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Correspondence to
Professor Alain Cohen-Solal,
Department of Cardiology,
Lariboisière Hospital, UMR-S
942, DHU FIRE, Paris Diderot
University, Assistance Publique
—Hôpitaux de Paris,
Paris 75010, France;
alain.cohen-solal@inserm.fr
Received 10 February 2014
Revised 12 May 2014
Accepted 23 May 2014
To cite: Cohen-Solal A,
Leclercq C, Deray G, et al.
Heart Published Online First:
[please include Day Month
Year] doi:10.1136/heartjnl-
2014-305669
Copyright Article
Cohen-Solal A, author
et al. Heart
2014;0:1–7. their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Iron deficiency: an emerging therapeutic target
in heart failure
Alain Cohen-Solal,1 Christophe Leclercq,2 Gilbert Deray,3 Sigismond Lasocki,4
Jean-Jacques Zambrowski,5 Alexandre Mebazaa,6 Pascal de Groote,7 Thibaud Damy,8
Michel Galinier9
ABSTRACT
In patients with heart failure, iron deficiency is frequent
but overlooked, with a prevalence of 30%–50%. Since
it contributes to cardiac and peripheral muscle
dysfunction, iron deficiency is associated with poorer
clinical outcomes and a greater risk of death,
independent of haemoglobin level. Therefore, iron
deficiency emerges as a new comorbidity and a
therapeutic target of chronic heart failure in addition to
chronic renal insufficiency, anaemia and diabetes. In a
series of placebo-controlled, randomised studies in
patients with heart failure and iron deficiency,
intravenous iron had a favourable effect on exercise
capacity, functional class, LVEF, renal function and
quality of life. These clinical studies were performed in
the context of a renewed interest in iron metabolism.
During the past 10 years, knowledge about the
transport, storage and homeostasis of iron has improved
dramatically, and new molecules involved in iron
metabolism have been described (eg, hepcidin,
ferroportin, divalent metal transporter 1). Recent
European guidelines recommend the monitoring of iron
parameters (ie, serum ferritin, transferrin saturation) for
all patients with heart failure. Ongoing clinical trials will
explore the benefits of iron deficiency correction on
various heart failure parameters.
Recently, the European Society of Cardiology
(ESC) defined iron deficiency in the context of
heart failure and recommended its assessment as
with other comorbidities.1 These recommendations
were the consequence of an improved understand-
ing of iron metabolism. The aim of the present
review is to summarise recent advances in iron defi-
ciency pathophysiology and iron supplementation
in the context of chronic heart failure.
IRON DEFICIENCY: AN OVERLOOKED
COMORBIDITY IN CHRONIC HEART FAILURE
Chronic heart failure remains a frequent and severe
disease with a poor outcome. Comorbidities (eg,
diabetes, chronic obstructive pulmonary disease,
chronic renal failure, anaemia) are often associated
with chronic heart failure and can complicate treat-
ment and negatively affect outcomes. Although
iron deficiency is now recognised as an important
comorbidity, it is often ignored or explored only in
the context of anaemia. There are multiple causes
of iron deficiency in heart failure patients, includ-
ing gastrointestinal blood loss related to the use of
aspirin and oral anticoagulation, poor nutrition and
malabsorption. Since iron deficiency symptoms are
(or doi:10.1136/heartjnl-2014-305669
Review
not specific, only systematic assessment of bio-
logical iron parameters allows for the diagnosis of
iron deficiency.
PREVALENCE OF IRON DEFICIENCY
Studies have reported a high prevalence of iron
deficiency—up to 30%–50%—in chronic heart
failure, even in the absence of anaemia.2–4 In a
large study of 955 heart failure patients, 43% of
anaemic patients and 15% of non-anaemic patients
had iron deficiency.2 In a study including 37
patients with advanced heart failure, iron deficiency
anaemia diagnosed by bone marrow aspiration was
present in up to 73% of patients.4 A more recent
study reported an iron deficiency prevalence of
37% in 546 heart failure patients; importantly, the
prevalence was 32% in patients without anaemia.5
In another study of 157 chronic heart failure
patients, iron stores were seemingly adequate, but
functional iron deficiency was observed in 43% of
patients.6 Iron deficiency was diagnosed in 37% of
patients scheduled for cardiac surgery.7 In another
cohort of 1506 chronic heart failure patients, the
prevalence of iron deficiency was 50%, including
45.6% among patients without anaemia.3
CONSEQUENCES OF IRON DEFICIENCY
The causal relationship between iron deficiency and
physical work capacity has been clearly established
in animal models.8 In humans, several studies have
confirmed the effects of iron deficiency (with and
without anaemia) on aerobic capacity, endurance
capacity, physical performance and work effi-
ciency.8 Iron deficiency also had consequences on
cognitive performance, emotions, fatigue and
behaviour; moreover, iron supplementation
improved cognition and exercise performance in
iron-deficient patients.9 10
A prospective study in 157 chronic heart failure
patients showed that non-anaemic, iron-deficient
patients had a twofold greater risk of death than
anaemic, iron-replete patients.6 In another study of
546 heart failure patients, iron deficiency predicted
unfavourable outcome independent of anaemia,
with an increased risk of death or heart transplant-
ation.5 In an international, pooled cohort of 1506
chronic heart failure patients, iron deficiency (but
not anaemia) was an independent predictor of mor-
tality and was associated with disease severity
(assessed with New York Heart Association
(NYHA) functional score and level of N-terminal
fragment of pro-B-type natriuretic peptide
(NT-proBNP)).3
1
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Review
IRON METABOLISM AND PATHOPHYSIOLOGY
The ubiquitous role of iron
Iron is a cofactor for several enzymes and plays a central role in
oxidative metabolism (mitochondrial respiratory chain, oxida-
tive enzymes, protection against oxidative stress), oxygen
storage (myoglobin), oxygen transport (haemoglobin) and other
processes, such as β-oxidation of fatty acids. Iron homeostasis is
tightly regulated to avoid two pitfalls: first, iron overload with a
risk of toxicity (mainly through oxidative stress induction) and,
second, iron deficiency with a risk of anaemia, which is the best
known and described consequence of iron deficiency. However,
iron deficiency appears before anaemia onset and may be diffi-
cult to recognise clinically because its main symptoms are
fatigue and poorer physical abilities related to decreased energy
efficiency and mitochondrial dysfunction. Iron metabolism and
regulation have been recently revisited; classical clinical findings,
such as iron sequestration during chronic inflammation, are now
explained at the molecular level.11 12
Storage and transport of iron
Three proteins (transferrin, transferrin receptor and ferritin)
play a key role in the storage and transport of iron in the body
(figure 1). Transferrin carries iron in plasma and extracellular
fluids. The transferrin receptor, present on cell membranes,
fixes and internalises transferrin to acquire intracellular iron.
Ferritin stores iron in tissues.
In practice, serum ferritin is the best indicator of iron stores:
a low serum ferritin level reflects insufficient tissue iron stores.
However, serum ferritin levels increase very rapidly in the pres-
ence of inflammation; therefore, elevated ferritin levels are not
always indicative of high iron stores. Serum transferrin is less
affected by changes in iron metabolism. A decrease of transfer-
rin iron saturation indicates a failure to deliver iron to erythro-
blasts and other iron-requiring cells; it defines ‘functional iron
deficiency.’ The dynamic exchanges between the different iron
compartments are described in figure 1.
Hepcidin and ferroportin: new players in iron metabolism
The passage of iron through intestinal cells or macrophages of
the reticuloendothelial system involves proteins specialised
in the intracellular transport of iron. The main carrier (apical
pole) that imports iron (non-haeme) into intestinal cells is the
divalent metal transporter 1. Iron is stored in intestinal cells via
ferritin or exported through ferroportin, a transmembrane
protein, towards the basement membrane and into circulation,
where it can bind to transferrin. For macrophages of the reticu-
loendothelial system, the import of iron is ensured by the
binding of transferrin to specific receptors (non-haeme iron)
and phagocytosis of senescent erythrocytes (haeme iron;
figure 1). The export of iron is through ferroportin, similar to
that of intestinal cells. The involvement of a transporter in
dietary iron absorption explains why absorption cannot increase
once the transporter is saturated. Indeed, less than 20% of iron
is absorbed after an oral intake of 100–200 mg of iron, and
higher doses are therefore ineffective for correction of iron
deficiency.
The peptide hormone hepcidin is synthesised by the liver and
is now considered the master regulator of iron homeostasis.13
Hepcidin binds to ferroportin and induces its internalisation,
thus blocking iron export from intestinal cells and iron recycling
in macrophages of the reticuloendothelial system (figure 1).
Circulating levels of hepcidin are regulated by iron stores: iron
deficiency, or hypoxia, represses hepcidin expression, while iron
2 Cohen-Solal A, et al. Heart 2014;0:1–7. doi:10.1136/heartjnl-2014-305669
overload induces hepcidin expression; synthesis of hepcidin is
also strongly induced by inflammation.14 Therefore, hepcidin
plays a major role in iron deficiency and anaemia of chronic dis-
eases and inflammation.12
Iron and muscle cells
Iron is essential in cells that require large amounts of energy,
such as skeletal myocytes and cardiomyocytes.15 16 Many
chronic diseases worsen in the context of iron deficiency, even
in the absence of anaemia.12 15 Besides impaired erythropoiesis,
impaired oxidative metabolism and energy production play
important roles in chronic heart failure. In animals, chronic iron
deficiency results in structural abnormalities and increased size
and weight of the heart.17 Chronic iron deficiency is also asso-
ciated with impaired exercise capacity (ie, decrease of endurance
capacity and maximal performance), which is related to a
decrease of oxygen storage in myoglobin, a decrease of energetic
efficiency and mitochondrial dysfunction (figure 2).8 A recent
study showed that iron content and transferrin receptor expres-
sion in cardiomyocytes of heart failure patients were reduced
compared with controls.18
WHICH DEFINITION OF IRON DEFICIENCY SHOULD BE
USED IN HEART FAILURE?
Normal ranges for iron parameters and diagnosis of iron
deficiency
The serum ferritin concentration is correlated with total body
iron stores and is therefore a convenient laboratory test to assess
iron stores. The normal range of serum ferritin is generally
defined as 30–300 mg/L, and a value <30 mg/L defines iron defi-
ciency. However, in chronic heart failure and other chronic dis-
eases, inflammatory processes are common and, as a
consequence, serum ferritin is frequently increased. Therefore,
standard laboratory cut-off values may not be used in these clin-
ical conditions to diagnose functional iron deficiency. One com-
monly accepted gold standard for the diagnosis of depleted iron
stores is bone marrow aspiration examination using specific
staining of iron (Perls’ staining). Nanas et al4 showed that serum
ferritin minimised the incidence of iron deficiency compared
with this gold standard and was therefore not a reliable marker
in patients with heart failure. The routine use of bone marrow
aspiration is, however, limited by inconvenience to the patient,
cost and need for expertise.
In the 2012 ESC guidelines for the diagnosis and treatment
of heart failure, systematic measurement of iron parameters is
recommended in all patients suspected of having heart failure.1
The definition of iron deficiency in these guidelines is:
1. Serum ferritin <100 mg/L (absolute iron deficiency)
2. Serum ferritin 100–299 mg/L and transferrin saturation
<20% (functional iron deficiency).
As serum iron exhibits large individual nycthemeral varia-
tions, it is less informative than serum ferritin and should not
be prescribed. Following these recommendations, iron tests
(serum ferritin and transferrin saturation) should be systematic-
ally included in the biological tests performed during admission
of heart failure patients and at their follow-up visits.1
Absolute or functional iron deficiency: what difference does
it make?
Iron deficiency is absolute when iron stores in tissues are insuffi-
cient (serum ferritin <100 mg/L) and can no longer meet the
needs of the body (transferrin saturation <20%; figure 3).
Absolute deficiency may be the result of insufficient iron intake,
increased use of iron or chronic blood loss.
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Figure 1 Iron homeostasis and the role of hepcidin. In healthy individuals, about 10 mg of iron are ingested daily, but only 1–2 mg are absorbed
by duodenal cells and an equivalent amount is lost due to the shedding of cells or physiological bleeding.30 In the circulation, about 3 mg of iron
(<0.2% of total iron) is bound to transferrin. Approximately two-thirds of iron is contained in the haemoglobin of mature erythrocytes (1800 mg)
and precursors of the erythropoietic lineage (300 mg), while 10%–15% is found in myoglobin and different enzymes. Iron is also stored in liver
parenchymal cells (1000 mg). Macrophages of the reticuloendothelial system (liver, spleen, bone marrow) temporarily store iron recycled from
senescent red blood cells that have been destroyed by the spleen and the liver (600 mg). Iron metabolism is thus a closed, but dynamic,
metabolism: iron is constantly exchanged between senescent red blood cells and bone marrow, with daily recycling of 20–25 mg.

Functional iron deficiency is observed when the mobilisation

of iron from the tissue stores to the circulating pool is compro-
mised while iron stores are sufficient (ferritin levels are normal
or high); iron intake by erythropoietic or other cells that require
iron is insufficient, as evidenced by transferrin saturation <20%
(figure 3). Functional iron deficiency is observed in chronic
inflammation and is characterised by decreased circulating iron,
iron retention in macrophages and decreased intestinal iron
absorption.19 All of these mechanisms are consistent with an
increase in hepcidin found in patients with inflammatory
anaemia.20 Therefore, functional iron deficiency is more effi-
ciently and quickly corrected after intravenous administration of
iron because this route allows for bypassing the intestinal barrier
and overcoming the iron sequestration. Treating the cause of
inflammation may also help to correct functional iron deficiency.

TREATMENT OF IRON DEFICIENCY IN PATIENTS WITH

Figure 2 Pathophysiological consequences of iron deficiency in
haematopoietic and non-haematopoietic tissues of heart failure
patients. Chronic iron deficiency is associated with impaired exercise
capacity due to a decrease of oxygen storage in myoglobin, a decrease
of energetic efficiency and mitochondrial dysfunction. Indeed, there is a
need for iron in erythropoietic cells and cells that require large amounts
of energy, such as skeletal myocytes and cardiomyocytes.
HEART FAILURE
Iron administration in patients with chronic heart failure
The administration of intravenous iron in patients with chronic
heart failure has been assessed in five studies, including three
randomised, placebo-controlled studies, which are summarised
in table 1.21–25
▸ The study by Toblli et al24 was a prospective, randomised,
double-blind, placebo-controlled trial. The effect of intraven-
ous iron sucrose (five doses of 200 mg/week) was compared
with isotonic saline placebo in 40 chronic heart failure patients

Cohen-Solal A, et al. Heart 2014;0:1–7. doi:10.1136/heartjnl-2014-305669 3

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Figure 3 Absolute and functional

iron deficiency. In absolute iron
deficiency, iron stores assessed with
serum ferritin are decreased and
bioavailable iron assessed with
transferrin saturation is decreased (A);
in functional iron deficiency, the
mobilisation of iron from stores and
circulating pool is insufficient
regardless of iron stores (B).

(LVEF ≤35%), anaemia, iron deficiency (serum ferritin
<100 mg/L and/or transferrin saturation <20%) and mild
renal insufficiency. Patients were followed-up for 6 months.
▸ Compared with placebo, intravenous iron sucrose signifi-
cantly increased haemoglobin and iron parameters; more-
over, NT-proBNP (p<0.01) and C reactive protein ( p<0.01)
were significantly decreased. In the iron sucrose group, there
were significant improvements in NYHA functional score,
Minnesota Living with Heart Failure (MLHF) questionnaire
score, 6-min walk distance and LVEF ( p<0.01 for all).
▸ The Ferric Iron Sucrose in Heart Failure (FERRIC-HF) study
was a randomised, controlled, observer-blinded trial that
included 35 chronic heart failure patients (NYHA functional
class II–III) with iron deficiency who were randomised to
receive 16 weeks of intravenous iron sucrose (200 mg/week
for 3 weeks followed by 200 mg at 4, 8, 12 and 16 weeks) or
no treatment in a 2:1 ratio.23 Compared with the placebo
group, there was no significant increase in absolute peak
oxygen uptake ( pVO2) (95% CI −12 to 205 mL/min;
p=0.08) in iron group. However, pVO2 adjusted to body
weight increased significantly in the iron group (95% CI 0.5
to 4 mL/kg/min; p=0.01).
▸ The Ferinject Assessment in Patients with Iron Deficiency
and Chronic Heart Failure (FAIR-HF) study was as a multi-
centric, prospective, double-blind, randomised, placebo-
controlled trial.21 Symptoms, functional capacity and quality
of life were significantly improved after treatment with intra-
venous ferric carboxymaltose in patients with chronic heart
failure and iron deficiency, with or without anaemia (details
of results in legend of figure 4).

Table 1 Clinical trials with intravenous iron in patients with heart failure
Disease
Authors Patients (n) Iron and anaemia status severity Follow-up Study results

Uncontrolled studies
Bolger et al22 16 Anaemia NYHA class 92 days Improvement of NYHA functional class (p<0.02), MLHF questionnaire score
II–III (p=0.002) and 6-min walk distance
Usmanov et al25 32 Anaemia with iron deficiency NYHA class 26 weeks Improvement of cardiac remodelling and NYHA functional class in patients
III–IV with baseline NYHA class III (p<0.01)
Randomised, placebo-controlled studies
Toblli et al24 40 Iron deficiency and anaemia NYHA class 6 months Reduction in NT-proBNP (p<0.01) and CRP (p<0.01)
II–IV Improvement of LVEF, NYHA functional class, exercise capacity, renal
EF ≤35% function and quality of life (all p<0.01)
Okonko et al23 35 Iron deficiency with and NYHA class 18 weeks Increase of pVO2/kg (p=0.01)
(FERRIC-HF study) without anaemia II–III Improvement of NYHA functional class (p=0.007) and patient global
assessment (p=0.002)
Anker et al 459 Iron deficiency with or NYHA class 24 weeks Improvement of patient global assessment and NYHA functional class
(2009)21 without anaemia II–III (primary criteria; p<0.001)
(FAIR-HF study) Improvement of 6-min walk distance and quality of life (p<0.001)
Comparable effect in patients with or without anaemia
CRP, C reactive protein; MLHF, Minnesota Living with Heart Failure; NT-proBNP, N-terminal fragment of pro-B-type natriuretic peptide; NYHA, New York Heart Association; pVO2, peak
oxygen uptake.

4 Cohen-Solal A, et al. Heart 2014;0:1–7. doi:10.1136/heartjnl-2014-305669

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Figure 4 Effect of intravenous iron administration on 6-min walk
distance (Ferinject Assessment in Patients with Iron Deficiency and
Chronic Heart Failure (FAIR-HF) study).21 The FAIR-HF study compared
intravenous ferric carboxymaltose with placebo in a double-blind,
randomised, placebo-controlled trial (New York Heart Association
(NYHA) functional class II–III) and iron deficiency in 459 heart failure
patients (with or without anaemia; haemoglobin 9.5–13.5 g/dL). Iron
deficiency was defined as ferritin level <100 mg/L or ferritin level 100–
299 mg/L with transferrin saturation <20%. During the correction
phase, all patients received intravenous ferric carboxymaltose 200 mg
or placebo once weekly until repletion of iron stores. The correction
phase (8 or 12 weeks) was followed by a maintenance phase of
200 mg every 4 weeks. At 24 weeks, compared with the placebo
group, serum ferritin and haemoglobin levels were significantly
increased in the intravenous iron group. These significant biological
differences were associated with a significant functional improvement
in the patient self-reported global assessment (50% of patients in the
iron group vs 28% in the placebo group; p<0.001). Similarly, 47% and
30% of patients were in NYHA functional class I–II in the iron group
compared with the placebo group, respectively ( p<0.001).
Health-related quality-of-life assessments and 6-min walk distance also
improved significantly among patients in the iron group. Comparable
results were reported for patients with and without anaemia, even
though the haemoglobin level in the non-anaemic subgroup did not
change in response to intravenous iron.
Interest and limits of the clinical trials on iron
administration in chronic heart failure
The randomised, placebo-controlled FAIR-HF study was an
important step that brought to light a new research area. Before
this study, the relationship between iron deficiency and chronic
heart failure remained largely ignored. Nevertheless, this
research area is recent, with only a few clinical trials that
included limited numbers of patients (except for the FAIR-HF
study). Therefore, many questions remain unanswered. As an
example, although pathophysiological and clinical arguments
are in favour of the intravenous route in heart failure, no trial
has formally compared the oral versus intravenous routes. In
addition, optimal values of iron parameters and the effects of
long-term management of iron deficiency in chronic heart
failure should be more precisely defined in future studies. It has
to be underscored that blinding is difficult in these studies since
intravenous iron is dark and it is not possible to obtain a dark
placebo; therefore, particular attention to blinding (such as in
FAIR-HF study) is required.
Ongoing clinical trials
With the development of new therapies that have improved sur-
vival and disease severity, a global management of heart failure
Cohen-Solal A, et al. Heart 2014;0:1–7. doi:10.1136/heartjnl-2014-305669
Review
is necessary, evaluated in terms of cardiac remodelling, quality
of life and physical performances as well as outcome. Ongoing
studies of iron supplementation in chronic heart failure will
address these issues by assessing endpoints that have a direct
impact on daily symptoms and exercise capacity. Unfortunately,
none of these ongoing studies has planned to assess mortality.
▸ The primary endpoint of the Iron Supplementation in Heart
Failure Patients with Anemia study (IRON-HF; clinicaltrials.
gov identifier: NCT00386126; estimated enrolment, n=117)
is to assess the impact of iron supplementation alone (intra-
venous or oral) on changes in pVO2 assessed by
ergospirometry.26
▸ The aim of a study from the Anemia Working Group
Romania is to assess the efficiency of intravenous iron in
mild to moderate anaemia associated with chronic heart
failure (NYHA functional class III) and concomitant moder-
ate chronic kidney disease (NCT00384657; n=200). The
primary endpoint of this study is the percentage of patients
with increased EF.
▸ The Effect of Ferric Carboxymaltose on Exercise Capacity in
Patients with Iron Deficiency and Chronic Heart Failure
study (EFFECT-HF; NCT01394562; n=160): The rationale
of this study is to confirm that treatment with intravenous
ferric carboxymaltose improves exercise capacity, symptoms
and quality of life in patients with iron deficiency and
chronic heart failure. The primary endpoint is the change in
pVO2.
▸ The Comparison of Ferric Carboxymaltose With Placebo in
Patients With Chronic Heart Failure and Iron Deficiency
study (CONFIRM-HF; NCT01453608; n=300): The
purpose of this study is to assess the effect of iron repletion
therapy using intravenous ferric carboxymaltose on exercise
capacity in patients with chronic heart failure and iron defi-
ciency. The primary endpoint is the change in 6-min walk
distance.
▸ The CARDIOFER study is assessing the prevalence of iron
deficiency in France in chronic heart failure patients hospita-
lised for acute cardiac decompensation (n=900).
IRON SUPPLEMENTATION IN HEART FAILURE IN PRACTICE
According to the Summaries of Product Characteristics of iron
complexes, oral iron is initially given to patients with iron defi-
ciency (100–200 mg/day); administration of intravenous iron is
indicated when oral iron is poorly tolerated, ineffective, cannot
be used or if a rapid replenishment of depleted iron stores is
required. Oral iron preparations are often poorly tolerated
because of gastrointestinal adverse effects, resulting in a reduc-
tion in adherence to iron treatment and certain heart failure
treatments (eg, diuretics, ACE inhibitors, β-blockers, angiotensin
receptor blockers and aldosterone antagonists). Moreover, oral
iron treatment interacts with drugs such as proton pump
inhibitors.
In functional iron deficiency, intravenous iron is more effect-
ive than oral iron.27 In the 2012 ESC guidelines, only the intra-
venous route is considered for iron administration in iron
deficient heart failure patients.1 In the guidelines from the
‘Kidney Disease: Improving Global Outcomes’ group, which
synthesise the long experience of nephrologists in iron therapy
management, the intravenous route is possible for initial iron
administration in non-dialysed patients with chronic kidney
disease.28
In practice, oral iron should be prescribed for absolute iron
deficiency for at least 3 months with assessment of iron replen-
ishment after 1 month; in case of inefficacy or intolerance, oral
5
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Table 2 Dosage and administration of intravenous iron complexes
Intravenous iron
complexes Dosage
Iron carboxymaltose Intravenous infusion at 15 mg/kg (for a total ≤1000 mg)
once/week
Bolus intravenous injection of 200 mg/day
(≤3 injections/week)
Iron hydroxide 100–300 mg/injection; 1–3 injections/week with a 48-h
sucrose interval between each injection
Iron hydroxide 100–200 mg/injection (not exceeding 20 mg/kg); 1–3
dextran injections/week with a 48-h interval between each
injection
therapy is stopped and intravenous iron is administered. In case
of functional iron deficiency, initial administration of intraven-
ous iron is required since oral iron is ineffective in this clinical
condition.
Different intravenous iron complexes are available. The
administration and dosages of the most frequently used intra-
venous iron complexes are described in table 2. Biological iron
tests should be performed 1 month after intravenous iron
administration for evaluation of iron stores.
ECONOMIC ANALYSES OF IRON DEFICIENCY AND
ANAEMIA
A recent pharmacoeconomic study has been performed by
Gutzwiller et al29 based on the data of the FAIR-HF trial.
Results were expressed as quality-adjusted life year (QALY), an
index that includes both the quality and the quantity of life
lived. From the perspective of the UK National Health Service,
managing iron deficiency in chronic heart failure patients using
iron carboxymaltose is cost effective. The cost per QALY-gained
ratio of iron carboxymaltose compared with placebo was €4414
for the FAIR-HF dosing regimen. This result was clearly below
the threshold of €22200–€33 300/QALY gained typically used
by the UK National Institute for Health and Clinical Excellence
for prioritising health expenses. These results were mainly
related to improved symptoms and better quality of life of
chronic heart failure patients.
CONCLUSIONS
A third to a half of patients with heart failure have iron defi-
ciency, and recent European guidelines recommend the monitor-
ing of iron parameters for all patients with heart failure.1 Iron
deficiency contributes to cardiac and peripheral muscle dysfunc-
tion, and clinical trials have demonstrated that intravenous iron
has favourable effects on NYHA functional class, exercise cap-
acity, LVEF, renal function and quality of life. Ongoing clinical
trials are exploring the benefits of iron deficiency correction on
various heart failure parameters.
Additional references that helped in the preparation of this
article can be found as online supplementary file.
Author affiliations
1
Department of Cardiology, Lariboisière Hospital, AP-HP, Paris, France
2
Department of Cardiology and Vascular Disease, Pontchaillou Hospital, Rennes,
France
3
Department of Nephrology, Pitié-Salpêtrière Hospital, Paris, France
4
Department of Anesthesia and Critical Care Medicine, CHU Angers, Angers, France
5
Department of Internal Medicine, Bichat-Claude Bernard Hospital, AP-HP, Paris,
France
6
Department of Anesthesia and Critical Care Medicine, Lariboisière Hospital, AP-HP,
Paris, France
6 Cohen-Solal A, et al. Heart 2014;0:1–7. doi:10.1136/heartjnl-2014-305669
Administration
Intravenous infusion in NaCl 0.9% with iron concentration >2 mg/mL:
▸ From 100 to <200 mg: 50 mL of 0.9% NaCl
▸ From 200 to <500 mg: 100 mL of 0.9% NaCl (in ≥6 min)
▸ From 500 to 1000 mg: 250 mL of 0.9% NaCl (in ≥15 min)
Bolus intravenous injection at a maximal dose of 200 mg
Slow intravenous infusion (3.5 mL/min) with a duration ≥1.5 h; 1 ampoule diluted in
≤100 mL of 0.9% NaCl
Intravenous infusion of 1 or 2 ampoules (100 or 200 mg) in 100 mL of 0.9% NaCl or
5% glucoseSlow intravenous injection of 100–200 mg of iron (0.2 mL/min), preferably
diluted in 10–20 mL of 0.9% NaCl or 5% glucose
7
Pôle Cardiologie et Médecine Vasculaire, Hôpital Cardiologique, CHRU Lille, Lille,
France
8
Department of Cardiology, Henri-Mondor Hospital, AP-HP, Créteil, France
9
Department of Cardiology, CHU Rangueil, Toulouse, France
Acknowledgements We would like to acknowledge Michel Borcier and Francis
Beauvais for their help in the writing of this manuscript.
Contributors AC-S wrote the first draft after a meeting with all coauthors. CL, GD,
SL, J-JZ, MA, PdG, TD and MG revised the manuscript. All authors approved the
final version.
Competing interests AC-S, CL, GD, SL, J-JZ, MA, PdG, TD and MG received
honoraria as expert board members from Vifor Pharma.
Provenance and peer review Not commissioned; externally peer reviewed.
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Iron deficiency: an emerging therapeutic

target in heart failure
Alain Cohen-Solal, Christophe Leclercq, Gilbert Deray, et al.

Heart published online June 23, 2014

doi: 10.1136/heartjnl-2014-305669

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http://heart.bmj.com/content/early/2014/06/23/heartjnl-2014-305669.full.html

These include:
Data Supplement "Supplementary Data"
http://heart.bmj.com/content/suppl/2014/06/23/heartjnl-2014-305669.DC1.html

References This article cites 30 articles, 6 of which can be accessed free at:
http://heart.bmj.com/content/early/2014/06/23/heartjnl-2014-305669.full.html#ref-list-1

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