303 E Superior Street,
tuation of iron levels along the life course of HF, iron Chicago, Illinois 60611, USA. E-mail: h-ardehali@
chelation therapy, and iron replacement for ID in northwestern.edu. @ArdehaliHossein. OR Dr Baljash
patients with HF with preserved EF. Cheema, Northwestern University Feinberg School of
Medicine, 676 North Saint Clair Street, Arkes Pavilion,
ACKNOWLEDGMENT All figures were created with Suite 600, Chicago, Illinois 60611, USA. E-mail:
BioRender.com. [email protected]. @JCheemaMD.

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