Volume 1 • Issue 1 • Spring 2015 • Promotional Supplement www.CFRjournal.com Iron Deficiency in Heart Failure – the Relevance for the Patient Proceedings of a satellite symposium held at the ESC Congress 2014 on 1 September 2014 in Barcelona Katrina Mountfort, Medical Writer, Radcliffe Cardiology This symposium was organised and fully financed by Vifor Pharma Vifor Pharma funded the author to attend the symposium and develop this manuscript accordingly Radcliffe Cardiology Lifelong Learning for Cardiovascular Professionals
Iron Deficiency in Heart Failure – the Relevance for the PatientProceedings of a satellite symposium held at the ESC Congress 2014 on 1 September 2014 in Barcelona
Katrina Mountfort, Medical Writer, Radcliffe Cardiology
This symposium was organised and fully financed by Vifor Pharma
Vifor Pharma funded the author to attend the symposium and develop this manuscript accordingly
Radcliffe CardiologyLifelong Learning for Cardiovascular Professionals
Proceedings of Symposium organised and fully financed by Vifor Pharma
AbstractA satellite symposium at the 2014 European Society of Cardiology (ESC) congress discussed the importance of iron deficiency (ID) in
heart failure (HF). ID is the main cause of anaemia and is observed in almost 50 % of HF patients in Europe and up to 80 % of patients
in Asia. ID is an independent factor associated with reduced exercise capacity, reduced quality of life (QoL) and poor outcomes in HF.
The importance of ID in HF is reflected in the fact that the current ESC Guidelines for HF recognise ID as a co-morbidity in HF for the
first time, and recommend routine diagnosis and monitoring for ID based on iron parameters. Intravenous (i.v) administration of ferric
carboxymaltose (FCM) was considered as a possible treatment option according to the findings of the Ferric Carboxymaltose Assessment
in Patients With IRon Deficiency and Chronic Heart Failure (FAIR-HF) clinical study, which showed that treatment with FCM in HF patients
with ID improves symptoms, exercise capacity and QoL. These findings were confirmed by the recent Ferric CarboxymaltOse evaluatioN
on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) study, which demonstrated that,
in symptomatic patients with chronic HF and ID treatment with i.v. FCM over one year resulted in sustainable improvements in exercise
capacity, symptoms and QoL, and was associated with a reduced risk of hospitalisations due to worsening HF.
KeywordsFerric carboxymaltose, heart failure, iron deficiency
Disclosure: Josep Comin-Colet has received consulting fees from Vifor Pharma and was a member of the FAIR-HF and CONFIRM-HF steering committees. Stefan Anker
has received honoraria for consultancy, lectures, clinical trial committee work and/or trial adjudication work as well as he received research grants from Vifor Pharma.
Carolyn SP Lam has received unrestricted research grants and honoraria from Vifor Pharma. Piotr Ponikowski has received honoraria from Vifor Pharma as a member of
the FAIR-HF and CONFIRM-HF steering committees; consultancy and speakers bureau from Vifor Pharma and Amgen Inc; and a research grant from Vifor Pharma.
Received: 8 September 2014 Accepted: 13 November 2014 Citation: Cardiac Failure Review, 2015;1(1): Epub ahead of print
Support: Support is indicated in the editorial process box above.
Iron Deficiency in Heart Failure – the Relevance for the Patient
Katr ina Mountfort
Medical Writer
Proceedings of a Satel l i te Symposium Held at the ESC Congress 2014, 1 September 2014, Barcelona, Spain
Reviewed for accuracy by: Josep Comin-Colet, 1 Carolyn SP Lam, 2 Piotr Ponikowski 3 and Stefan Anker 4
1. Department of Cardiology, Hospital del Mar, Barcelona, Spain; 2. Women’s Heart Health Clinic; National University Heart Centre;
Yong Loo Lin School of Medicine; Asia Pacific Association of Women’s Cardiovascular Disease, Singapore;
3. Department of Heart Diseases Clinical Military Hospital, Medical University, Wroclaw, Poland;
4. Department of Cardiology, Charité Campus Virchow-Klinikum, Berlin, Germany
This symposium was organised and ful ly f inanced by Vifor Pharma
A satellite symposium, sponsored by Vifor Pharma and chaired by
Josep Comin-Colet, Barcelona, Spain and Stefan Anker, Berlin, Germany
was held at the European Society of Cardiology (ESC) congress in
Barcelona on the 1st September 2014. Its objectives were to raise
awareness on the epidemiology, aetiology and pathophysiology of
iron deficiency (ID) in heart failure (HF), to raise awareness of the
clinical impact of ID on patient outcomes and quality of life (QoL)
in HF; to discuss the latest guidelines for chronic HF in the context
of ID; to present data from the Ferric CarboxymaltOse evaluatioN
on perFormance in patients with IRon deficiency in coMbination
with chronic Heart Failure (CONFIRM-HF) clinical trial; and to share
diagnostic and treatment algorithms based on clinical evidence.
Editorial ProcessRadcliffe Cardiology (RC) approached Vifor Pharmaceuticals Ltd (Vifor) to develop a proceedings article summarising presentations from
their industry-supported symposium that took place at the European Society of Cardiology Meeting in Barcelona on September 1 2014.
Vifor provided funding to RC for a medical writer to attend the sponsored session and develop a manuscript accordingly. This draft was
reviewed for scientific accuracy by each of the session chairmen and presenters; and two blinded peer reviewers with suggested amends
incorporated. On approval by all reviewing parties, the symposium was submitted to Radcliffe Cardiology and accepted for publication in
Cardiac Failure Review (CFR).
Iron Deficiency in Heart Failure – the Relevance for the Patient
C A R D I A C FA I L U R E R E V I E W 3
Iron Deficiency, a Common Neglected Burden in Heart Failure
Carolyn SP Lam
Director, Women’s Heart Health Clinic; Consultant, National University Heart Centre; Associate Professor, Yong Loo Lin School of Medicine; Chair,
Asia Pacific Association of Women’s Cardiovascular Disease, Singapore
Dr Carolyn Lam began by discussing data from the recent prevalence
study of ID in HF,3 for which the study cohort was from European
countries only. A study of ID in Asian patients with HF (n=751) found
a higher prevalence of ID (61 %).8 The prevalence was particularly
high in women (71 % versus 59 % in men) and in South Asian
Indian populations (a prevalence of 82 %).8 South Asians tend to
be vegetarian and also drink black tea, which has been shown
to decrease iron absorption by 80 % when taken with food.9
Genetic factors are also important in determining ID; a number of
studies have investigated TMPRSS6, which encodes a transmembrane
serine protease produced by the liver that regulates the expression of
the systemic iron-regulatory hormone hepcidin. Germline mutations
in TMPRSS6 have been found in extended families where more than
one member had ID.10 Variants in TMPRSS6 have also been found to be
risk factors for ID and iron deficiency anaemia (IDA) in 2,139 unrelated
elderly Chinese women.11
In order to evaluate the impact of ID in HF, it is important to
understand iron metabolism. Dietary iron is utilised not only in
circulating erythrocytes, but also in muscle myoglobin and other
iron containing enzymes.12 Patients with HF may be iron deficient
as a result of reduced iron storage (absolute ID), which may be
caused by malnutrition, malabsorption and gastrointestinal (GI)
oedema and blood losses (due to use of anticoagulants, non-steroidal
anti-inflammatory drugs [NSAIDs] and loss of mucosal integrity).13 Another
important cause of ID in HF is impaired iron mobilisation (functional ID),
resulting from the inflammatory processes that characterise chronic
HF. Activation of pro-inflammatory cytokines such as interleukin-6 (IL-6),
interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-α) causes over-
expression of hepcidin by the liver. This blocks the intestinal absorption
of iron and diverts iron from the circulation into the reticuloendothelial
system (RES), causing reticuloendothelial block, as well as blunting
responses to erythropoietin (EPO) and causing apoptosis of erythroid
progenitors.13–15 At the cellular level, ID reduces the delivery of oxygen to
the mitochondria but also directly decreases the activity of key enzymes
of the citric acid cycle and of the respiratory chain of the mitochondria,
resulting in reduced oxygen utilisation (which is, in the clinical setting,
observed as reduced peak oxygen consumption [pVO2]).16
ID reduces work capacity and energy efficiency in HF17,18 and iron
status correlates to NYHA status.3 The fact that ID but not anaemia
HF has a significant impact on QoL that is worse than the impact of
other chronic diseases, particularly in terms of physical function.1 HF
is characterised by exercise intolerance, fatigue and dyspnoea, and is
classified according to severity in New York Heart Association (NYHA)
classes I–IV, where Class I is no limitation of physical activity and Class IV
is the inability to undertake any physical activity without discomfort.2 An
emerging problem in HF is ID. ID is prevalent among patients with HF; in a
recent international pooled cohort study (n=1,506), ID (defined as serum
ferritin <100 µg/L or <299 µg/L if transferrin saturation [TSAT] <20 %) was
found in 50 % of the total patient population. ID is the commonest cause
of anaemia, but even in the absence of anaemia, ID was present in 45.6
% of patients (see Figure 1).3 Disease severity, assessed by NYHA class
and N-terminal of pro-brain natriuretic peptide (NT-proBNP) levels, proved
to be powerful and independent predictors of a disordered iron status.
Furthermore, ID has been found to be an independent factor associated
with reduced exercise capacity,4 reduced QoL5,6 and poor outcome.3
In 2012, the ESC Guidelines for the diagnosis and treatment of acute and
chronic HF recognised ID as a co-morbidity in HF for the first time and
recommended diagnosis of ID based on iron parameters in all patients
suspected of having HF.2,7 Furthermore, the guidelines now detail the
mechanism of action of iron in muscle function (and therefore the
explanation for deficiency-related pathology and onset of symptoms
in HF independent of the pro-erythropoietic function of iron); the need
for routine monitoring for ID; and the beneficial effects on symptoms,
physical performance and QoL of treating ID with intravenous (i.v) ferric
carboxymaltose (FCM). Based on the findings of the Ferric Carboxymaltose
Assessment in Patients With IRon Deficiency and Chronic Heart Failure
(FAIR-HF) study, which found that treatment with i.v. FCM in iron deficient
patients with chronic HF improves symptoms, exercise capacity and
QoL irrespective of whether anaemia was present or not. FCM is now
considered as a possible treatment option in the current ESC Guidelines
for HF.2,7,8 In conclusion, ID is a significant burden in HF and merits
further investigation. n
Impact of Iron Deficiency in Heart Failure
Josep Comin-Colet
Department of Cardiology, Hospital del Mar, Barcelona, Spain
Figure 1: Prevalence of Iron Deficiency in Chronic Heart Failure
0
10
20
30
40
70
60
50
Anaemic
61.2 %
Non-anaemic
45.6 %
Whole population
50 %
n=1,506
Perc
ent (
%)
Source: Klip et al., 2013.3
Proceedings of Symposium organised and fully financed by Vifor Pharma
C A R D I A C FA I L U R E R E V I E W 4
Figure 2: Association Between Iron Deficiency and Mortality in Heart Failure
00 1 2 3
Time in study (years)
Cum
ulat
ive
surv
ival
(%)
4 5 6 7 8
20
40
100
80
60
n=1,506
No IDNo Anaemia
IDNo Anaemia
*
IDAnaemia
†
*p<0.01†p<0.001
No IDAnaemia
HR
(95
% C
I) fo
r all-
caus
e m
orta
lity
1
2
3
Patients without iron deficiency Patients with iron deficiency
p=0.001
CI = confidence interval; HR = hazard ratio; ID = iron deficiency. Source: Klip et al., 2013.3
is associated with reduced exercise capacity in HF4 can be explained
by the non-haematopoietic effects of iron, including its role in
mitochondrial function in cells with high energy requirements, such as
cardiomyocytes and skeletal myocytes. In patients with chronic HF, ID
but not anaemia has also been associated with reduced QoL (assessed
using the Minnesota Living with Heart Failure [MLWHF] questionnaire),
mostly due to physical factors.5,6 Furthermore, ID is a stronger negative
prognostic indicator for all-cause mortality than anaemia (see Figure
2).3 A recent study in Singapore assessed the impact of ID in Asian
patients with HF. Functional ID was found in the majority (64 %) of
patients with HF. Patients with ID were more symptomatic with higher
NYHA class and MLWHF score, regardless of ejection fraction (EF).19
Patients with concurrent ID and anaemia had the poorest prognosis
regardless of EF.
In the 2012 ESC Guidelines for the diagnosis and treatment of acute and
chronic heart failure, the ESC recommended ID testing in HF patients
based on the assessments of ferritin and TSAT.2,7 This raises the question
of which iron indices are the most useful. Two are currently used: ferritin
(a measure of stored iron) and TSAT (a measure of circulating iron for
functional utilisation). However, ferritin is also an acute phase protein
and can be falsely elevated if inflammation or subclinical infection is
present, but a low ferritin level is a clear indication of ID (absolute). If
ferritin is increased TSAT (<20 %) can be used for the diagnosis of ID
(functional). The only limitation of TSAT is the circadian differences since
the calculated value is dependent on the serum iron. Due to their intrinsic
limitations, the combination of thresholds of these two parameters
is suggested, as for the FAIR-HF study (ferritin <100 ng/mL or ferritin
100–300 ng/mL if TSAT <20 %). The ideal marker would probably be the
soluble transferrin receptor (sTfR); however, this is not widely available
or used in clinical practice.13 Based on the ESC recommendations and
data from the FAIR-HF clinical trial, a suggested algorithm for diagnosis
on ID in HF is proposed (see Figure 3). Recommendations worldwide
are being changed to incorporate the need to assess and treat ID in
patients with chronic HF.20
In conclusion, ID is present in half of all HF patients in Europe
and in up to 80 % of Asian patients. While it is the main cause of
anaemia in HF, ID occurs in over 45 % of non-anaemic patients and
is independently associated with reduced exercise capacity, reduced
QoL and poor outcomes. n
Figure 3: Suggested Algorithm for Diagnosis of Iron Deficiency in Heart Failure
Yes
No Yes
No
Yes No
Chronic HF(NYHA II–IV)
ID:Ferritin <100 ng/mL orFerritin 100–299 ng/mL
when TSAT <20 %
Exclude other causes for anaemiadepending on clinical status:
• Occult bleeding(e.g. Gl, malignancies)
• Renal insufficiency (erythropoietin)• Other deficiencies
(e.g. Vit B12, folic acid)• Other haemoglobinopathies
(e.g. thalassaemia, sickle cell anaemia)
AnaemiaMale Hb <13 g/dL
Female Hb <12 g/dL
Notreatment
ConsiderID treatment
AnaemiaMale Hb <13 g/dL
Female Hb <12 g/dL
GI = gastrointestinal; Hb = haemoglobin; HF = heart failure; ID = iron deficiency; NYHA = New York Heart Association; TSAT = transferrin saturation; Vit = vitamin.
Iron Deficiency in Heart Failure – the Relevance for the Patient
C A R D I A C FA I L U R E R E V I E W 5
Figure 4: The CONFIRM-HF Study – Change in Six-minute Walking Test Distance at 24 Weeks
Figure 5: The CONFIRM-HF Study – First Hospitalisation Due to Worsening Heart Failure
0
10
-10
-20
-30
20
30
Week 24
LSM
cha
nge
in 6
MW
T di
stan
ce fr
om
base
line
(m)
p=0.002
FCM (N=150) Placebo (N=151)
00 90
Time (days)
Log-rank test, p=0.009
Hos
pita
lisat
ion
rate
(per
100
sub
ject
s)
180 270 360
10
30
20
FCM Placebo
FCM = ferric carboxymaltose; LSM = least square mean; 6MWT = six-minute walk test. Source: Ponikowski et al., 2014.35
FCM = ferric carboxymaltose. Source: Ponikowski et al., 2014.35
ID is a frequent co-morbidity in stable HF and in patients admitted to
hospital due to HF worsening.3,6,21,22 Its association with impaired exercise
capacity, poor QoL and increased mortality, irrespective of anaemia,3–5
make it an attractive therapeutic target – a hypothesis that has recently
been tested in clinical studies.22 Several options are available for the
correction of ID. Blood transfusion is generally not recommended since
it is associated with high mortality and a lengthy stay in hospital;23
its use should be reserved for life-threatening emergency situations.
Erythropoiesis-stimulating agents (ESA) are used mainly to correct
anaemia. In the Reduction of Events with Darbepoetin alfa in Heart
Failure (RED-HF) study, a randomised, double-blind trial on anaemic
patients with chronic HF (n=2,278), correcting anaemia with darbepoetin
alpha did not lead to improvement in survival nor clinically meaningful
change in QoL.24 Furthermore, patients treated with darbepoetin alpha
had an increased risk for thromboembolic adverse effects.24 One
potential explanation of the neutral treatment effects on the outcomes
could be due to the fact that ESA therapy can further exacerbate ID by
stimulating the production of red blood cells, which requires a large
amount of iron. Therefore, there could be a subpopulation of patients
included in the RED-HF study with underlying untreated ID based on
the current definition of ID in the ESC Guidelines for HF. Post hoc sub-
analysis investigating the association between ID and the outcomes in
the RED-HF trial is undergoing.
Another option for correcting ID is iron therapy, which may be
administered by oral or i.v. routes. There is no evidence for the
clinical benefits of oral iron supplementation – studies comparing
oral iron with ESA in patients with HF and anaemia found no clinically
meaningful benefits associated with such combination.25–29 A recent
pilot study (n=18) suggested that i.v. and not oral iron improves
exercise capacity in HF patients.30 Early clinical studies have also
demonstrated the efficacy of i.v. therapy but were either single-arm,
open-label studies with a short-term follow-up or small sample
size.31–34 A larger, randomised, double-blind, placebo-controlled trial
was therefore needed. Therefore, the FAIR-HF (n=459) trial was
performed and showed that treatment of HF patients with i.v FCM in
patients with chronic HF and ID, with or without anaemia, improved
symptoms, exercise capacity and Qol at six months, including
significant improvements in self-reported patient global assessment
(PGA), NYHA functional class, six-minute walk test (6MWT),
Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score and
EQ-5D visual analogue scale (VAS) score.22 Improvements were seen
from week 4 onwards irrespective of whether or not the patients
were anaemic.
In order to broaden the evidence in support to treat ID with i.v.
iron in HF, it was necessary to replicate these findings in a further
study, and also to evaluate different, more robust and objective
endpoints, including safety endpoints as well as a longer follow-up.
In addition, the FAIR-HF study employed repeated 200 mg doses,
therefore an evaluation of higher single-dose (up to 1,000 mg) was
needed. To address these questions, the CONFIRM-HF clinical trial
was designed.
CONFIRM-HF was a multicentre, randomised (1:1) double-blind,
placebo-controlled trial of stable, ambulatory HF patients.35 The main
inclusion criteria were:
• NYHA class II/II with left ventricle ejection fraction (LVEF) ≤45 %;
• Brain natriuretic peptide (BNP) >100 pg/mL or the prohormone
NT-proBNP >400 pg/mL;
• ID, defined as serum ferritin <100 ng/mL or 100–300 ng/mL if TSAT <20
%; and
• haemoglobin (Hb) <15 g/dL and no lower Hb cut-off level.
Patients who needed a blood transfusion were excluded from the
study. The methodology involved blinded and unblinded personnel and
CONFIRM-HF – Targeting for Improvement in Exercise Capacity in Heart Failure
Piotr Ponikowski
Department of Heart Diseases, Clinical Military Hospital, Medical University, Wroclaw, Poland
Proceedings of Symposium organised and fully financed by Vifor Pharma
C A R D I A C FA I L U R E R E V I E W 6
The link for the webcast of the presentations is now available: http://congress365.escardio.org/Session/14186#.VFukzrFbDIW The CONFIRM-HF results were also discussed at the Expert on the Spot session and webcast is also available by this link: http://congress365.escardio.org/Session/14134#.VFulWLFbDIV
ID remains under-recognised among cardiologists – an audience
survey revealed that a significant minority regularly monitor ID in
their HF patients. The take-home messages of the symposium were
the following:
• ID is the main cause of anaemia, but also highly prevalent
in non-anaemic patients; it is observed in almost 50 % of HF
patients in Europe and the prevalence is even higher in Asia.
the usage of curtains and black syringes for injections, to mask the
brownish colour of FCM. Treatment involved a correction phase (given
as 1–2 i.v. injections of 500–1,000 iron as single dose treatment (500 mg)
continued (at weeks 12, 24 and 36) if ID was not corrected. The primary
endpoint was the change in 6MWT distance from baseline to Week
24. Key secondary endpoints included the 6MWT distance at Week 6,
12, 36 and 52; PGA score, NYHA class, KCCQ, EQ-5D and fatigue score
at Week 6, 12, 24, 36 and 52. Outcome-related secondary endpoints
included hospitalisation rate (all hospitalisation, for any cardiovascular
[CV] reason, due to worsening HF); time to first hospitalisation (all
hospitalisation, for any CV reason and due to worsening HF); and time to
death (any death, death for any CV reason and due to worsening HF).35
At Week 24, there was an increase in 6MWT distance by 18 ± 8 m in the
FCM group, whereas in the placebo group 6MWT distance decreased
by 16 ± 8 m (both least squares mean + standard error [SE]). It resulted
in a significant increase in 6MWT distance at Week 24 in FCM by 33 ±
11 m (least squares mean ± SE) compared with placebo (p=0.002, see
Figure 4), a treatment effect that had only previously been seen for
cardiac resynchronisation therapy. In all subgroups examined, including
those patients with and without anaemia, the treatment effect was
preserved. The improvement in exercise capacity was striking in that it
was reported not only at 24 weeks, but also at 36 and 52 weeks, with a
sustained improvement in fatigue score also observed. Throughout the
study, improvements in other secondary endpoints in patients treated
with FCM were detected with statistical significance observed from
Week 24 onwards. Treatment with FCM was associated with a significant
reduction in the risk of hospitalisations for worsening HF (hazard ratio
[95 % confidence interval]: 0.39 [0.19–0.82], p=0.009; see Figure 5). The
number of deaths (FCM: 12, placebo: 14 deaths) and the incidence of
adverse events were comparable between both groups.35
In conclusion, the CONFIRM-HF trial demonstrated that in symptomatic
patients with chronic HF and ID treatment with i.v. FCM over one year
resulted in sustainable improvements in exercise capacity, symptoms
and QoL and may be associated with a reduced risk of hospitalisations
due to worsening HF. Further studies are planned and ongoing,
including a meta-analysis, the EFfect of Ferric carboxymaltose on
Exercise Capacity in PaTients with iron deficiency and chronic Heart
Failure (EFFECT-HF), iron in Congestive Heart Failure (iCHF)36 and the
Ferric Carboxymaltose Assessment in Patients With IRon Deficiency
and Chronic Heart Failure with preserved ejection fraction (FAIR-HFpEF)
studies.37 Based on current data, a suggested treatment algorithm has
been proposed (see Figure 6). n
Figure 6: Suggested Treatment Algorithm for Iron Deficiency in Heart Failure, Based on Evidence from Clinical Trials
Evidence-based inCONFIRM-HF
Being assessed inEFFECT-HF
Evidence-based inFAIR-HF
ID Treatment
FCM: Weekly 200 mg single dosesto correct ID according
Ganzoni formula
Check ferritin/TSAT within nextscheduled visit
(preferable 1–3 months)
FCM: 500–1,000 mg single dosesto correct ID (SmPC)
Check ferritin/TSAT within nextscheduled visit
(preferable 1–3 months)
FCM: 4-weekly 200 mg singledoses for maintenance
FCM: 500 mg to maintainferritin/TSAT on target
Check ferritin/TSAT if changein clinical picture or Hb decrease
or 1–2 x/year
CONFIRM-HF = Ferric carboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure; EFFECT-HF = EFfect of Ferric carboxymaltose on Exercise Capacity in PaTients with iron deficiency and chronic Heart Failure; FAIR-HF = Ferric Carboxymaltose Assessment in Patients With IRon Deficiency and Chronic Heart Failure; FCM = ferric carboxymaltose; haemoglobin = Hb; ID = iron deficiency; smPC = summary of product characteristics; TSAT = transferrin saturation.
Iron Deficiency in Heart Failure – the Relevance for the Patient
C A R D I A C FA I L U R E R E V I E W 7
1. Lesman-Leegte I, Jaarsma T, Coyne JC, et al., Quality of life and depressive symptoms in the elderly: a comparison between patients with heart failure and age- and gender-matched community controls, J Card Fail, 2009;15:17–23.
2. McMurray JJ, Adamopoulos S, Anker SD, et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur Heart J, 2012;33:1787–847.
3. Klip IT, Comin-Colet J, Voors AA, et al., Iron deficiency in chronic heart failure: an international pooled analysis, Am Heart J, 2013;165:575–82 e3.
4. Jankowska EA, Rozentryt P, Witkowska A, et al., Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure, J Card Fail, 2011;17:899–906.
5. Comin-Colet J, Enjuanes C, González G, et al., Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status, Eur J Heart Fail, 2013;15:1164–72.
6. Enjuanes C, Klip IT, Bruguera J, et al., Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study, Int J Cardiol, 2014;174:268–75.
7. McMurray JJ, Adamopoulos S, Anker SD, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur J Heart Fail, 2012;14:803–69.
8. Yeo TJ, Yeo PS, Ching-Chiew Wong R, et al., Iron deficiency in a multi-ethnic Asian population with and without heart failure: prevalence, clinical correlates, functional significance and prognosis, Eur J Heart Fail, 2014;16:1125–32.
9. Zijp IM, Korver O, Tijburg LB, Effect of tea and other dietary factors on iron absorption, Crit Rev Food Sci Nutr, 2000;40:371–98.
10. Finberg KE, Heeney MM, Campagna DR, et al., Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA), Nat Genet, 2008;40:569–71.
11. An P, Wu Q, Wang H, et al., TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia, Hum Mol Genet, 2012;21:2124–31.
12. Andrews NC, Disorders of iron metabolism, N Engl J Med, 1999;341:1986–95.
13. Jankowska EA, von Haehling S, Anker SD, et al., Iron deficiency and heart failure: diagnostic dilemmas and
therapeutic perspectives, Eur Heart J, 2013;34:816–29.14. Ganz T, Hepcidin and its role in regulating systemic iron
metabolism, Hematology Am Soc Hematol Educ Program, 2006;29–35, 507.
15. Zhang AS, Enns CA, Molecular mechanisms of normal iron homeostasis, Hematology Am Soc Hematol Educ Program, 2009;207–14.
16. Oexle H, Gnaiger E, Weiss G, Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation, Biochim Biophys Acta, 1999;1413:99–107.
17. Haas JD, Brownlie T 4th, Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship, J Nutr, 2001;131:676S–88S; discussion 688S–90S.
18. Dallman PR, Iron deficiency: does it matter?, J Intern Med, 1989;226:367–72.
19. Yeo TJ, Yeo PS, Sim DKL, et al., Functional iron deficiency in heart failure with preserved versus reduced ejection fraction, J Am Coll Cardiol, 2014;63(12 S):A778.
20. Krum H, Jelinek MV, Stewart S, et al., 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006, Med J Aust, 2011;194:405–9.
21. Jankowska EA, Kasztura M, Sokolski M, et al., Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure, Eur Heart J, 2014;35:2468–76.
22. Anker SD, Comin Colet J, Filippatos G, et al., Ferric carboxymaltose in patients with heart failure and iron deficiency, N Engl J Med, 2009;361:2436–48.
23. Kao DP, Kreso E, Fonarow GC, Krantz MJ, Characteristics and outcomes among heart failure patients with anemia and renal insufficiency with and without blood transfusions (public discharge data from California 2000-2006), Am J Cardiol, 2011;107:69–73.
24. Swedberg K, Young JB, Anand IS, et al., Treatment of anemia with darbepoetin alfa in systolic heart failure, N Engl J Med, 2013;368:1210–9.
25. Ghali JK, Anand IS, Abraham WT, et al., Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia, Circulation, 2008;117:526–35.
26. Parissis JT, Kourea K, Panou F, et al., Effects of darbepoetin alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy,
Am Heart J, 2008;155:751 e1–7.27. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al.,
Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia, Eur Heart J, 2007;28:2208–16.
28. Kourea K, Parissis JT, Farmakis D, et al., Effects of darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure, Eur J Cardiovasc Prev Rehabil, 2008;15:365–9.
29. Palazzuoli A, Silverberg DS, Iovine F, et al., Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome, Am Heart J, 2007;154:645 e9–15.
30. Beck-da-Silva L, Piardi D, Soder S, et al., IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia, Int J Cardiol, 2013;168:3439–42.
31. Bolger AP, Bartlett FR, Penston HS, et al., Intravenous iron alone for the treatment of anemia in patients with chronic heart failure, J Am Coll Cardiol, 2006;48:1225–7.
32. Toblli JE, Lombraña A, Duarte P, Di Gennaro F, Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency, J Am Coll Cardiol, 2007;50:1657–65.
33. Okonko DO, Grzeslo A, Witkowski T, et al., Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial, J Am Coll Cardiol, 2008;51:103–12.
34. Usmanov RI, Zueva EB, Silverberg DS, Shaked M, Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency, J Nephrol, 2008;21:236–42.
35. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al., Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency, Eur Heart J, 2014 [Epub ahead of print].
36. Iron in Congestive Heart Failure (iCHF). Available at: http://clinicaltrials.gov/ct2/show/NCT01837082?term=iCHF&rank=1 (accessed 17 September 2014).
37. EFfect of Ferric carboxymaltose on Exercise Capacity in PaTients with iron deficiency and chronic Heart Failure (EFFECT-HF). Available at: http://clinicaltrials.gov/show/NCT01394562 (accessed 3 September 2014).
8 UK/FER/15/0105 December 2014
Ferinject® (ferric carboxymaltose)Prescribing Information - UK
For full prescribing information refer to the Summary of Product Characteristics (SmPC)
Active ingredient: Ferric carboxymaltose (50mg/mL)Presentation: Solution for injection/infusion. Available as a 2mL vial (as 100mg of iron), 10mL vial (as 500mg of iron) and 20mL vial (as 1000mg of iron).Indication: Treatment of iron deficiency when oral iron preparations are ineffective or cannot be used. The diagnosis must be based on laboratory tests.Dosage and Administration: The cumulative dose for repletion of iron using Ferinject is determined based on the patient’s body weight and haemoglobin level and must not be exceeded.The table in the SmPC should be used to determine the cumulative iron dose.Intravenous injection: A maximum single dose of up to15mg/kg bodyweight. For doses <200mg there is no prescribed administration time. For doses >200mg to ≤500mg, Ferinject should be administered at a rate of 100mg/min. For doses >500mg Ferinject should be administered over 15mins.Intravenous drip: A maximum single dose of up to 20mg/kg bodyweight. Ferinject must be diluted in 0.9% m/V NaCl.Do not administer 1000mg of iron (20ml) more than once a week.Contraindications: Hypersensitivity to Ferinject or any of its excipients. Known serious hypersensitivity to other parenteral iron products. Anaemia not attributed to iron deficiency. Iron overload or disturbances in utilisation of iron.Special warnings and precautions: Parenterally administered iron preparations can cause potentially fatal anaphylactic/anaphylactoid reactions. The risk is enhanced for patients with known allergies, a history of severe asthma, eczema or other atopic allergy, and in patients with immune or inflammatory conditions.Ferinject should only be administered in the presence of staff trained to manage anaphylactic reactions where full resuscitation facilities are available (including 1:1000 adrenaline
solution). Each patient should be observed for 30 minutes following administration. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benefit assessment. Careful monitoring of iron status is recommended to avoid iron overload. There is no safety data on the use of single doses of more than 200mg iron in haemodialysis-dependant chronic kidney disease patients. Parenteral iron must be used with caution in case of acute or chronic infection, asthma, eczema or atopic allergies. It is recommended that treatment with Ferinject is stopped in patients with ongoing bacteraemia.In patients with chronic infection a benefit/risk evaluation has to be performed. Caution should be exercised to avoid paravenous leakage when administering Ferinject. Special populations: The use of Ferinject has not been studied in children. A careful risk/benefit evaluation is required before use during pregnancy. Ferinject should not be used during pregnancy unless clearly necessary.Undesirable effects: Common (≥1/100 to <1/10): Headache, dizziness, hypertension, nausea, injection site reaction, alanine aminotransferase increased, hypophosphataemia. Please consult the SmPC in relation to other undesirable effects. Legal category: POMPrice: pack of 5 x 2ml = £95.50; pack of 5 x 10ml = £477.50pack of 1 x 20ml = £181.45MA Number: 15240/0002Date of Authorisation: 19.07.2007MA Holder: Vifor France S.A. 7-13 Boulevard Paul-Emile victor, 92200 Neuilly-sur-Seine, France.
Further details available from : Vifor Pharma UK Limited, The Old Stables, Bagshot Park, Bagshot, Surrey GU19 5PJT: +44 1276 853 600 F: +44 1276 452 341 [email protected]
Ferinject® is a registered trademark
Date of revision: 10/13
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcardAdverse events should also be reported to Vifor Pharma UK Ltd. Tel: +44 1276 853633
