Review

Treating iron deficiency in patients with heart

Heart: first published as 10.1136/heartjnl-2022-322030 on 19 August 2024. Downloaded from http://heart.bmj.com/ on December 4, 2024 by guest. Protected by copyright.
failure: what, why, when, how, where and who
Fraser J Graham ‍ ‍,1 Kaushik Guha,2 John G Cleland ‍ ‍,1 Paul R Kalra ‍ ‍3,4
1
British Heart Foundation Centre ABSTRACT around three-­quarters of those hospitalised due to
of Research Excellence, School For patients with heart failure and reduced or heart failure.3 6 7 Fortunately, iron deficiency is so
of Cardiovascular & Metabolic
Health, University of Glasgow, mildly reduced left ventricular ejection fraction, iron common in this population that almost any defini-
Glasgow, UK deficiency is common and associated with more severe tion would include a large proportion of patients
2
Portsmouth Hospitals University symptoms, worse quality of life and an increased risk who actually are iron deficient.
NHS Trust, Portsmouth, UK of hospitalisations and death. Iron deficiency can be There is substantial evidence supporting the use
3
Cardiology, Portsmouth
swiftly, effectively and safely treated by administering of high-­dose intravenous iron to treat iron defi-
Hospitals University NHS Trust,
Portsmouth, UK intravenous iron, either as ferric carboxymaltose or ferric ciency in patients with heart failure and reduced
4
University of Glasgow Institute derisomaltose, which improves patient well-­being and LVEF to improve symptoms and quality of life and
of Health & Wellbeing, Glasgow, reduces the risk of hospitalisations including those for reduce the risk of cardiovascular hospitalisation.
UK heart failure. However, the current definition of iron In this article, we review current evidence, discuss
deficiency in heart failure has serious flaws. A serum which patients have most to gain from treatment,
Correspondence to
ferritin <100 µg/L does not identify patients more likely the challenges required to incorporate intravenous
Dr Fraser J Graham;
​fraser.​graham@g​ lasgow.​ac.u​ k to respond to intravenous iron. In contrast, patients with iron into routine clinical practice, and highlight
transferrin saturations <20%, most of whom are also remaining uncertainties.
Received 21 February 2024 anaemic, are more likely to have a beneficial response
Accepted 25 June 2024 to intravenous iron. In this review, we summarise the
Published Online First WHY IS IRON DEFICIENCY IMPORTANT IN
19 August 2024 available evidence for use of intravenous iron in heart
failure and provide recommendations for targeted future HEART FAILURE AND HOW CAN WE ASSESS IT?
research and practical considerations for the general Iron is of fundamental importance for haemo-
cardiologist. globin and myoglobin production and therefore
oxygen transport and uptake. Intracellular iron
is also vital for mitochondrial energy production
I keep six honest serving-­men and other metabolic pathways.8 9 For patients
(They taught me all I knew); with heart failure, correction of iron deficits may
Their names are What and Why and When and How increase haemoglobin and myoglobin production
and Where and Who.
and improve metabolic function of mitochondrial-­
- Rudyard Kipling rich organs including cardiac and skeletal myocytes
and the proximal renal tubule.
INTRODUCTION The mechanism and classification of iron defi-
Iron deficiency and anaemia, alone or in combi- ciency is controversial. The WHO defines iron
nation, are common in patients with heart failure deficiency as a serum ferritin <15 µg/L, which
and associated with increased risk of cardiovascular is generally associated with low or absent bone
hospitalisation and death.1–3 The WHO4 defines marrow iron stores.10 Almost all such patients have
anaemia as a haemoglobin <120 g/L for women a TSAT <20%.3 There are problems with using
and <130 g/L for men. Recent data suggest that serum ferritin in the presence of chronic inflamma-
even borderline anaemia (ie, 10 g/L above the tory diseases like heart failure. Activated inflamma-
WHO threshold) is associated with an increase in tory pathways increase ferritin synthesis, thereby
mortality for patients with cardiovascular disease2 increasing serum ferritin. Upregulated intracel-
and highlight the need to re-­evaluate historic labo- lular ferritin may trap iron reducing bioavailability.
ratory ‘normal’ ranges. Inflammation can increase hepcidin, which impairs
Challenges around the optimal definition of absorption of dietary iron and traps iron recycled
iron deficiency for patients with heart failure are by macrophages from senescent erythrocytes.11
complex. The current definition of iron deficiency Accordingly, many patients with low available iron
in international heart failure guidelines is a serum for metabolic functions will have normal or raised
ferritin of <100 µg/L, or 100–299 µg/L with a trans- serum ferritin.
ferrin saturation (TSAT) of <20%.5 This definition Given that most iron transported in the blood is
originates from recommendations for advanced bound to transferrin, assessment of readily avail-
© Author(s) (or their
employer(s)) 2024. Re-­use renal disease, introduced to help encourage use of able markers such as TSAT and serum iron may
permitted under CC BY-­NC. No intravenous iron to minimise use of erythropoiesis-­ be more useful for identifying iron deficiency and,
commercial re-­use. See rights stimulating agents. Although there is no good more importantly, patients who benefit from iron
and permissions. Published scientific foundation for this definition, it has supplementation. In heart failure, a TSAT <20%
by BMJ.
been integral to most trials of intravenous iron in and/or a serum iron ≤13 µmol/L identify patients
To cite: Graham FJ, Guha K, heart failure.5 By this definition, iron deficiency, at higher risk of adverse outcome and those with
Cleland JG, et al. Heart irrespective of left ventricular ejection fraction more to gain from treatment with intravenous
2024;110:1201–1207. (LVEF), affects more than half of outpatients and iron.3 12–14
Graham FJ, et al. Heart 2024;110:1201–1207. doi:10.1136/heartjnl-2022-322030   1201
 Review
TREATING IRON DEFICIENCY IN HEART FAILURE: IMPACT The IRONOUT trial randomised 225 ambulatory patients
ON SYMPTOMS AND QUALITY OF LIFE with LVEF <40% to 150 mg two times per day oral iron polysac-

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While clinicians tend to focus on hospitalisations and death, charide versus placebo.19 There was no significant improvement
many patients lay greater emphasis on symptoms and quality in the primary endpoint, peak oxygen consumption at 16 weeks,
of life.15 In a placebo-­controlled trial including 459 ambulatory in those treated with oral iron versus placebo (+23 mL/min vs
patients with chronic heart failure and LVEF <45%, adminis- −2 mL/min; difference, 21 mL/min (95% CI −34 to +76);
tration of intravenous ferric carboxymaltose (FCM) improved p=0.46). However, many in the trial had TSAT >20% and may
symptoms, quality of life and exercise capacity.16 Improvements not have been iron deficient. Also, only when iron depletion
in quality of life were seen within 4 weeks and persisted for at exceeds 1000–2000 mg is it likely to be clinically apparent, a
least 24 weeks. Benefit was observed whether or not patients had deficit that would take a long time to correct with oral iron.
anaemia, defined by the authors as a haemoglobin of <120 g/L. Oral iron is certainly ineffective in correcting iron deficiency in
The CONFIRM-­HF trial evaluated FCM versus placebo in the shorter term and is not recommended by heart failure guide-
304 ambulatory patients with heart failure and LVEF <45%.17 lines.5 20
For patients randomised to FCM, the 6 min walk test distance While acknowledging further large-­ scale trial data were
(6MWTd) was about 35 m longer at 24 and 52 weeks, which needed, these trials (table 1) influenced international guide-
was associated with improved symptoms and quality of life. lines. The 2021 European Society of Cardiology (ESC) heart
The effect tended to be greater in patients with haemoglobin failure guidelines gave class 1 (level C) recommendation to
<120 g/L. Improvement in exercise capacity might reflect a screen patients with heart failure for iron deficiency.5 Following
direct effect on skeletal muscle, as suggested by a small trial of publication of additional data (below), the ESC guidelines were
ferric derisomaltose (FDI) showing augmentation in skeletal updated in 2023, and intravenous iron was recommended (class
muscle energetics 2 weeks after a single infusion.18 I, level A) to reduce symptoms and improve quality of life for

Table 1 Trials of iron therapy and the effects on symptoms, quality of life and exercise capacity
FAIR-­HF CONFIRM-­HF EFFECT-­HF IRONOUT-­HF
Year 2009 2015 2017 2017
Country 11 countries 9 countries 9 countries USA; 23 sites
(top 3 recruiting countries) (Russia, Ukraine, Poland) (Russia, Ukraine, Poland) (NR)
Patients, n 459 304 174 225
Definition of ID Ferritin <100 µg/L or Ferritin <100 µg/L or Ferritin <100 µg/L or 100– Ferritin 15–100 µg/L or ferritin
ferritin 100–300 µg/L if TSAT<20% ferritin 100–300 µg/L if TSAT<20% 300 µg/L if TSAT<20% 101–299 µg/L if TSAT<20%
Inclusion criteria ► NYHA II/III ► LVEF≤45% ► LVEF≤45% ► LVEF<40%
► LVEF≤40% (NYHA II) ► BNP≥100 ng/L ► NYHA II–IV ► NYHA II–IV
► LVEF≤45% (NYHA III) ► NT-­proBNP>400 ng/L ► BNP>100 ng/L ► Haemoglobin
► Hb 90–135 g/L ► NT-­proBNP>400 ng/L – Men 90–150 g/L
– Women 90–135 g/L
Age (mean, years) 68±10 69±10 63±12 63 (54–71)
Women 255 (55%) 141 (47%) 43 (25%) 81 (36%)
Form of iron therapy and Intravenous FCM (200 mg) weekly Intravenous FCM (500−1000 Intravenous FCM 500–1000 mg. Oral iron polysaccharide 150 mg
dosing regimen until iron replete (calculated by mg as single dose at day 0 with Initial doses (day 0 and day 6) two times per day.
Ganzoni formula)±further doses at further dosing at week 6 based on based on Ganzoni formula.
weeks 8 and 12 depending on initial screening Hb) with redosing (500 Redosing at week 12 if iron
iron repletion dose. mg) at weeks 12, 24 and 36 weeks deficient.
if iron deficient.
Median total dose 1500 mg.
Blind/placebo Yes/yes Yes/yes Yes/yes Yes/yes
Follow-­up 24 24 for primary EP 24 16
(weeks) 52 for safety and other analyses
TSAT (%) (mean±SD if 17.7±12.6 20.2±17.6 17.3 18 (15–22)
available)
Primary endpoint Self-­reported PGA and NYHA class Mean difference in change Change in peak oxygen uptake Change in peak oxygen uptake
between groups in 6MWTd at 24 (VO2) at 24 weeks from baseline (VO2) at 16 weeks
weeks
Primary outcome Improvement in PGA, NYHA (both Improvement in 6MWTd Improvement in peak VO2 No difference in peak VO2 between
p<0.001 for being in better rank/ difference FCM versus placebo: between groups; difference of groups: 21mL/min (−34 to 76 mL/
improving in class). 33±11 m (p=0.002). square means: 1.04±0.44 mL/kg/ min); p=0.46.
Sustained at week 52. min; p=0.02.
Secondary outcome Improvement in 6MWTd Benefit in PGA from week 12 Improvement in NYHA from week No difference in change in 6MWTd
difference FCM versus placebo at (p=0.035). 6 onwards (p<0.05). between groups: −13 m (−32 to
weeks 4, 12 and 24 (all p<0.001). Reduction in HHF at week 52: OR Improvement in PGA at 12 weeks −6 m); p=0.19.
0.39 (0.19–0.82); p=0.009. onwards (p<0.05).
Data presented as mean±SD or median (IQR) as available and categorical as number (%). Laboratory results for the treatment group used if whole population not available.
BNP, B-­type natriuretic peptide; EP, endpoint; FCM, ferric carboxymaltose; Hb, haemoglobin; HHF, hospitalisation for heart failure; ID, iron deficiency; LVEF, left ventricular ejection
fraction; 6MWTd, 6 min walk test distance; NR, not reported; NT-­proBNP, N-­terminal pro brain natriuretic peptide; NYHA, New York Heart Association; PGA, patient global
assessment; TSAT, transferrin saturation; VO2, peak myocardial oxygen demand.

1202 Graham FJ, et al. Heart 2024;110:1201–1207. doi:10.1136/heartjnl-2022-322030

 Review

Table 2 Outcome trials of intravenous iron in patients with heart failure

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AFFIRM-­AHF IRONMAN HEART-­FID
Year 2020 2022 2023
Country 15 countries; international UK 14 countries; international
(top 3 recruiting countries) (Georgia, Ukraine, Romania) (North America, EU, Russia/Ukraine)
Patients, n 1108 (1:1 FCM vs placebo) 1137 (1:1 FDI vs SoC) 3065 (1:1 FCM vs placebo)
Definition of ID Ferritin<100 µg/L or TSAT<20%+ferritin<400 µg/L or Ferritin<100 µg/L or
100–299 µg/L if TSAT<20% ferritin<100 µg/L 100–300 µg/L if TSAT<20%
Inclusion criteria ► LVEF<50% ► LVEF≤45% ► LVEF≤40%
► HF hospitalisation ► Current or recent (<6 m) HF hospitalisation ► Hb
► NT-­proBNP ≥1600 pg/mL (SR) or or NT-­proBNP>250 pg/mL (SR) or >1000 pg/ – Women 90–135 g/L
≥2400 pg/mL (AF) mL (AF) – Men 90–150 g/L
► ≥40 mg intravenous furosemide ► Hb ► HF hospitalisation (<12 m) or NT-­
► Hb 80–150 g/L – Women 90–130 g/L proBNP>600 pg/mL (SR) or >1000 pg/mL (AF)
– Men 90–140 g/L
Age (years) 71±11 73 (67–80) 69±11
Women 494 (45%) 300 (26%) 1037 (34%)
Form of iron therapy; dose (mean Intravenous FCM; 1352 mg Intravenous FDI; 1978 mg Intravenous FCM; 2317 mg
dosage)
Follow-­up (years) 1* 2.7 (1.8–3.6) 1.9 (1.3–3.0)
Blind/placebo Yes/yes Open label versus standard care (blinded Yes/yes
endpoint adjudication)
Primary endpoint Composite of total HF hospitalisations Composite of recurrent HF hospitalisations and Hierarchical composite of death within 12 months,
and CV death CV death HF hospitalisation within 12 months or change in
6MWTd at 6 months (predefined significance level
of p=0.01)
TSAT (%) 15±8 15 (11–20) 24±11
TSAT<20% 83% 76% ~40%
Primary outcome ► Primary EP: RR 0.79 (0.62–1.01); ► Primary EP: RR 0.82 (0.66–1.02); p=0.07 ► Primary EP: HR 1.10 (0.99–1.23); p=0.02†
p=0.059
Secondary analyses ► Total HF hospitalisation: RR 0.74 ► Fewer cardiac SAEs in FDI group versus SoC ► First HF hospitalisation or CV death: 0.93
(0.58–0.94); p=0.013 (p=0.016) (0.81–1.06)
COVID-­19 sensitivity analysis ► Primary outcome COVID-­19 ► Primary outcome COVID-­19 sensitivity ► Not done
sensitivity analysis: RR 0.75 (0.59– analysis: RR 0.76 (0.58–1.00); p=0.047
0.96); p=0.024
Data presented as mean±SD or median (IQR) as available. Laboratory results for the treatment group used if whole population not available.
*Maximum follow-­up, no mean or median follow-­up provided.
†P<0.01 was prespecified level for significance.
AF, atrial fibrillation; CV, cardiovascular; EP, endpoint; EU, European Union; FCM, ferric carboxymaltose; FDI, ferric derisomaltose; Hb, haemoglobin; HF, heart failure; ID, iron
deficiency; LVEF, left ventricular ejection fraction; 6MWTd, 6 min walk test distance; NT-­proBNP, N-­terminal pro brain natriuretic peptide; RR, rate ratio; SAEs, serious adverse
events; SoC, standard of care; SR, sinus rhythm; TSAT, transferrin saturation.

patients with heart failure and reduced or mildly reduced LVEF cardiovascular death. Because follow-­ up was affected by the
if iron deficient.5 20 COVID-­ 19 pandemic, a sensitivity analysis was performed
(shortening follow-­up), which demonstrated benefit with FCM
INTRAVENOUS IRON THERAPY IN OUTCOME TRIALS IN for the primary endpoint (RR 0.75; 95% CI 0.59 to 0.96,
PATIENTS WITH HEART FAILURE p=0.024). The trial also suggested that administration of iron
To date, three large trials have assessed the effect of intravenous improved well-­being.22
iron versus placebo or standard care on hospitalisations and IRONMAN23 differed from AFFIRM-­AHF in several ways: it
mortality in patients with heart failure (table 2). AFFIRM-­AHF enrolled mainly ambulatory patients (86%) with LVEF ≤45%;
assessed intravenous FCM in 1108 patients hospitalised for iron deficiency was defined as TSAT <20% (provided ferritin
heart failure, LVEF <50% and fulfilling the current definition <400 µg/L) or ferritin <100 µg/L; length of follow-­ up was
of iron deficiency.21 Patients were randomised after stabilisa- longer (median 2.7 years); iron was given as FDI; patients were
tion to a predischarge infusion of FCM (maximum 1000 mg) randomised open label with blinded endpoint adjudication. The
or placebo based on haemoglobin and patient weight. A second dose of FDI was calculated according to weight and haemo-
‘repletion dose’ was delivered at week 6. Further doses could be globin (maximum of 2000 mg per infusion). Further doses were
given at weeks 12 and 24 if the patient remained iron deficient given at 4 weeks, 4 months and then four monthly if ferritin
and haemoglobin was <150 g/L. No iron was given thereafter. was <100 µg/L or TSAT <25% (providing ferritin <400 µg/L).
Patients were followed for 52 weeks. The primary outcome, a The primary endpoint in IRONMAN, recurrent heart failure
composite of recurrent heart failure hospitalisation or cardio- hospitalisation and cardiovascular death was lower for patients
vascular mortality, favoured FCM (rate ratio (RR) 0.79; 95% assigned to FDI (RR 0.82; 95% CI 0.66 to 1.02; p=0.07). A
CI 0.62 to 1.01; p=0.059). Total hospitalisations for heart large proportion of follow-­up in IRONMAN was affected by
failure for those treated with FCM were reduced (RR 0.74; the COVID-­19 pandemic, in particular, for periods investiga-
95% CI 0.58 to 0.94; p=0.013) without difference in risk of tors were forbidden to have in-­person research follow-­up visits,
Graham FJ, et al. Heart 2024;110:1201–1207. doi:10.1136/heartjnl-2022-322030 1203
 Review
preventing reassessment of iron status and redosing. Prespeci- of intravenous iron on heart failure hospitalisation, Martens and
fied COVID-­19 analysis of IRONMAN (including 1063 patients colleagues performed a meta-­ regression analysis and showed

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randomised by end of March 2020 with data censored on 30 that trials enrolling patients with lower TSAT (≤20%) had a
September 2020) showed a reduction in the primary endpoint more marked benefit with intravenous iron.14
with FDI (RR 0.76; 95% CI 0.58 to 1.00; p=0.047). There
were fewer serious adverse cardiac events in the treatment group
SUMMARY OF DATA AND CURRENT GUIDELINES
versus control (p=0.016), and no excess of adverse events was
The totality of evidence supports the benefits of high-­dose intra-
seen with FDI.
venous iron (FCM or FDI) in patients with heart failure and
A meta-­ analysis including AFFIRM-­ AHF, IRONMAN and
a reduced LVEF, provided patients are iron deficient. These
eight smaller trials of intravenous iron showed reduction in the
modern iron preparations have a good safety profile28 without
composite outcome of recurrent heart failure hospitalisation or
the same risk of serious anaphylactoid-­type reactions associated
cardiovascular mortality in those treated with intravenous iron
with older compounds. No instances of severe anaphylaxis were
compared with placebo/standard care (RR 0.75; 0.61–0.93;
reported in any of the large heart failure trials.16 17 21 23 26 29
p<0.01).13 This effect was predominantly driven by reduc-
Updated ESC heart failure guidelines in 202320 suggest use
tions in heart failure hospitalisations rather than cardiovascular
of intravenous iron (FCM or FDI) to improve symptoms and
mortality, but favourable, although non-­significant, trends were
quality of life and to reduce the risk of heart failure hospitalisa-
seen for the latter. In line with observational data demonstrating
tion for patients with heart failure, iron deficiency and reduced
that low TSAT but not low ferritin identify those at highest risk
or mildly reduced LVEF (class IIa, level A).
of death,3 12 24 25 patients with a TSAT <20% obtained more
benefits from intravenous iron with respect to the endpoint of
recurrent heart failure hospitalisation and cardiovascular death IMPLICATIONS FOR CLINICAL PRACTICE
(RR 0.67; 0.49–0.92) as compared with patients with TSAT Patients with symptomatic heart failure (with reduced or mildly
≥20% (RR 0.99; 0.74–1.30).13 In contrast, serum ferritin did reduced LVEF) should have their iron status checked periodi-
not predict benefit. cally. Although trials and guidelines have typically used ferritin
HEART-­FID is the most recent, and largest (n=3065), trial <100 µg/L or TSAT <20% (when ferritin is 100–299 µg/L)
in patients with heart failure.26 Patients, mainly in the USA and as the definition for iron deficiency in heart failure, it is the
Europe, with LVEF ≤40%, were randomised to intravenous authors’ opinion that this needs to be challenged. There is little
FCM or placebo. Although the primary endpoint was evalu- evidence that patients with TSAT ≥20% benefit from intrave-
ated at 52 weeks, the mean follow-­up for clinical events was nous iron, presumably because they are not iron deficient. In
99 weeks. The primary outcome differed from AFFIRM-­AHF contrast, there is a wealth of data to suggest that patients with
and IRONMAN, being a hierarchical endpoint consisting of, in a TSAT <20% are likely to benefit.13 14 27 30 Recent data from
descending order of importance, all-­cause mortality, heart failure IRONMAN further reinforce this: lower TSAT (especially when
hospitalisation (both within 12 months) or change in 6MWTd ferritin was >100 µg/L) and haemoglobin were associated with
at 6 months. A p value <0.01 was required to achieve statis- higher event rates and greater reduction in events with intra-
tical significance as advised by the Food and Drug Administra- venous FDI.31 Furthermore, there may be concerns about the
tion for regulatory approval based on a single trial. There were safety of giving intravenous iron when TSAT is ≥24%.30
numerically fewer deaths (n=131, 8.6% vs n=158, 10.3%) and Accordingly, the authors consider that treatment with intra-
hospitalisations for heart failure (n=297 vs n=332) within the venous iron should focus on patients with a TSAT <20%. This
first 12 months in the treatment group compared with placebo opinion has recently been echoed by several experts, including
but no substantial effect on 6MWTd. This led to an overall authors from major outcome trials of intravenous iron in
effect that narrowly missed the predefined statistical threshold heart failure.32 33 Patients with serum ferritin >400 µg/L were
(p=0.02 rather than p<0.01). It is important to highlight that excluded from IRONMAN because of fear of causing iron
only around 40% of patients in HEART-­FID had a TSAT <20%, overload, although there is no evidence to support such a risk
compared with >75% in AFFIRM-­AHF and IRONMAN. Intra- when TSAT is <20%. TSAT is rarely <20% when ferritin is
venous iron is only likely to exert benefit if given to patients with >300 µg/L: only 2% (n=88) in a large outpatient cohort of
iron deficiency. patients with confirmed heart failure (n=4422).3 Although those
Missed follow-­up visits (greatly impacted by COVID-­19) with with markedly raised serum ferritin and TSAT <20% may be a
resultant underdosing of intravenous iron in the treatment arms high responder group, further data are required to allay fears
and out-­of-­protocol dosing of intravenous iron in placebo/stan- about iron overload in these patients. It is the authors’ opinion
dard care arms (17% in IRONMAN; 9% in HEART-­FID) may that if patients with heart failure and TSAT <20% have ferritin
have reduced the magnitude of benefit of intravenous iron in >400 µg/L that reassessment of iron biomarkers be considered.
these trials. If intravenous iron is contemplated, then discussion highlighting
An individual patient data meta-­ analysis including uncertainties of benefit and safety should be undertaken with
CONFIRM-­HF, AFFIRM-­AHF and HEART-­FID showed greater patients to permit informed decision-­making.
reductions in cardiovascular hospitalisations and cardiovascular High-­dose intravenous FCM and FDI can be given in a low-­
deaths for patients treated with intravenous iron when TSAT was volume infusion. FDI, up to 20 mg/kg depending on haemo-
<20% (RR 0.80; 0.67–0.95) as compared with those with TSAT globin concentration, can be given in a single infusion of 100
≥20% (RR 1.00; 0.81–1.23).27 This analysis also suggested a mL over 30 min.34 As such, many patients can receive total iron
reduction in cardiovascular hospitalisations and mortality in replacement with a single infusion.
those treated with intravenous iron versus placebo when TSAT Haemoglobin and iron status should be assessed routinely for
was <15% and an excess when ≥24%, with a significant inter- hospitalised patients with heart failure and reduced or mildly
action across TSAT subgroups. Serum ferritin above or below reduced LVEF. Informed from data from AFFIRM-­AHF21 and
100 µg/L was unhelpful in identifying either response or harm. IRONMAN,23 intravenous iron should be considered prior to
To help understand the influence of baseline TSAT on the benefit discharge if the patients are iron deficient and LVEF is <50%.
1204 Graham FJ, et al. Heart 2024;110:1201–1207. doi:10.1136/heartjnl-2022-322030
 Review

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Figure 1 Stepwise guidance on how to assess, diagnose, manage and monitor patients with heart failure and iron deficiency. Abbreviations:- HF:
heart failure; HFrEF: heart failure with reduced ejection fraction; HFmrEF: heart failure with mildly reduced ejection; TSAT: transferrin saturation; IV:
intravenous; Hb: haemoglobin; FCM: ferric carboxymaltose; FDI: ferric derisomaltose; GI: gastrointestinal; wks: weeks. *Single dose range for each
preparation of intravenous iron. The iron need estimation can be performed using a Simplified Table (that uses patients weight and haemoglobin)
for FCM or FDI from their respective Summary of Product Characteristics, or Ganzoni formula for FDI. For FCM the maximum single dose infusion is
1,000 mg and for FDI it is 20 mg/kg without upper limit. In practice, it is common to see 500 mg intervals used since this tracks with the respective
Simplified Tables, and there are 500 mg and 1,000 mg vials.38 39

Incorporating administration of intravenous iron into outpa- WHAT DATA ARE STILL REQUIRED?
tient heart failure services presents a greater challenge for many The current definition of iron deficiency in heart failure should
centres, but it can be administered in day care wards or outpa- be revised. Although traditional markers such as TSAT and
tients. Often renal or gastroenterology services have facilities haemoglobin concentration are not perfect, they identify those
to deliver intravenous iron for outpatients, which they may more likely to benefit from intravenous iron.30 A role for novel
be willing to expand. Practical guidance on monitoring and biomarkers, such as serum soluble transferrin receptor, should
treatment with intravenous iron in heart failure is presented in be explored,35 but may be expensive and not widely available.
figure 1. Serum iron might be a better marker of iron deficiency than
While there is no excess risk of severe infections with intra- TSAT but has not yet been reported in the clinical trials thus
venous iron in patients with heart failure,23 infusion should be far.24
avoided until active infection has been treated. Guidelines recommend routine screening for iron deficiency
Trials have typically rechecked haemoglobin and iron in all patients with heart failure irrespective of LVEF although
biomarkers after 4–6 weeks. In clinical practice, this may be treatment is recommended only for those with a reduced
unrealistic, but repeat checks should be incorporated into LVEF.5 18 Iron deficiency is also common in patients with heart
routine care. An early recurrence of iron deficiency should alert failure and a preserved LVEF.3 These patients, typically older
the clinician to potential ongoing blood loss. The risk of gastro- and with more comorbidities, may be a good target for intra-
intestinal and urinary tract cancers increases with age and may venous iron repletion to improve symptoms and quality of life,
cause blood loss and recurrent iron deficiency. Testing faeces but currently data are lacking. This is being investigated in the
and urine for blood is simple and inexpensive and should be FAIR-­HF-­PEF trial (NCT03075591). A larger outcome trial of
considered. intravenous iron may be warranted depending on the results.
Graham FJ, et al. Heart 2024;110:1201–1207. doi:10.1136/heartjnl-2022-322030 1205
 Review
Whether treatment with SGLT2 inhibitors influences the REFERENCES
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Heart: first published as 10.1136/heartjnl-2022-322030 on 19 August 2024. Downloaded from http://heart.bmj.com/ on December 4, 2024 by guest. Protected by copyright.
iron will often not normalise haemoglobin but combination with following a hospitalization for acute heart failure. Eur J Heart Fail 2016;18:798–802.
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repeated intravenous iron dosing. Whether greater increases the diagnosis and treatment of acute and chronic heart failure: developed by the
in haematocrit increase the risk of thromboembolic events is a task force for the diagnosis and treatment of acute and chronic heart failure of the
concern, although no increase in cardiovascular events has been European society of cardiology (ESC) with the special contribution of the heart failure
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12 Grote Beverborg N, Klip IjT, Meijers WC, et al. Definition of iron deficiency based on
obtain more benefits from intravenous iron. We must now cham- the gold standard of bone marrow iron staining in heart failure patients. Circ Heart
pion changes to clinical pathways to ensure that opportunities to Fail 2018;11.
deliver the benefits of intravenous iron to the right patients are 13 Graham FJ, Pellicori P, Kalra PR, et al. Intravenous iron in patients with heart failure
not missed. and iron deficiency: an updated meta-­analysis. Eur J Heart Fail 2023;25:528–37.
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treatment effect of intravenous iron in iron-­deficient heart failure. JACC Heart Fail
Correction notice This article has been corrected since it was first published.
2024;12:525–36.
Haemoglobin is now expressed in g/L in all instances. Additionally, the open access
licence type was changed to CC BY-­NC. 23rd September 2024. 15 Cleland JGF. Nature and magnitude of the benefits of dapagliflozin and empagliflozin
for heart failure. Circulation 2024;149:839–42.
X Fraser J Graham @FJ_Graham 16 Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with
Contributors Manuscript concept and design: PRK, FJG, KG. Manuscript writing: heart failure and iron deficiency. N Engl J Med 2009;361:2436–48.
FJG, KG, PRK, JGC. Critical revision of manuscript for intellectual content: JGC, PRK. 17 Ponikowski P, van Veldhuisen DJ, Comin-­Colet J, et al. Beneficial effects of long-­term
All authors approved the final version and are accountable for the integrity of the intravenous iron therapy with ferric carboxymaltose in patients with symptomatic
work. heart failure and iron deficiency. Eur Heart J 2015;36:657–68.
18 Charles-­Edwards G, Amaral N, Sleigh A, et al. Effect of iron isomaltoside on skeletal
Funding JGC is supported by the British Heart Foundation Centre of Research muscle energetics in patients with chronic heart failure and iron deficiency. Circulation
Excellence (RE/18/6134217). FJG and JGC have been awarded a project grant from
2019;139:2386–98.
the British Heart Foundation to assess the prevalence of iron deficiency in patients
19 Lewis GD, Malhotra R, Hernandez AF, et al. Effect of Oral Iron Repletion on Exercise
undergoing elective cardiac surgery (PG/2019/35089). PRK reports research grants
Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron
from the British Heart Foundation and Pharmacosmos.
Deficiency: the IRONOUT HF Randomized Clinical Trial. JAMA 2017;317:1958–66.
Competing interests FJG reports receipt of sponsorship from Pharmacosmos to 20 McDonagh TA, Metra M, Adamo M, et al. Focused Update of the 2021 ESC
attend an international meeting and consultancy fees from Vifor. KG has received Guidelines for the diagnosis and treatment of acute and chronic heart failure:
honoraria from Novartis, AstraZeneca, Pfizer, Bayer, Boehringer Ingelheim and developed by the task force for the diagnosis and treatment of acute and
Servier Laboratories. JGC reports receipt of personal honoraria for lectures and chronic heart failure of the European Society of Cardiology (ESC) With the
advisory boards from Pharmacosmos and Vifor, and from AstraZeneca, Amgen, Bayer, special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J
Novartis and Servier. The University of Glasgow has received research grants from 2023;44:3627–39.
Pharmacosmos and Vifor. PRK reports consulting fees from Amgen, Bayer, Boehringer 21 Ponikowski P, Kirwan B-­A, Anker SD, et al. Ferric carboxymaltose for iron deficiency at
Ingelheim, Pharmacosmos and CSL Vifor; payment for lectures from AstraZeneca, discharge after acute heart failure: a multicentre, double-­blind, randomised, controlled
Bayer, Novartis, Pfizer, Pharmacosmos and CSL Vifor; and support for attending trial. The Lancet 2020;396:1895–904.
meetings from Pharmacosmos. 22 Filippatos G, Ponikowski P, Farmakis D, et al. Association between hemoglobin
Patient consent for publication Not applicable. levels and efficacy of intravenous ferric carboxymaltose in patients with acute
heart failure and iron deficiency: an AFFIRM-­AHF subgroup analysis. Circulation
Ethics approval Not applicable.
2023;147:1640–53.
Provenance and peer review Commissioned; externally peer reviewed. 23 Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisomaltose in patients
Open access This is an open access article distributed in accordance with the with heart failure and iron deficiency in the UK (IRONMAN): an investigator-­
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which initiated, prospective, randomised, open-­label, blinded-­endpoint trial. The Lancet
permits others to distribute, remix, adapt, build upon this work non-­commercially, 2022;400:2199–209.
and license their derivative works on different terms, provided the original work is 24 Graham FJ, Pellicori P, Masini G, et al. Influence of serum transferrin concentration
properly cited, appropriate credit is given, any changes made indicated, and the use on diagnostic criteria for iron deficiency in chronic heart failure. ESC Heart Fail
is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 2023;10:2826–36.
25 Graham FJ, Masini G, Pellicori P, et al. Natural history and prognostic significance of
ORCID iDs iron deficiency and anaemia in ambulatory patients with chronic heart failure. Eur J
Fraser J Graham http://orcid.org/0000-0001-7539-9958 Heart Fail 2022;24:807–17.
John G Cleland http://orcid.org/0000-0002-1471-7016 26 Mentz RJ, Garg J, Rockhold FW, et al. Ferric carboxymaltose in heart failure with iron
Paul R Kalra http://orcid.org/0000-0002-5288-3074 deficiency. N Engl J Med 2023;389:975–86.

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27 Ponikowski P, Mentz RJ, Hernandez AF, et al. Efficacy of ferric carboxymaltose in heart 34 Ferric derisomaltose pharmacosmos 100 mg/ml solution for injection/infusion -
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