Why is iron deficiency important in heart failure and how can we assess it?

Iron is of fundamental importance for haemoglobin and myoglobin production and therefore oxygen transport and uptake. Intracellular iron is also vital for mitochondrial energy production and other metabolic pathways.8 9 For patients with heart failure, correction of iron deficits may increase haemoglobin and myoglobin production and improve metabolic function of mitochondrial-rich organs including cardiac and skeletal myocytes and the proximal renal tubule.

The mechanism and classification of iron deficiency is controversial. The WHO defines iron deficiency as a serum ferritin <15 µg/L, which is generally associated with low or absent bone marrow iron stores.10 Almost all such patients have a TSAT <20%.3 There are problems with using serum ferritin in the presence of chronic inflammatory diseases like heart failure. Activated inflammatory pathways increase ferritin synthesis, thereby increasing serum ferritin. Upregulated intracellular ferritin may trap iron reducing bioavailability. Inflammation can increase hepcidin, which impairs absorption of dietary iron and traps iron recycled by macrophages from senescent erythrocytes.11 Accordingly, many patients with low available iron for metabolic functions will have normal or raised serum ferritin.

Given that most iron transported in the blood is bound to transferrin, assessment of readily available markers such as TSAT and serum iron may be more useful for identifying iron deficiency and, more importantly, patients who benefit from iron supplementation. In heart failure, a TSAT <20% and/or a serum iron ≤13 µmol/L identify patients at higher risk of adverse outcome and those with more to gain from treatment with intravenous iron.3 12–14

Treating iron deficiency in heart failure: impact on symptoms and quality of life

While clinicians tend to focus on hospitalisations and death, many patients lay greater emphasis on symptoms and quality of life.15 In a placebo-controlled trial including 459 ambulatory patients with chronic heart failure and LVEF <45%, administration of intravenous ferric carboxymaltose (FCM) improved symptoms, quality of life and exercise capacity.16 Improvements in quality of life were seen within 4 weeks and persisted for at least 24 weeks. Benefit was observed whether or not patients had anaemia, defined by the authors as a haemoglobin of <120 g/L.

The CONFIRM-HF trial evaluated FCM versus placebo in 304 ambulatory patients with heart failure and LVEF <45%.17 For patients randomised to FCM, the 6 min walk test distance (6MWTd) was about 35 m longer at 24 and 52 weeks, which was associated with improved symptoms and quality of life. The effect tended to be greater in patients with haemoglobin <120 g/L. Improvement in exercise capacity might reflect a direct effect on skeletal muscle, as suggested by a small trial of ferric derisomaltose (FDI) showing augmentation in skeletal muscle energetics 2 weeks after a single infusion.18

The IRONOUT trial randomised 225 ambulatory patients with LVEF <40% to 150 mg two times per day oral iron polysaccharide versus placebo.19 There was no significant improvement in the primary endpoint, peak oxygen consumption at 16 weeks, in those treated with oral iron versus placebo (+23 mL/min vs −2 mL/min; difference, 21 mL/min (95% CI −34 to +76); p=0.46). However, many in the trial had TSAT >20% and may not have been iron deficient. Also, only when iron depletion exceeds 1000–2000 mg is it likely to be clinically apparent, a deficit that would take a long time to correct with oral iron. Oral iron is certainly ineffective in correcting iron deficiency in the shorter term and is not recommended by heart failure guidelines.5 20

While acknowledging further large-scale trial data were needed, these trials (table 1) influenced international guidelines. The 2021 European Society of Cardiology (ESC) heart failure guidelines gave class 1 (level C) recommendation to screen patients with heart failure for iron deficiency.5 Following publication of additional data (below), the ESC guidelines were updated in 2023, and intravenous iron was recommended (class I, level A) to reduce symptoms and improve quality of life for patients with heart failure and reduced or mildly reduced LVEF if iron deficient.5 20

Intravenous iron therapy in outcome trials in patients with heart failure

To date, three large trials have assessed the effect of intravenous iron versus placebo or standard care on hospitalisations and mortality in patients with heart failure (table 2). AFFIRM-AHF assessed intravenous FCM in 1108 patients hospitalised for heart failure, LVEF <50% and fulfilling the current definition of iron deficiency.21 Patients were randomised after stabilisation to a predischarge infusion of FCM (maximum 1000 mg) or placebo based on haemoglobin and patient weight. A second ‘repletion dose’ was delivered at week 6. Further doses could be given at weeks 12 and 24 if the patient remained iron deficient and haemoglobin was <150 g/L. No iron was given thereafter. Patients were followed for 52 weeks. The primary outcome, a composite of recurrent heart failure hospitalisation or cardiovascular mortality, favoured FCM (rate ratio (RR) 0.79; 95% CI 0.62 to 1.01; p=0.059). Total hospitalisations for heart failure for those treated with FCM were reduced (RR 0.74; 95% CI 0.58 to 0.94; p=0.013) without difference in risk of cardiovascular death. Because follow-up was affected by the COVID-19 pandemic, a sensitivity analysis was performed (shortening follow-up), which demonstrated benefit with FCM for the primary endpoint (RR 0.75; 95% CI 0.59 to 0.96, p=0.024). The trial also suggested that administration of iron improved well-being.22

IRONMAN23 differed from AFFIRM-AHF in several ways: it enrolled mainly ambulatory patients (86%) with LVEF ≤45%; iron deficiency was defined as TSAT <20% (provided ferritin <400 µg/L) or ferritin <100 µg/L; length of follow-up was longer (median 2.7 years); iron was given as FDI; patients were randomised open label with blinded endpoint adjudication. The dose of FDI was calculated according to weight and haemoglobin (maximum of 2000 mg per infusion). Further doses were given at 4 weeks, 4 months and then four monthly if ferritin was <100 µg/L or TSAT <25% (providing ferritin <400 µg/L). The primary endpoint in IRONMAN, recurrent heart failure hospitalisation and cardiovascular death was lower for patients assigned to FDI (RR 0.82; 95% CI 0.66 to 1.02; p=0.07). A large proportion of follow-up in IRONMAN was affected by the COVID-19 pandemic, in particular, for periods investigators were forbidden to have in-person research follow-up visits, preventing reassessment of iron status and redosing. Prespecified COVID-19 analysis of IRONMAN (including 1063 patients randomised by end of March 2020 with data censored on 30 September 2020) showed a reduction in the primary endpoint 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 versus control (p=0.016), and no excess of adverse events was seen with FDI.

A meta-analysis including AFFIRM-AHF, IRONMAN and eight smaller trials of intravenous iron showed reduction in the composite outcome of recurrent heart failure hospitalisation or cardiovascular mortality in those treated with intravenous iron compared with placebo/standard care (RR 0.75; 0.61–0.93; p<0.01).13 This effect was predominantly driven by reductions in heart failure hospitalisations rather than cardiovascular mortality, but favourable, although non-significant, trends were seen for the latter. In line with observational data demonstrating that low TSAT but not low ferritin identify those at highest risk 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 (RR 0.67; 0.49–0.92) as compared with patients with TSAT ≥20% (RR 0.99; 0.74–1.30).13 In contrast, serum ferritin did not predict benefit.

HEART-FID is the most recent, and largest (n=3065), trial in patients with heart failure.26 Patients, mainly in the USA and Europe, with LVEF ≤40%, were randomised to intravenous FCM or placebo. Although the primary endpoint was evaluated at 52 weeks, the mean follow-up for clinical events was 99 weeks. The primary outcome differed from AFFIRM-AHF and IRONMAN, being a hierarchical endpoint consisting of, in descending order of importance, all-cause mortality, heart failure hospitalisation (both within 12 months) or change in 6MWTd at 6 months. A p value <0.01 was required to achieve statistical significance as advised by the Food and Drug Administration for regulatory approval based on a single trial. There were numerically fewer deaths (n=131, 8.6% vs n=158, 10.3%) and hospitalisations for heart failure (n=297 vs n=332) within the first 12 months in the treatment group compared with placebo but no substantial effect on 6MWTd. This led to an overall effect that narrowly missed the predefined statistical threshold (p=0.02 rather than p<0.01). It is important to highlight that only around 40% of patients in HEART-FID had a TSAT <20%, compared with >75% in AFFIRM-AHF and IRONMAN. Intravenous iron is only likely to exert benefit if given to patients with iron deficiency.

Missed follow-up visits (greatly impacted by COVID-19) with resultant underdosing of intravenous iron in the treatment arms and out-of-protocol dosing of intravenous iron in placebo/standard care arms (17% in IRONMAN; 9% in HEART-FID) may have reduced the magnitude of benefit of intravenous iron in these trials.

An individual patient data meta-analysis including CONFIRM-HF, AFFIRM-AHF and HEART-FID showed greater reductions in cardiovascular hospitalisations and cardiovascular deaths for patients treated with intravenous iron when TSAT was <20% (RR 0.80; 0.67–0.95) as compared with those with TSAT ≥20% (RR 1.00; 0.81–1.23).27 This analysis also suggested a reduction in cardiovascular hospitalisations and mortality in those treated with intravenous iron versus placebo when TSAT was <15% and an excess when ≥24%, with a significant interaction across TSAT subgroups. Serum ferritin above or below 100 µg/L was unhelpful in identifying either response or harm. To help understand the influence of baseline TSAT on the benefit of intravenous iron on heart failure hospitalisation, Martens and colleagues performed a meta-regression analysis and showed that trials enrolling patients with lower TSAT (≤20%) had a more marked benefit with intravenous iron.14

Summary of data and current guidelines

The totality of evidence supports the benefits of high-dose intravenous iron (FCM or FDI) in patients with heart failure and a reduced LVEF, provided patients are iron deficient. These modern iron preparations have a good safety profile28 without the same risk of serious anaphylactoid-type reactions associated with older compounds. No instances of severe anaphylaxis were reported in any of the large heart failure trials.16 17 21 23 26 29

Updated ESC heart failure guidelines in 202320 suggest use of intravenous iron (FCM or FDI) to improve symptoms and quality of life and to reduce the risk of heart failure hospitalisation for patients with heart failure, iron deficiency and reduced or mildly reduced LVEF (class IIa, level A).

Implications for clinical practice

Patients with symptomatic heart failure (with reduced or mildly reduced LVEF) should have their iron status checked periodically. Although trials and guidelines have typically used ferritin <100 µg/L or TSAT <20% (when ferritin is 100–299 µg/L) as the definition for iron deficiency in heart failure, it is the authors’ opinion that this needs to be challenged. There is little evidence that patients with TSAT ≥20% benefit from intravenous iron, presumably because they are not iron deficient. In contrast, there is a wealth of data to suggest that patients with a TSAT <20% are likely to benefit.13 14 27 30 Recent data from IRONMAN further reinforce this: lower TSAT (especially when ferritin was >100 µg/L) and haemoglobin were associated with higher event rates and greater reduction in events with intravenous FDI.31 Furthermore, there may be concerns about the safety of giving intravenous iron when TSAT is ≥24%.30

Accordingly, the authors consider that treatment with intravenous iron should focus on patients with a TSAT <20%. This opinion has recently been echoed by several experts, including authors from major outcome trials of intravenous iron in heart failure.32 33 Patients with serum ferritin >400 µg/L were excluded from IRONMAN because of fear of causing iron overload, although there is no evidence to support such a risk when TSAT is <20%. TSAT is rarely <20% when ferritin is >300 µg/L: only 2% (n=88) in a large outpatient cohort of patients with confirmed heart failure (n=4422).3 Although those with markedly raised serum ferritin and TSAT <20% may be a high responder group, further data are required to allay fears about iron overload in these patients. It is the authors’ opinion that if patients with heart failure and TSAT <20% have ferritin >400 µg/L that reassessment of iron biomarkers be considered. If intravenous iron is contemplated, then discussion highlighting uncertainties of benefit and safety should be undertaken with patients to permit informed decision-making.

High-dose intravenous FCM and FDI can be given in a low-volume infusion. FDI, up to 20 mg/kg depending on haemoglobin concentration, can be given in a single infusion of 100 mL over 30 min.34 As such, many patients can receive total iron replacement with a single infusion.

Haemoglobin and iron status should be assessed routinely for hospitalised patients with heart failure and reduced or mildly reduced LVEF. Informed from data from AFFIRM-AHF21 and IRONMAN,23 intravenous iron should be considered prior to discharge if the patients are iron deficient and LVEF is <50%. Incorporating administration of intravenous iron into outpatient heart failure services presents a greater challenge for many centres, but it can be administered in day care wards or outpatients. Often renal or gastroenterology services have facilities to deliver intravenous iron for outpatients, which they may be willing to expand. Practical guidance on monitoring and treatment with intravenous iron in heart failure is presented in figure 1.

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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

While there is no excess risk of severe infections with intravenous iron in patients with heart failure,23 infusion should be avoided until active infection has been treated.

Trials have typically rechecked haemoglobin and iron biomarkers after 4–6 weeks. In clinical practice, this may be unrealistic, but repeat checks should be incorporated into routine care. An early recurrence of iron deficiency should alert the clinician to potential ongoing blood loss. The risk of gastrointestinal and urinary tract cancers increases with age and may cause blood loss and recurrent iron deficiency. Testing faeces and urine for blood is simple and inexpensive and should be considered.

What data are still required?

The current definition of iron deficiency in heart failure should be revised. Although traditional markers such as TSAT and haemoglobin concentration are not perfect, they identify those more likely to benefit from intravenous iron.30 A role for novel biomarkers, such as serum soluble transferrin receptor, should be explored,35 but may be expensive and not widely available. Serum iron might be a better marker of iron deficiency than TSAT but has not yet been reported in the clinical trials thus far.24

Guidelines recommend routine screening for iron deficiency in all patients with heart failure irrespective of LVEF although treatment is recommended only for those with a reduced LVEF.5 18 Iron deficiency is also common in patients with heart failure and a preserved LVEF.3 These patients, typically older and with more comorbidities, may be a good target for intravenous iron repletion to improve symptoms and quality of life, but currently data are lacking. This is being investigated in the FAIR-HF-PEF trial (NCT03075591). A larger outcome trial of intravenous iron may be warranted depending on the results.

Whether treatment with SGLT2 inhibitors influences the safety and efficacy of intravenous iron is unclear. Intravenous iron will often not normalise haemoglobin but combination with SGLT2 inhibitors may achieve this.36 SGLT2 inhibitors quickly increase haematocrit, almost certainly by causing a contraction of plasma volume. This is followed by a more gradual increase in haemoglobin likely reflecting improved erythropoiesis due to increases in erythropoietin and improved iron availability mediated by reductions in hepcidin, which may release iron trapped in ferritin stores and improve iron absorption.9 SGLT2i will not correct iron deficits quickly but may reduce the need for repeated intravenous iron dosing. Whether greater increases in haematocrit increase the risk of thromboembolic events is a concern, although no increase in cardiovascular events has been observed so far.37

Summary

Iron deficiency in heart failure is common, clinically important but underappreciated. Iron deficiency can be quickly corrected with intravenous FCM or FDI, which are safe, improve symptoms and quality of life and reduce cardiovascular hospitalisations. Clinical trials may have underestimated the true potential of intravenous iron therapy because they enrolled many who did not have iron deficiency due to its flawed definition. Patients with a TSAT <20%, particularly if anaemic (which most are), obtain more benefits from intravenous iron. We must now champion changes to clinical pathways to ensure that opportunities to deliver the benefits of intravenous iron to the right patients are not missed.