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