Int J Heart Fail.

2023 Oct;5(4):173-183
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pISSN 2636-154X·eISSN 2636-1558

Review Article Iron Deficiency in Heart Failure:

A Korea-Oriented Review

Ewa A. Jankowska , MD, PhD1,2, and Piotr Ponikowski , MD, PhD1,2

Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland

1

Institute of Heart Diseases, 10 University Hospital, Wroclaw, Poland

2

Received: Jun 16, 2023

Revised: Aug 24, 2023
ABSTRACT
Accepted: Sep 27, 2023
Published online: Oct 25, 2023 Iron deficiency (ID) occurs at high frequency across the spectrum of heart failure (HF), with HF
severity and race being potentially important predictors for its development. ID, irrespective
Correspondence to
of anaemia status, leads to poor outcomes in patients with HF, including exacerbated reduc-
Ewa A. Jankowska, MD, PhD
Institute of Heart Diseases, Wroclaw Medical
tion in exercise capacity, poor quality of life (QoL) and increased risk of HF hospitalisation. As
University, Chalubinskiego 6a, 50-368 ID has a large public health and economic burden in Asia, and patients hospitalised with acute
Wroclaw, Poland. HF in the Asia Pacific vs. other regions commonly present with more severe clinical symptoms,
Email: [email protected] there is a clear need to identify and treat ID promptly in Asian patients with HF. The biomark-
ers serum ferritin and transferrin saturation are used for ID diagnosis, and periodic screening
Copyright © 2023. Korean Society of Heart
Failure is recommended in all patients with HF. The intravenous iron treatments, ferric carboxymalt-
This is an Open Access article distributed ose (FCM) and ferric derisomaltose, have demonstrated efficacy and tolerability in patients
under the terms of the Creative Commons with acute or chronic HF and ID, with FCM shown to be cost-effective (and in some cases
Attribution Non-Commercial License (https:// cost-saving). Meta-analyses support the likely benefits of intravenous FCM for improving QoL
creativecommons.org/licenses/by-nc/4.0)
and reducing HF hospitalisation, without reducing mortality risk in patients with HF and ID.
which permits unrestricted noncommercial
use, distribution, and reproduction in any
Accordingly, European Society of Cardiology guidelines recommend considering intravenous
medium, provided the original work is properly FCM for patients with symptomatic HF with left ventricular ejection fraction ≤50% who were
cited. recently hospitalised for HF and have ID. Although analyses of Asian patients with HF and ID
are limited, the effects of intravenous iron would be expected to be similar to that in White
populations; further clarifying studies may be of interest.

Keywords: Asia; Heart failure; Iron deficiency; Iron; Supplies; Korea

EPIDEMIOLOGY OF IRON DEFICIENCY (ID)

ID is the most prevalent micronutrient deficiency, affecting greater than one-third of the
world’s population.1) It can result in microcytic anaemia, causing symptoms such as fatigue,
weakness and shortness of breath.1) ID is particularly common in countries with a low and
low–middle sociodemographic index.1) In 2019, the age-standardised prevalence rate of ID per
100,000 persons was greater than 14,000 globally, with rates in Asia varying from 4,724 in East
Asia to 27,404 in South Asia.1)

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Iron Deficiency in HF: Korea-Oriented Review

EPIDEMIOLOGY OF ID IN HEART associated with significantly increased odds of having ID.10) In

FAILURE (HF) Korea, a higher heart rate, anaemia, and use of clopidogrel were
independent predictors of ID in patients hospitalised with acute
HF is a considerable health burden, affecting approximately 64.3 HF, as was female sex.11) Although these factors can help predict
million people globally.2) In the Western Pacific region, HF has patients at the highest risk of ID, periodic ID screening is recom-
been found to occur at a slightly younger mean age of 67 years mended for all patients with HF.13)
compared with 70 years in the USA, with an even younger mean
age of 54 years observed for HF diagnosis in Southeast Asia.3) ID is associated with poorer outcomes in patients with HF, ir-
In Korea specifically, the prevalence of HF has been increasing respective of whether the patient has anaemia or not.7,8,14) In
in the last 2 decades, from 0.77% of the population reported as a prospective, multicentre cohort study in Korea, 53.8% of pa-
having HF in 2002 to 2.24% reported in 2018.4) tients hospitalised with acute HF had ID, while only 34.9% had
ID anaemia.11)
ID is a non-cardiovascular co-morbidity that occurs at high fre-
quency across the whole spectrum of HF, affecting as many as
37–83% of patients with HF overall and 65–83% of patients fol- PATHOPHYSIOLOGY OF ID IN HF
lowing an acute HF episode.5-9) In a multi-ethnic Southeast Asian
population, the odds of having ID was 3.5-fold higher in patients Iron is essential for the functioning of haematopoietic and
with HF than control patients who did not have HF.10) In this non-haematopoietic cells. Iron is required for erythropoiesis and
study, the prevalence of ID in the Southeast Asian population immune responses, is present in every cell and is essential for
with HF (61%) exceeded that reported for European counterparts various metabolic processes(Figure 1).15-17) Therefore, ID has crit-
with HF (37–50%).10) In Korea, 53.8% of patients hospitalised ical consequences for organs in which the tissue has high energy
with acute HF were reported to have ID.11) requirements, such as the kidneys, skeletal muscle and myocar-
dium(Figure 2).17,18)
HF severity and race have been highlighted as important pre-
dictors of ID in patients with HF. In global studies, significant, The mechanism behind the high prevalence of ID in HF has not
independent associations were seen between ID and New York been fully elucidated. One hypothesis is that the mechanism un-
Heart Association Functional Classification (NYHA) > II, high derpinning ID in chronic kidney disease (inflammation leading
serum high-sensitivity C-reactive protein, and high plasma to a cascade of hepcidin production, which triggers the migra-
N-terminal pro-B-type natriuretic peptide (NT-proBNP).7,12) In tion of iron into reticuloendothelial cells where it is unavailable
a Southeast Asian population, a lower left ventricular ejection for metabolic processes) may also apply to the pathogenesis of
fraction (LVEF), and being an inpatient (vs. an outpatient), with ID in HF.17,19-21) However, the inflammation-catalysed iron redis-
a higher body-mass index, and Indian (vs. Chinese) race were all tribution hypothesis remains disputed because of the limited

Iron deficiency

Haematopoietic pathway Non-haematopoietic pathway

· Decreased myoglobin content and
Impaired erythropoiesis O2 storage
· Impaired ROS defence
· DNA replication, repair and
Iron-deficiency anaemia
cell-cycle abnormalities
· Immune response abnormalities
Pathophysiological effects · Potential neural and
hormonal abnormalities

Deleterious biological consequences of iron deficiency

Figure 1. Involvement of iron in haematopoietic and non-haematopoietic metabolic pathways.15-17)

ROS = reactive oxygen species.

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Iron Deficiency in HF: Korea-Oriented Review

ferritin and transferrin saturation (TSAT) are the standard bio-

markers recommended in European Society of Cardiology (ESC)
Heart guidelines for diagnosing ID in patients with HF.13) Ferritin is
· Progressive worsening of HF state
a blood protein that stores iron and is predominantly found in
· Deteriorating LV systolic function
and contractility reticuloendothelial cells and hepatocytes.25) Transferrin is a pro-
· Impaired LV diastolic function tein that transports iron in the blood serum; thus, the measure
and relaxation of TSAT is given as a percentage of transferrin binding and trans-
porting iron. This percentage is calculated as the serum iron di-
Kindneys vided by the total iron binding capacity of transferrin, which is
· Renal dysfunction/impairment then multiplied by 100.17,26,27)
· Poor control of blood pressure
One proposed definition of ID in HF is low levels of serum fer-
Skeletal muscle ritin (<100 ng/mL).13) However, ferritin production is increased
· Exercise intolerance during periods of inflammation (as seen in HF), meaning that
· Weakness/fatigue serum ferritin alone cannot be used to definitively diagnose ID
· Insulin resistance
in HF.17,27) Therefore, a secondary biomarker, TSAT, is used to
provide further indication of iron depletion.17,27) In the presence
of ID, transferrin is upregulated, leading to a higher volume of
Figure 2. Iron deficiency impairs functioning of organs characterised by high
circulating non-iron bound transferrin, which results in a relative
daily energy consumption.17,18)
HF = heart failure; LV = left ventricular. TSAT decrease. Thus, a decrease in TSAT indicates ID. Therefore,
the second definition of ID in HF is defined as TSAT <20% with
supporting evidence for inflammation as a catalyst in ID and the serum ferritin 100–299 ng/mL.13) To account for the inflammation
contrasting finding that patients with chronic22,23) or acute8) HF seen in HF, researchers and treating clinicians apply a high cut-
have very low levels of circulating hepcidin as opposed to high off level for serum ferritin in combination with a low TSAT to di-
levels of hepcidin. This suggests that ID in patients with HF may agnose ID in HF more accurately.17,27) ESC 2021 HF guidelines and
instead be associated with iron store depletion.23) The reliability the 2022 Korean Society of Heart Failure (KSHF) Guideline for
of hepcidin as a sole marker for ID in HF may be limited because the Management of HF recommend diagnosis of ID in patients
the level of hepcidin can be influenced by various factors.24) with HF if serum ferritin values are <100 ng/mL, or 100–299 ng/
mL accompanied by TSAT <20%.13,28) This definition has been
Iron store depletion may result from a reduction in iron con- used as an inclusion criterion in several clinical studies investi-
sumption or iron absorption, abnormal iron loss (i.e., from gas- gating the effect of intravenous (IV) iron in patients with ID and
trointestinal disorders such as peptic ulcers and colitis, or blood HF, which have demonstrated improved clinical outcomes.29-31)
loss from the urinary tract) or iron deposition to stores that are This suggests that the definition can help to identify patients
inaccessible for metabolic processes.24) However, while these with ID who are likely to benefit from iron-repletion therapy.
mechanisms are logical, their contribution to ID in HF remains
unclear. More research is required to investigate the mechanisms An alternative definition of ID has been explored using the novel
underlying ID in HF. iron biomarkers: hepcidin and soluble transferrin receptors.8,22)
Low serum hepcidin reflects depleted iron stores more accurate-
ly than ferritin, while high soluble transferrin receptors reflect
DEFINING ID IN HF depleted intracellular iron that is insufficient for metabolic pro-
cesses.8,22) Future studies assessing the specificity and selectivity
Haematological assessment of iron stores within bone marrow of different combinations and cut-offs of the aforementioned ID
is considered the gold standard approach to diagnosing ID.16,24) biomarkers would be informative for their potential diagnostic
However, the invasiveness and lack of availability of the bone application and to help guide therapy.
aspiration procedure renders it impractical outside specialist
haematology settings.24) Additionally, results from bone marrow
predominantly provide insight into iron status for erythropoietic CLINICAL CONSEQUENCES OF ID IN HF
processes. Thus, biomarker identification is considered a more
suitable method to diagnose ID in patients with HF.24) Serum HF is a condition in which there is high morbidity and mortali-

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Iron Deficiency in HF: Korea-Oriented Review

Clinical consequences of iron deficiency in patients with heart failure

Inpaired exercise capacity Poor quality of life High hospitalisation risk High mortality risk High healthcare cost

Figure 3. Clinical consequences of iron deficiency in patients with heart failure.7,14,33-36)

ty.32) ID (irrespective of anaemia status) exacerbates the clinical Iron sucrose is another type of IV iron complex, and while it is a
symptoms of HF33) and has been associated with reduced exercise different complex to that of FCM and FDI, it has also showcased
capacity,34) poor health-related quality of life (QoL),35) increased desirable effects in patients with HF.47,48) In the FERRIC-HF48) and
risk of non-fatal cardiovascular events (HF hospitalisation, acute IRON-HF47) trials, iron sucrose use resulted in an improvement
coronary syndrome, severe arrythmia and stroke),14) and in- in exercise capacity in patients with HF. However, patients can
creased risk of all-cause death,7) as well as high healthcare costs be administered a much higher iron dosage in a single admin-
(Figure 3).36) istration with FCM compared with iron sucrose, which requires
multiple administrations to reach the optimal dose.39)
Patients hospitalised with acute HF in the Asia Pacific region
commonly present with more severe clinical symptoms and at Key trials investigating IV iron in patients with ID
an earlier age than patients from other regions,37) suggesting and HF
an ‘Asian phenotype’ of aggressive disease progression.38) This The FAIR-HF and CONFIRM-HF trials investigated the effects of
highlights the large public health and economic burden of HF IV FCM vs. placebo on clinical and QoL outcomes in patients with
in Asia.10) As such, the need to identify and treat ID promptly in ID (with or without anaemia) and chronic HF with reduced ejec-
patients with HF in Asia may be even more important. tion fraction (LVEF <45%).29,30,49) In both trials, improvements
in 6-minute walk test (6MWT) distance, QoL, NYHA class, and
self-reported disease activity and overall health (based on patient
EXISTING DATA ON IRON REPLETION global assessment score), were seen with FCM vs. placebo. In
THERAPY IN PATIENTS WITH HF CONFIRM-HF, IV FCM was also found to reduce the secondary
endpoint of risk of hospitalisation for worsening HF at week 52.30)
While inexpensive and widely available, oral formulations of iron Results were found to be independent of anaemia status.29,49)
sulphate, gluconate, or fumarate39) are not recommended to treat
iron deficiency in patients with HF13) because there is a lack of Two pooled analyses of the FAIR-HF and CONFIRM-HF trials
evidence for their clinical benefit.40,41) However, there is growing with increased statistical power reinforced the findings of the
evidence supporting the use of IV iron treatment for patients with individual trials. In the first pooled analysis, significantly higher
HF, which is recognised in the ESC13) and the 2022 KSHF Guide- proportions of patients in the FCM arm experienced a clinically
line for the Management of HF.28) IV ferric carboxymaltose (FCM) meaningful (≥20 m) improvement in 6MWT compared with pla-
and ferric derisomaltose (FDI) are iron (III) hydroxides in com- cebo at week 12 (56.8% vs. 37.4%; odds ratio [OR], 2.156; 95%
plex with carboxymaltose42) and derisomaltose,43) respectively. confidence interval [CI], 1.571–2.960; p<0.0001).50) Among the
While the exact mechanism of action of iron (III) hydroxide com- patients who had a significant improvement in 6MWT at week
plexes—such as FCM—is not known, studies have reported that 12, >80% sustained this improvement at week 24.50) In the second
iron released from these complexes binds to transferrin and is de- pooled analysis, a significantly higher proportion of patients
livered to reticuloendothelial cells.42,44) In clinical trials, FCM and experienced a clinically meaningful (≥4.3-point) improvement
FDI have demonstrated efficacy and tolerability in patients with in Kansas City Cardiomyopathy Questionnaire (KCCQ) over-
ID in acute and chronic HF (results are summarised in Table 1).29- all summary score (OSS; representing QoL) with IV FCM than
31,45)
Initial adverse effects such as nausea, hypotension and pe- placebo at week 12 (60.5% vs. 46.6%; OR, 1.75; 95% CI, 1.26–
ripheral oedema were originally observed with IV iron due to the 2.44; p=0.0008).51) Thus, pooled data from FAIR-HF and CON-
oxyhydroxide complex formulation; however, in the more recent- FIRM-HF showed that FCM can improve HF clinical status, ex-
ly-developed formulations, FCM and FDI, the iron is encased in a ercise capacity and QoL in patients with ID and chronic HF with
carbohydrate shell, largely averting these adverse effects.29-31,45,46) reduced ejection fraction compared with placebo.50,51)

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Iron Deficiency in HF: Korea-Oriented Review

Table 1. Intravenous iron in heart failure clinical trials

Characteristics FAIR-HF29) CONFIRM-HF30) IRONMAN45,53) AFFIRM-AHF29) PRACTICE-ASIA-HF55)
Patient population
Number of patients 459 304 1,137 1,132 50
Mean age in IV iron vs. 67.8 vs. 67.4 68.8 vs. 69.5 73.2 vs. 73.5 71.2 vs. 70.9 61.1 vs. 64.0
comparator arm (years)
Region Europe Europe UK Europe, South America, Singapore Southeast Asia*
HF type Chronic Chronic Chronic and acute Acute Acute
NYHA class II/III II/III II/III/IV I/II/III/IV Not specified
LVEF ≤45% ≤45% ≤45% ≤50% Regardless of LVEF
Definition of ID Serum ferritin <100 Serum ferritin 100 Serum ferritin <100 Serum ferritin <100 µg/L or Serum ferritin <300
μg/L or 100–299 µg/L or 100–300 µg/L and/or TSAT 100–299 µg/L if TSAT <20% µg/L if TSAT <20%
μg/L if TSAT <20% µg/L if TSAT <20% <20%
Type of IV iron FCM FCM FDI FCM FCM
Endpoints
Primary PGA at week 24 6MWT at week 24 Composite of recurrent Composite of total HF Difference in 6MWT
(OR, 2.51; 95% CI, (LS mean difference ± HF hospitalisations hospitalisations and CV death up distance over 12
1.75–3.61; p<0.001) SE 33±11 m; p=0.002) and CV death at 12 to 52 weeks (RR, 0.79; 95% CI, weeks (adjusted mean
Improvement by one months (RR, 0.82; 0.62–1.01; p=0.059) distance 0.9 m [95%
NYHA class at week 95% CI, 0.66–1.02; CI, –30.2 to 32.0;
24 (OR, 2.40; 95% CI, p=0.070) p=0.956)
1.55–3.71; p<0.001)
Key secondary • 6MWT distance • NYHA class • CV death or first HF • CV hospitalisations and CV death • QoL (KCCQ and VAS)
• KCCQ • PGA hospitalisation • HF hospitalisations • HF readmissions
• EQ-5D • 6MWT distance • MLHFQ • Time to first HF hospitalisation
• VAS • Fatigue score and • EQ-5D or CV death
HRQoL (KCCQ, EQ-5D) • 6MWT distance • Days lost owing to HF
• HF hospitalisation hospitalisations or CV death
6MWT = 6-minute walk test; CI = confidence interval; CV = cardiovascular; EQ-5D = European Quality of Life–5 Dimensions; FCM = ferric carboxymaltose; FDI
= ferric derisomaltose; HF = heart failure; ID = iron deficiency; IV = intravenous administration; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left
ventricular ejection fraction; NYHA = New York Heart Association Functional Classification; OR = odds ratio; PGA = patient global assessment score; QoL =
quality of life; RR = rate ratio; VAS = visual analogue scale; TSAT = transferrin saturation; SE = standard error; HRQoL = health related quality of life; MLHFQ =
Minnesota Living with Heart Failure Questionnaire.
*Two centres in Singapore.

Following on from the success of FCM in patients with ID and week 4 after the start of treatment (adjusted mean difference for
chronic HF, the AFFIRM-AHF clinical trial investigated the effect OSS: 2.9, 95% CI, 0.5–5.3; p=0.018), lasting up to week 24 (ad-
of IV FCM compared with placebo in patients with ID after stabi- justed mean difference for OSS: 3.0, 95% CI, 0.3–5.6; p=0.028).52)
lisation following an acute HF episode (when risk of rehospital- These latter findings were drivers of dominance (cost saving with
isation and mortality is high) with LVEF <50%.31) Given the lack additional health improvement; Switzerland, UK and USA) and
of data on the safety of IV iron supplementation in this high-risk high cost-effectiveness (Italy) in a pharmacoeconomic analysis
population, repeat dosing was only performed up to week 24 in of IV FCM in acute HF based on AFFIRM-AHF data,36) with no
AFFIRM-AHF, with clinical efficacy endpoints assessed at week 52. effect of FCM vs. placebo on cardiovascular death observed in the
The trial narrowly missed its composite primary endpoint of total AFFIRM-AHF trial (hazard ratio [HR], 0.96; 95% CI, 0.70–1.32;
HF hospitalisations and cardiovascular death at week 52 (rate ratio p=0.81).31) Other secondary clinical endpoints, including time to
[RR], 0.79; 95% CI, 0.62–1.01; p=0.059). This was potentially in first HF hospitalisation or cardiovascular death (HR, 0.80; 95%
part due to the impact of the coronavirus disease 2019 (COVID-19) CI, 0.66–0.98; p=0.030) and days lost due to HF hospitalisations
pandemic on data collection and follow-up. A sensitivity analysis and cardiovascular death (RR, 0.67; 95% CI, 0.47–0.97; p=0.035)
that censored patients at the first date of COVID-19 detection in also significantly favoured FCM vs. placebo31); however, second-
their region revealed a significant effect of FCM vs. placebo on the ary endpoints were considered hypothesis-generating only, given
primary endpoint (RR, 0.75; 95% CI, 0.59–0.96; p=0.024). the non-significant primary endpoint.

In terms of secondary endpoints in AFFIRM-AHF, IV FCM was as- The investigator-initiated, open-label, randomised IRONMAN
sociated with a significant reduction in total HF hospitalisations trial investigating another IV iron preparation, FDI, in patients
vs. placebo at week 52 (RR, 0.74; 95% CI, 0.58–0.94; p=0.013),31) with ID and new or established symptomatic HF with LVEF
as well as a significantly greater improvement in QoL score (eval- ≤45%, was reported in November 2022.45) This trial assessed sim-
uated using KCCQ-12 OSS and clinical summary score) as early as ilar outcomes to the AFFIRM-AHF trial, but in a lower-risk pop-

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Iron Deficiency in HF: Korea-Oriented Review

ulation and over a longer follow-up period (median of 2.7 years), Taken together, results from individual trials support the likely
with repeat dosing permitted throughout the trial. benefit of IV iron supplementation for reducing hospitalisation
for HF and improving QoL across a spectrum of patients with
While AFFIRM-AHF only enrolled patients during hospitalisation acute or chronic HF and ID, with the cost-effectiveness (and in
for an acute HF episode, IRONMAN also enrolled non-hospital- some cases cost-savings) of FCM predicted from a number of
ised patients with elevated plasma NT-proBNP, elevated plasma healthcare system perspectives.
B-type natriuretic peptide or prior hospitalisation for HF within
the last 6 months. Furthermore, the iron parameters indicating IV iron in Asian populations with ID and HF
a patient for redosing in IRONMAN (serum ferritin <100 µg/L or Of the 1,108 patients included in AFFIRM-AHF analyses and the
<400 µg/L if TSAT <25%) were more lenient compared with prior 1,137 patients included in IRONMAN analyses, 4.3% and 5.8%,
trials.53) Despite these differences, IRONMAN data were largely respectively, were of Asian race,29,45) with analyses by race cur-
in agreement with findings from the AFFIRM-AHF trial. rently unavailable. No patients from Asia were included in the
FAIR-HF and CONFIRM-HF analyses; however, FAIR-HF data
While the composite primary endpoint of recurrent hospitalisa- have been used to perform cost-effectiveness and cost-utility
tions for HF and cardiovascular death with IV FDI vs. usual care analyses of FCM in patients with chronic HF and ID anaemia
(excluding IV iron) was missed in IRONMAN, a numeric reduc- from a Korean healthcare payer perspective, based on the ratio
tion in this endpoint was observed (RR, 0.82; 95% CI, 0.66–1.02; of healthcare resource utilisation in Korea using NYHA class and
p=0.070). Similar to AFFIRM-AHF, the COVID-19 pandemic had NYHA improvement rates in FAIR-HF.54) In the base-case sce-
a considerable impact on the IRONMAN trial, influencing the nario, IV FCM was cost-effective vs. placebo for ID, with an in-
ability of patients to attend in-person visits for assessment of iron cremental cost-effectiveness ratio of ₩25,010,451 ($22,192) per
levels and repeat IV FDI dosing, as well as recruitment and reten- quality-adjusted life year.
tion. As in AFFIRM-AHF, when a sensitivity analysis accounting
for the effects of COVID-19 in IRONMAN was performed, a sig- One small pilot study, PRACTICE-ASIA-HF, of IV iron in South-
nificant reduction in the primary endpoint was observed with east Asian patients with ID and HF has been conducted.55) A
IV FDI compared with usual care (RR, 0.76; 95% CI, 0.58–1.00; single 1,000 mg dose of IV FCM or placebo was administered
p=0.047). This suggests that COVID-19 was a key, unanticipated to 50 Southeast Asian patients with ID (defined as serum ferri-
interferent in both AFFIRM-AHF and IRONMAN statistical anal- tin <300 ng/mL with TSAT <20%), who had stabilised follow-
ysis plans, with potentially greater influence in IRONMAN due to ing acute decompensated HF (regardless of LVEF) (results are
COVID-19 restricting FDI dosing from March 2020. summarised in Table 1).55) This study differed from other trials
of IV FCM (FAIR-HF, CONFIRM-HF and AFFIRM-AHF) in sever-
The impact of COVID-19 is also reflected in many of the second- al ways. To account for the average lower weight of a Southeast
ary clinical endpoints in IRONMAN, including hospitalisation Asian patient with HF compared with a Caucasian patient with
for HF (RR, 0.80; 95% CI, 0.62–1.03; p=0.085) and change in HF and assuming an Hb of ≥10 g/dL, a fixed dose of 1,000 mg was
6MWT at 20 months (estimated mean difference: −35.9, 95% CI, administered in PRACTICE-ASIA-HF, with no repeat dosing for
−74.4 to 2.64; p=0.068). Only the secondary endpoint of time to persistent ID. This resulted in incomplete iron repletion in some
first cardiovascular death or hospital admission for stroke, myo- patients. As PRACTICE-ASIA-HF was a pilot study, it was small
cardial infarction or HF was significantly reduced in the FDI vs. (25 patients per treatment arm) and relatively short (12 weeks),
usual care arm (HR, 0.83; 95% CI, 0.69–1.00; p= 0.045). Addi- which greatly limited the statistical power available to detect sig-
tionally, although patients treated with IV FDI had a significantly nificant treatment effects.
better overall Minnesota Living with HF Questionnaire (MLHFQ)
score at 4 months (adjusted mean difference −3.33, 95% CI, −6.67 PRACTICE-ASIA-HF found an increase in mean 6MWT distance
to 0.00; p=0.050) when compared with the usual care group, from 252 m at baseline to 334 m at week 12 in the FCM arm, with
no significant difference in overall MLHFQ score was observed continued incremental improvement throughout the 12 weeks,
between the 2 groups at 20 months (adjusted mean difference and from 243 m at baseline to 301 m at week 12 in the placebo
−2.57, 95% CI, −6.72 to 1.59; p=0.23).The role of COVID-19 in lim- arm, with a plateau after 4 weeks. However, no significant effect
iting FDI redosing may potentially have affected this outcome, of FCM vs. placebo on change from baseline in 6MWT distance
similar to the attenuation of the treatment effect after cessation at 12 weeks (primary endpoint) was observed following covari-
of FCM dosing in AFFIRM-AHF.52) ate adjustment (mean difference: 0.88 m, 95% CI, −30.2 to 32.0;
p=0.956). Given that significant treatment effects for the 6MWT

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Iron Deficiency in HF: Korea-Oriented Review

became apparent at 24 weeks in CONFIRM-HF,30) the shorter diovascular hospitalisations and cardiovascular mortality vs.
study duration of PRACTICE-ASIA-HF may have been insuffi- placebo in patients with systolic HF and ID (RR, 0.59; 95% CI,
cient to capture significant improvements in exercise capacity 0.40–0.88; p=0.009).58) However, a more recent meta-analysis
with IV FCM. that included 7 trials in patients with HF and ID suggested that a
reduction in cardiovascular, rather than mortality, events with IV
Similarly, changes in QoL measures (secondary endpoints) did iron, may be the key driver of composite endpoint results includ-
not differ significantly between treatment arms in PRACTICE- ing such events.59) In this meta-analysis, IV iron reduced the rate
ASIA-HF. Respective mean KCCQ OSS scores at baseline and of HF hospitalisations or cardiovascular death (OR, 0.73; 95% CI,
week 12 increased from 50.0 to 82.4 in the FCM arm and from 0.59–0.90; p=0.003); however when the individual components
51.2 to 87.1 in the placebo arm (adjusted mean difference: −1.48, of this composite endpoint were analysed, the rate of first HF
95% CI, −8.27 to 5.31; p=0.67). Mean visual analogue scale scores hospitalisation remained significantly reduced (OR, 0.67; 95%
increased from 6.4 at baseline to 7.7 at week 4 in the FCM arm, CI, 0.54–0.85; p=0.0007), but the rate of cardiovascular death
before decreasing slightly to 6.8 at week 12 (potentially high- did not (OR, 0.89; 95% CI, 0.66–1.21; p=0.47). This finding is in
lighting initial benefits of iron repletion followed by fall-off of agreement with the results of the AFFIRM-AHF analysis, which
the effect due to lack of repeat dosing); in the placebo arm, scores showed a reduction in HF hospitalisations but not cardiovascular
increased from 5.7 at baseline to 6.9 at week 4, remaining stable death with FCM vs. placebo.31)
thereafter (adjusted mean difference in change from baseline
to week 12 with FCM vs. placebo: 0.26, 95% CI, −0.33 to 0.86; Thus, the totality of evidence suggests that IV iron should be
p=0.39). IV FCM was well tolerated in PRACTICE-ASIA-HF with considered in patients with ID and HF to reduce hospitalisation
no serious treatment-associated adverse events reported. Given rates, and improve functional outcomes and QoL, without an
the aforementioned limitations of PRACTICE-ASIA-HF, data expectation for reduced mortality risk. Indeed, recommenda-
from this pilot study are encouraging but insufficient to draw tions surrounding the use of IV iron in patients with HF are now
firm conclusions regarding the efficacy of IV FCM in Southeast included in a number of regional cardiology society guidance
Asian patients with ID following an acute HF episode; further documents: the ESC guidelines include a class IIa recommenda-
clarifying studies in this population may be informative. tion to consider the use of IV FCM to reduce the risk of HF hos-
pitalisation in patients with symptomatic HF, LVEF ≤50% and
Totality of evidence ID who have been recently hospitalised for HF13); and the Asian
A meta-analysis investigated the effect of IV iron in 5 trials of pa- Pacific Society of Cardiology consensus statements include a
tients with systolic HF (LVEF ≤45%) and ID.56) The FAIR-HF30) and recommendation to consider IV FCM in patients with symptom-
CONFIRM-HF30) trials included in the meta-analysis investigated atic chronic HF with reduced (moderate level of evidence; 100%
IV FCM vs. placebo, whereas the Toblli et al.,57) FERRIC-HF,48) consensus) or mildly reduced (low level of evidence; 100% con-
and IRON-HF47) trials investigated IV iron sucrose vs. placebo. sensus) ejection fraction who have concomitant ID (defined as
Patients in IRON-HF were also treated with oral ferrous sulphate. serum ferritin <100 ng/mL or serum ferritin 100–299 ng/mL with
This meta-analysis revealed that IV iron reduced the composite TSAT <20%).60) Practical advice on treatment and diagnosis of ID
endpoint of hospitalisation for cardiovascular causes or all- in patients with HF has previously been given61); further consid-
cause death by 66% vs. placebo (OR, 0.44; 95% CI, 0.30–0.64; erations are outlined in Figure 4.
p<0.0001), as well as the composite endpoint of hospitalisation
for worsening HF or cardiovascular death (OR, 0.39; 95% CI,
0.24–0.63; p=0.0001). Outcomes for which individual endpoints CONCLUSIONS AND FUTURE
were given as mean net effects showed a reduction in NYHA class DIRECTIONS
of −0.54 classes (95% CI, −0.87 to −0.21; p=0.001), an increase in
6MWT distance of 31 m (95% CI, 18–43; p<0.0001) and an overall ID is common in patients with acute or chronic HF, where it is
improvement in QoL scores with FCM vs. placebo. These find- associated with undesirable effects, such as exacerbating reduc-
ings support those from individual trials. tions in exercise capacity and QoL, and increased risk of HF hos-
pitalisation. Data suggest a severe clinical phenotype in Asian
A second meta-analysis that extracted individual patient data patients with HF and ID, highlighting a need for early identifica-
from 4 double-blind, randomised controlled trials (FER- tion and treatment of ID in these patients. While the pathophys-
CARS-01, FAIR-HF, EFFICACY-HF and CONFIRM-HF) found iology underlying ID in HF is unclear, evidence suggests that IV
that IV FCM significantly reduced the rates of recurrent car- iron supplementation is beneficial for reducing hospitalisation

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Iron Deficiency in HF: Korea-Oriented Review

Regularly screen all patients with HF for ID, Screening for ID can be performed at any time
regardless of Hb level, kidney function or LVEF during the course of HF, also during
hospitalisation for HF worsening

Is serum ferritin:*
Re-evaluate iron status No
every 12 months <100 100–299 ng/mL+
OR
ng/mL? TSAT <20%?
Yes

ID confirmed
IV iron can be administered regardless of kidney
Oral iron Consider IV iron supplementation† in patients function, blood pressure and heart rate
supplementation is with symptomatic HF* that:
not effective in iron No allergenic testing is required before IV iron
· Are currently hospitalised for acute HF with ID
deficient patients with administration
· Have been recently hospitalised for HF and with
HF and cannot be LVEF <50% and ID
recommended · Have LVEF <45% and ID IV iron can be administered in
Do not administer IV iron if Hb >15 g/dL the outpatient setting

IV FCM dosing regimen in CONFIRM-HF and AFFIRM-AHF trials†

· IV FCM administered at weeks 0 and 6,
with dose based on body weight and Hb level
Body weight
Hb (g/dL) <35 kg ≥35 to <70 kg ≥70 kg
<10 500 mg FCM 1,500 mg FCM 2,000 mg FCM
≥10 to <14 500 mg FCM 1,000 mg FCM 1,500 mg FCM
Re-evaluate iron ≥14 to <15 500 mg FCM 500 mg FCM 500 mg FCM
status every 3–6 · If calculated dose exceeds 1,000 mg,
months after remaining dose above 1,000 mg is administered at week 6 If ID diagnosed in hospitalised
calculated dose of · Total dose: 0.5–2.0 g per patient patient after an episode of acute
IV iron‡ HF, the first dose should be
IV FDI dosing regimen in IRONMAN trial† administered prior to discharge
· IV FDI dose based on body weight and Hb level
Body weight
Hb (g/dL) <50 kg 50 to <70 kg ≥70 kg
<10 20 mg/kg FDI 20 mg/kg FDI 2,000 mg FDI
≥10 20 mg/kg FDI 1,000 mg/kg mg FDI 1,500 mg FDI
· Total dose: 20 mg iron/kg body weight

Figure 4. Practical considerations for the diagnosis and treatment of iron deficiency in patients with heart failure.13,31,45,61)
BNP = B-type natriuretic peptide; FCM = ferric carboxymaltose; FDI = ferric derisomaltose; Hb = haemoglobin; HF = heart failure; ID = iron deficiency; IV =
intravenous; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro-B-type natriuretic peptide; TSAT = transferrin saturation.
*AFFIRM-AHF only enrolled patients during hospitalisation for an acute HF episode31); in addition to enrolling those patients, IRONMAN also enrolled non-
hospitalised patients with elevated plasma NT-proBNP, elevated plasma BNP or with prior hospitalisation for HF within the last 6 months.45)
†
Note the 2021 European Society of Cardiology guidelines were updated prior to the availability of IRONMAN data, and so include a class IIa recommendation for
use of IV FCM in patients with symptomatic HF, LVEF ≤50% and ID that have been recently hospitalised for HF based on the results of the AFFIRM-HF trial, but
do not include FDI13); please refer to latest FCM and FDI Summary of Product Characteristics/Prescribing Information for approved indications and correct dosing.
‡
In IRONMAN following initial treatment of ID (defined as serum ferritin <100 ng/mL and/or TSAT <20%), FDI was readministered if serum ferritin was <100 ng/mL,
or ≤400 ng/mL when TSAT was <25% after 4 weeks and every 4 months with the aim of maintaining iron repletion between treatment visits45,53); please note that
IRONMAN uses a different definition of ID to the European Society of Cardiology and the Korean Society of Heart Failure Guidelines (serum ferritin values <100 ng/
mL, or 100–299 ng/mL accompanied by TSAT <20%).

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Iron Deficiency in HF: Korea-Oriented Review

rates and improving functional disease state, exercise capacity 5. Alcaide-Aldeano A, Garay A, Alcoberro L, et al. Iron deficiency: impact
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Piotr Ponikowski matory biomarkers in patients with acutely decompensated heart
https://orcid.org/0000-0002-3391-7064 failure: early in-hospital phase and 30-day follow-up. Eur J Heart Fail
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(London, UK), funded by Vifor Pharma Management Ltd. multi-ethnic Asian population with and without heart failure: preva-
lence, clinical correlates, functional significance and prognosis. Eur J
Conflict of Interest Heart Fail 2014;16:1125-32.
Jankowska EA has received research grants and personal fees from Vifor Pharma PUBMED | CROSSREF
(co-PI of the AFFIRM trial); and personal fees from Bayer, Novartis, Abbott, Boeh- 11. Park JJ, Yoon M, Cho HW, et al. Iron deficiency in Korean patients with
ringer Ingelheim, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cardiac Dimensions, heart failure. J Korean Med Sci 2023;38:e177.
Fresenius, Respicardia, Zoll, Sanofi, Takeda, and Gedeon Richter. Ponikowski P has PUBMED | CROSSREF
received research grants and personal fees from Vifor Pharma (PI of AFFIRM-AHF; 12. Parikh A, Natarajan S, Lipsitz SR, Katz SD. Iron deficiency in commu-
participation in clinical trials); and personal fees from Amgen, Bayer, Novartis, Abbott nity-dwelling US adults with self-reported heart failure in the National
Vascular, Boehringer Ingelheim, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, Health and Nutrition Examination Survey III: prevalence and associa-
BMS, Impulse Dynamics (participation in clinical trials). tions with anemia and inflammation. Circ Heart Fail 2011;4:599-606.
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