Iron deficiency: a comorbidity that goes unnoticed in heart failure
Iron deficiency (ID) is an important comorbidity in patients with heart failure (HF). However, since symptoms related to ID are not specific, only assessment of biological iron parameters allows its diagnosis. Either absolute or functional, ID is an independent predictor of outcomes and a major contributor to exercise intolerance, even in the absence of anaemia .
Studies have reported a high prevalence of ID in HF. In a cohort of 1,506 patients with chronic HF, the prevalence of ID was reported to be 50% (and 45.6% in patients without anaemia) . A more recent study reported an ID prevalence of 37% in 546 HF patients (and 32% in patients without anaemia) . In patients hospitalised for decompensation of chronic HF  and in patients with advanced HF , the rates were even higher.
Aetiology of ID in HF
Causes of ID in HF include gastrointestinal or genitourinary blood loss related to the use of antiplatelet drugs and/or oral anticoagulation, impaired nutrition, malabsorption (due to congestion and abnormal production of hepcidin ), and reduced intracellular uptake of iron (due to reduced transferrin receptor-1 (TfR1) expression in cardiomyocytes ).
How should ID be diagnosed?
Standard laboratory cut-off values should not be used to diagnose ID. In general, the normal range of serum ferritin is defined as 30-300 mg/L, and a value <30 mg/L defines ID. However, serum ferritin is increased in conditions accompanied by inflammation or oxidative stress, including chronic HF [7,8], as well as the acute clinical settings (acute HF) . Furthermore, catabolism and malnutrition may lower serum transferrin disproportionately to serum iron, leading to pseudo-transferrin saturation (TSAT) elevations .
Although the gold standard method to identify ID is bone marrow aspiration and specific staining of iron, it is limited by its invasive nature, cost and need for expertise. In the 2016 ESC guidelines for the diagnosis and treatment of HF , systematic measurement of iron parameters (serum ferritin and TSAT) is recommended in all patients suspected of having HF, as well as in the follow-up visits of HF patients. In these guidelines ID is defined as follows: 1) serum ferritin <100 mg/L (absolute iron deficiency), and 2) serum ferritin 100–299 mg/L and TSAT <20% (functional iron deficiency). The combination of ferritin and soluble TfR has been proposed to be the most accurate method to evaluate ID non-invasively , using the transferrin receptor-ferritin index (serum TfR/log ferritin).
Consequences of ID in HF
Iron is an essential component of haematopoiesis, as part of the haemprotein haemoglobin. In addition, it is an essential co-factor for the other haemprotein, myoglobin, for oxygen storage, and non-haemproteins involved in cellular activities such as cardiac muscle metabolism (as part of oxidative enzymes and mitochondrial respiratory chain proteins). It also functions as a co-factor of soluble guanylate cyclase, which is the downstream target of nitric oxide and other nitrovasodilators in vascular smooth muscle, and a transcription factor for signalling pathways involving neurotransmission, innate immunity, cell growth, and inflammation .
Iron deficiency is associated with HF disease severity, reflected in NYHA functional class and NT-proBNP levels . It has also been reported to be an independent predictor of all-cause and cardiovascular mortality [1,12].
Oral iron therapy in HF
Oral iron salts are frequently used for iron replacement therapy due to their relative low cost and ease of administration. However, gastrointestinal side effects are common and may lead to poor compliance. Another disadvantage is that their absorption from the gastrointestinal tract may be limited by many foods and medications, and oedema of the intestinal mucosa due to systemic venous congestion in HF patients . Last but not least, upregulation of hepcidin in HF reduces dietary iron absorption .
In a recently reported retrospective study of 105 HF patients with reduced ejection fraction (EF), significant increases in markers of iron stores were observed with oral iron supplementation . The Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial is underway to investigate oral iron polysaccharide (150 mg twice daily) compared with placebo with the primary endpoint of change in exercise capacity as measured by peak oxygen consumption (pVO2) at baseline and at 16 weeks in systolic HF subjects with and without anaemia and functional ID .
Intravenous iron therapy in HF
Various intravenous (IV) iron complexes, such as ferric carboxymaltose (FCM), ferric hydroxide sucrose, ferric gluconate, and ferric hydroxide dextran are available. There are limited comparative data for the available IV iron preparations . Ferric hydroxide sucrose and ferric gluconate are FDA-approved for use in dialysis populations, whereas FCM is FDA-approved for non-dialysis chronic kidney disease populations. The recommended dose for FCM (750 mg) is higher than that for ferric sucrose (100-400 mg) or ferric gluconate (125 mg), so fewer injections of FCM are needed to replenish iron stores. Advantages of IV iron therapy include the small number of injections required, rapid improvement in iron parameters , and the cost-effectiveness, probably due to improved QoL and reduced HF hospitalisations .
A meta-analysis of five trials, which included 509 patients who received IV iron therapy and 342 controls, examining the effects of IV iron therapy in ID patients with systolic HF, demonstrated a significant reduction in the risk of the combined endpoint of all-cause death or cardiovascular hospitalisation, and the combined endpoint of cardiovascular death or hospitalisation for worsening HF in ambulatory patient populations . IV iron therapy resulted in a significant reduction in NYHA class, an increase in the six-minute walking test (6MWT) distance, and an improvement in QoL 
Another meta-analysis, including a total of 907 patients from five clinical trials, showed that IV iron therapy significantly reduced the rate of hospitalisations for HF . However, most data in the meta-analysis came from the two larger trials: A Study to Compare the Use of Ferric Carboxymaltose With Placebo in Patients With Chronic Heart Failure and Iron Deficiency (CONFIRM-HF) (n=301)  and Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) (n=459) .
Intravenous iron replacement with FCM
The CONFIRM-HF trial  included 301 patients (251 completed the trial) with moderate HF symptoms (NYHA Class II-III), left ventricular EF (LVEF) ≤45%, increased levels of BNP >100 pg/mL and/or NT-proBNP >400 pg/mL, and ID. IV iron was given as an FCM solution equivalent to 500 or 1,000 mg of iron. At week 24, the 6MWT distance improved significantly more in the FCM group and the benefit was maintained up to 52 weeks . Fatigue and QoL scores also improved significantly up to week 52, as well as the NYHA class and patient global assessment scores . Furthermore, FCM was associated with a significant reduction in the risk of hospitalisation due to worsening HF .
The FAIR-HF study was as a multicentric, prospective, double-blind, randomised, placebo-controlled trial . Symptoms, functional capacity and QoL were significantly improved after treatment with IV FCM in patients with chronic HF and ID, with or without anaemia .
Intravenous iron replacement with ferric hydroxide sucrose
Toblli et al  compared the effects of IV ferric hydroxide sucrose with isotonic saline placebo in 40 chronic HF patients (LVEF ≤35%), anaemia, ID, and mild renal insufficiency in a prospective, randomised, double-blind, placebo-controlled trial. Patients were followed up for six months. Compared with placebo, IV ferric hydroxide sucrose significantly increased haemoglobin and iron parameters, accompanied by a significant decrease in NT-proBNP (p<0.01) and C-reactive protein (p<0.01) . In the ferric hydroxide sucrose group, there were also significant improvements in NYHA class, Minnesota Living with Heart Failure questionnaire score, 6MWT distance and LVEF (p<0.01 for all) .
Oral vs. IV iron therapy in HF
A Cochrane review that included a total of 64 RCTs, of which five were studies of HF patients, showed that both oral and parenteral iron reduced the proportion of people who required blood transfusion and increased haemoglobin levels, without any benefit on mortality . In all comparisons, there were no differences in the results comparing patients with and without heart failure .
Other ongoing studies and their primary outcome measures include: i) Intravenous Iron in Patients With Severe Chronic Heart Failure and Chronic Kidney Disease study (NCT00384657; n=200) to assess the impact of IV iron on ejection fraction in mild to moderate anaemia associated with chronic HF (NYHA Class III) and concomitant moderate chronic kidney disease patients; and ii) The Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Iron Deficiency and Chronic Heart Failure study (EFFECT-HF; NCT01394562; n=160) to investigate the change in pVO2 with IV FCM in patients with ID and chronic HF.
Recommendations and clinical practice
Making sure that the causes of absolute ID (e.g., gastric ulcer, colon cancer) have also been investigated and treated by other means when possible, ID should be treated in HF patients. In the 2016 ESC guidelines , only the IV route is considered for iron administration in iron-deficient HF patients (Level of evidence: Class IIA-a). In practice, oral iron may be prescribed for absolute ID for at least three months with assessment of iron replenishment after one month; in case of inefficacy or intolerance, oral therapy should be quitted and IV iron therapy should be initiated. In case of functional ID, only the IV route should be considered, since oral iron is ineffective in this clinical condition. Iron parameters should also be checked one month after IV iron administration. Meanwhile, pharmacological and device therapies known to improve outcomes in HF should be optimised in all cases, since optimisation may also exert favourable effects on iron metabolism.
More data are required before the routine use of IV iron for all HF patients with ID can be recommended. One limiting factor is that the treatments recommended for HF have evolved since the publication of many of the studies included in the meta-analyses, including the use of mineralocorticoid receptor antagonists or cardiac implantable devices, particularly cardiac resynchronisation therapy. Although IV iron replenishment therapy has revealed favourable results in HF patients, data regarding the comparison of the oral and IV routes for iron administration are scarce. In addition, further evidence is warranted regarding the effect of iron repletion in those with preserved ejection fraction HF. Long-term follow-up studies are also necessary to evaluate the safety of IV iron therapy in HF patients.