Intravenous Iron Therapy in Heart Failure: A Different Perspective

Iron is essential for various biological processes in human body. Every day, approximately 20–25 mg of iron is needed to meet the demands of the body. The majority of this iron comes from recycling of the aging red blood cells by macrophages that break down haemoglobin (Hb) and serve as temporary storage of iron. The release of iron from macrophages is regulated by hepcidin. This peptide is produced by the liver and functions as the main regulator of the iron efflux from the cells by controlling proteolytic degradation of the only known iron exporter in human cells, ferroportin 1. Additionally, iron is absorbed from the diet and temporarily stored in the intestinal epithelial cells. About 1–2 mg of iron is released every day from the gastrointestinal storage of iron into the systemic circulation and this release is also tightly regulated by hepcidin (Figure 1). Except blood loss, there is no mechanism to remove the iron that has already entered the systemic circulation.1, 2 Despite significant advancement in our understanding of iron metabolism, the exact pathophysiology, accurate definition and true prevalence of iron deficiency (ID) in patients with heart failure (HF) have remained unsettled. It is intriguing that despite ID being the most common nutrient deficiency in the world, cardiomyopathy is not a common consequence of ID, and patients with ID do not experience a reduction in their ejection fraction unless they have high-output HF due to severe anaemia.3, 4 This suggests that certain biological processes may be in play to protect our vital organs from ID-mediated damage. Patients with HF may be at risk of developing absolute ID, which is characterized by depletion of the total iron stores in the body. Several mechanisms have been postulated for this condition, including impaired nutrition,5, 6 reduced absorption due to bowel oedema,7, 8 reduced absorption due to use of proton pump inhibitors,9, 10 reduced absorption due to increased production of hepcidin,7, 11, 12 and increased iron loss in the gastrointestinal and genitourinary systems due to use of antiplatelets and anticoagulants.10 However, other than impaired nutritional status, the other proposed mechanisms are speculative and, to the best of our knowledge, there has been no study demonstrating a causative association between any of the above-proposed mechanisms and the development of absolute ID in HF. Additionally, patients with HF may be at risk of developing functional ID, which is characterized by inadequate iron mobilization despite normal iron stores. This condition — that should more properly be referred to as iron restriction rather than ID — is a hallmark of the anaemia of chronic inflammation. In chronic inflammatory states, increased production of hepcidin diminishes iron release from the gastrointestinal system and induces iron trapping in macrophages and hence, causes functional ID13-15 (Figure 1). However, this does not appear to be the mechanism of ID in the HF population. Since HF was associated with elevated levels of inflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor-α, it was originally postulated that similar to chronic inflammatory states, HF patients have functional ID due to elevated levels of serum hepcidin.9, 11, 16 However, recent studies in chronic9 and acute HF17 demonstrated the opposite and showed that serum hepcidin level is actually diminished in HF. So, the notion that the inflammatory state of HF would lead to elevated levels of hepcidin and hence, ID is not accurate. In summary, the underlying pathophysiologic mechanisms of ID in HF are not well understood and are likely distinct from those involved in iron sequestration and anaemia of chronic inflammation. Further research is needed to better understand the mechanisms and therapeutic implications of ID in HF. Ferritin is a cellular iron storage protein that is mainly produced by macrophages and its serum level reflects the baseline level of iron in macrophages (Figure 2).18-22 Serum ferritin level < 15 ng/mL is highly specific for diagnosis of absolute ID.9, 23, 24 Ferritin however, is an acute-phase protein that increases in response to inflammation (Figure 2). So, in conditions such as HF that is associated with elevated inflammatory markers, it is conceivable to consider a higher cut-off value for diagnosis of depleted iron stores. However, the accurate cut-off of ferritin and the applicability of this serum marker in general to diagnose ID in HF is debatable. The proposed criteria to diagnose ID in HF are serum ferritin < 100 ng/mL to define absolute ID or serum ferritin 100–300 ng/mL in combination with transferrin saturation (Tsat) < 20% to define iron restriction.9, 25 These definitions were originally used in patients with chronic kidney disease (CKD)26, 27 and were later adopted in the studies of intravenous (IV) iron therapy in HF.28-30 More recently, the same definitions were also reflected in HF guidelines.31-33 However, pathophysiology of ID and effects of iron supplementation in CKD patients are complex and likely very different from those involved in HF. So, adoption of these criteria to define ID in HF may not be accurate. Assessment of iron stores on bone marrow sample can be considered the gold standard for diagnosis of ID. In a recent study by Grote Beverborg et al.,34 the investigators assessed the validity of the above serum-based definition of ID in a group of HF patients against bone marrow iron stores. The definition of ID based on ferritin < 100 ng/mL or Tsat < 20% had a positive predictive value of 66.7%. Therefore, 33% of the HF patients in this particular cohort who were considered ‘iron-deficient’ based on the ferritin/Tsat criteria, had adequate amount of iron stores in their bone marrow. In this study, Tsat < 19.8% or simply serum iron level < 13 μmol/L (< 72 μg/dL) had the best correlation with bone marrow ID and the most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. In a prospective study of 165 patients with a recent episode of acute HF, Jankowska et al.17 defined ID as the concomitance of low serum hepcidin (as a marker of depleted body iron stores) and elevated serum soluble transferrin receptor (sTfR, as a marker of insufficient cellular iron). In multivariable analysis, this definition of ID was strongly predictive of all-cause mortality at 12 months. However, ID based on the definition of ferritin < 100 ng/mL or Tsat < 20% was not predictive of the outcomes. In this study, according to the ferritin/Tsat definition of ID in HF, 65% of the patients were iron-deficient. However, ID was present in only 37% of the patients, based on the above hepcidin/sTfR definition. Thus, the ferritin cut-off of 100 ng/mL or Tsat < 20% to define ID could be inclusive of patients who may not be truly iron-deficient. In the two major clinical trials that showed beneficial effects for IV iron in HF (FAIR-HF28 and CONFIRM-HF35), the positive effects were indeed seen below and above the median ferritin level but the median ferritin level in FAIR-HF was 39 ng/mL and in the CONFIRM-HF was 46 ng/mL, both markedly lower than the ferritin cut-off of 100 ng/mL. To date, there have been three large randomized clinical trials that evaluated the effect of IV iron therapy in HF patients with ID (Table 1).28, 35, 36 ↓ NT-proBNP ↓ CRP ↑ Hb ↑ Ferritin ↑ Tsat ↑ CrCl ↑ EF ↓ NYHA class ↑ 6MWT ↓ BMI Okonko et al.,42 2008 (FERRIC-HF) ↑ pVO2/kg ↑ Ferritin ↑ Tsat Anker et al.,28 2009 (FAIR-HF) ↓ NYHA class ↑ PGA ↑ 6MWT ↑ KCCQ score Beck-da-Silva et al.,51 2013 (IRON-HF) Ponikowski et al.,35 2015 (CONFIRM-HF) ↑ 6MWT distance ↓ NYHA class ↑ PGA ↓ Fatigue score ↑ KCCQ score Van Veldhuisen et al.,36 2017 (EFFECT-HF) ↔ pVO2/kg ↓ NYHA class ↑ PGA ↑ Ferritin ↑ Tsat ↑ Hb Lewis et al.,30 2017 (IRONOUT HF) ↔ pVO2/kg ↔ 6MWT ↔ KCCQ ↔ Ferritin ↑ Tsat FAIR-HF28 was a randomized, placebo-controlled trial that enrolled 459 ambulatory HF patients in New York Heart Association (NYHA) class II left ventricular ejection fraction (LVEF) ≤ 40% and class III (LVEF ≤ 45%). Eligible patients had a Hb level between 9.5 and 13.5 g/dL and were iron-deficient (defined as serum ferritin < 100 ng/mL or between 100 and 300 ng/mL if Tsat was < 20%). Participants were randomized in 2:1 ratio to receive either IV ferric carboxymaltose (FCM, provided by Vifor Pharma) or placebo (normal saline). FCM was administered weekly as an IV bolus injection at a dose of 200 mg until iron repletion was achieved (correction phase). Then, FCM injections were continued on a monthly basis during the course of the study (maintenance phase). The primary endpoints of the study were self-reported Patient Global Assessment (PGA) and NYHA functional class at week 24. Secondary endpoints included six-minute walk test (6MWT) distance and health-related quality-of-life surveys at weeks 4, 12 and 24, all adjusted for the baseline data. At week 24, treatment with FCM significantly improved self-reported PGA (with 50% of participants in the treatment group reporting that they were ‘much or moderately improved’ compared to 28% in the placebo arm) and NYHA class. Patients with anaemia at baseline showed a significant increase of 0.9 g/dL in the level of Hb at week 24. However, the symptomatic benefits were similar in patients with and without anaemia and in all pre-specified subgroups. The safety endpoints of deaths, hospitalization and adverse events were similar between the two groups of the study. CONFIRM-HF35 was a randomized, placebo-controlled trial that enrolled 304 ambulatory HF patients in NYHA class II and III with LVEF ≤ 45%. Eligible patients had elevated natriuretic peptide and were iron-deficient (defined as serum ferritin < 100 ng/mL or between 100 and 300 ng/mL if Tsat < 20%). Participants were randomized in 1:1 ratio to receive either IV FCM (Ferinject/Injectafer, Vifor Pharma) or placebo (normal saline). In the ‘therapy phase’ of the study, participants received FCM once at baseline and another time, at week 6 for a total dose of 500 to 2000 mg elemental iron (according to a fixed dose scheme that was based on weight and Hb level). The ‘maintenance phase’ of the study included three injections of 500 mg at weeks 12, 24 and 36 if ID was still present. The primary endpoint for the study was the change in 6MWT distance from baseline to week 24. Secondary endpoints included NYHA class, PGA, Fatigue Score and health-related quality-of-life surveys at weeks 6, 12, 24, 36 and 52. At week 24, treatment with FCM significantly improved the 6MWT distance (P = 0.002). Additionally, the use of FCM compared to placebo was associated with significant improvement in NYHA class, PGA score, Fatigue Score and the overall KCCQ score. EFFECT-HF36 was an open-label, randomized clinical trial that enrolled 174 stable ambulatory HF patients in NYHA class II and III with LVEF ≤ 45%. Eligible patients had elevated natriuretic peptide and were iron-deficient (defined as serum ferritin level < 100 ng/mL or between 100 and 300 ng/mL if Tsat < 20%). Participants were randomized in 1:1 ratio to receive either IV FCM (Ferinject/Injectafer, Vifor Pharma) or standard of care (SoC). Participants received FCM once at baseline and another time at week 6 for a total dose of 500 to 2000 mg elemental iron (according to a fixed dose scheme that was based on weight and Hb level). At week 12 another dose of FCM was given at fixed dose of 500 mg if ID was still present. The primary endpoint for the study was the change in peak oxygen uptake (VO2) from baseline to week 24. Secondary endpoints included NYHA class and PGA score. At week 24, peak VO2 decreased by 1.19 ± 0.38 mL/kg/min in the SoC group but was virtually unchanged in the FCM group. There was 1.04 mL/kg/min difference in the least square means of the change in peak VO2 and this was statistically significant (P = 0.02). Additionally, treatment with FCM compared to SoC improved the NYHA functional class and PGA score. Therapeutic effects of IV iron in HF patients have also been studied in two smaller size randomized clinical trials (Table 1). In a single-centre randomized clinical trial from Argentina, Toblli et al.41 randomized 40 ambulatory HF patients with LVEF ≤ 35%, anaemia and ID to receive infusions of iron sucrose (200 mg) or placebo (normal saline). Patients received five weekly infusions and were followed for 5 months. The treatment group showed significant improvement in virtually all the measured parameters including N-terminal pro B-type natriuretic peptide (NT-proBNP), NYHA class, Hb level, C-reactive protein, 6MWT distance, LVEF, serum creatinine level, and even body mass index (all P < 0.01). Considering the small sample size of this study, the magnitude and scope of the treatment effect are striking and need validation in larger studies. The FERRIC-HF trial42 randomized 35 symptomatic HF patients with LVEF ≤ 45%, NYHA class II–III and ID to receive in 2:1 ratio either iron sucrose or no iron therapy without placebo. At week 18, treatment with IV iron resulted in significant improvement in peak VO2 and NYHA class. However, these changes were only significant in the pre-specified subgroup of patients with anaemia (Hb < 12.5 g/dL). There was a statistically significant increase of Hb in the IV iron group compared to baseline. Although there is no evidence that therapy with IV iron can influence ‘major’ clinical outcomes, namely mortality or morbidity in HF, the above-mentioned trials showed that use of IV iron in patients with HF with reduced ejection fraction (HFrEF) can improve symptoms (PGA score, NYHA class), functional capacity (6MWT distance) and quality of life (KCCQ score). A plethora of review articles,43-45 editorials,11, 46, 47 meta-analysis48-50 and guidelines31-33 followed the publication of the above major clinical trials and advocated for the use IV iron in patients with HFrEF who simply had ferritin level < 100 ng/mL or a Tsat < 20%. Considering the lower cost and wider availability of oral formulations of iron, an important question remained whether oral iron could exert similar beneficial effects on symptoms as IV formulations. The only attempt to date, to compare IV vs. oral iron in HFrEF in the form of a randomized clinical trial was terminated prematurely due to competing trials and insufficient funding.51 The investigators of the IRON-HF trial (which was a randomized, double-blind, placebo-controlled clinical trial) were able to randomize 23 anaemic HF patients with LVEF < 40%, Tsat < 20% and ferritin < 500 ng/mL into three groups to receive IV iron (iron sucrose), oral iron (ferrous sulphate) or placebo. This trial was originally designed to enrol 119 patients. Over a 3-month follow-up period, the primary endpoint of change in peak VO2 numerically increased by 3.5 mL/kg/min in the IV group without a detectable increment by use of oral iron. Of note, both treatment groups showed significant increase in ferritin and Tsat levels compared to placebo. In 2015, Niehaus et al.52 reported on a retrospective study to assess the association between oral iron (mostly in the form of ferrous sulphate) and change in biochemical measures of iron stores in a cohort of 105 iron-deficient HF patients with LVEF < 45%. ID was defined similar to FAIR-HF and CONFIRM-HF trials. After a median of 164 days of therapy with oral iron, there was a significant increase in the values of serum iron (median 34 to 69 μg/dL), ferritin (median 39 to 75 ng/mL), Tsat (10% to 21%) and Hb (10.4 to 11.6 g/dL) (all P < 0.001). These two studies suggested that use of oral iron could improve indices of iron stores in patients with remained if improvement of iron stores with oral iron would also into improvement of clinical HF was an double-blind, placebo-controlled randomized clinical trial to test the that oral iron compared to capacity (as measured by peak in HF patients with In this study, stable HF patients with LVEF ≤ and ID ng/mL or between 100 and ng/mL if Tsat < were randomized to receive oral iron at mg or placebo. The primary endpoint was change in peak VO2 16 weeks of therapy (Table 1). After 16 weeks of peak VO2 virtually remained unchanged compared to baseline in both at 16 there was no significant difference in changes in 6MWT distance, NT-proBNP levels or KCCQ between the two However, compared to oral iron increased Tsat by (P = and ferritin level by ng/mL (P = Additionally, in response to oral iron participants in the lower of the baseline serum hepcidin showed more in Tsat and ferritin levels compared to baseline ferric iron iron and iron sucrose are for clinical use in the (Table only FCM has been for treatment of ID in HF, there are effects associated with all these formulations. Iron sucrose in human is associated with increased iron and impaired which is a marker for In a study of IV iron in iron iron and iron were all associated with increased and in the Iron sucrose and iron have also been to in patients on and in with study the increased iron sucrose to acute kidney a randomized clinical trial oral vs. IV iron sucrose in CKD patients had to patients who received IV iron had significantly higher of adverse including and that IV iron may actually have effects on the has also been demonstrated to increase in patients with Additionally, studies have reported and associated with of various formulations of iron, including FCM and iron proposed mechanism is This peptide is produced by the bone and systemic Iron supplementation the degradation of and increases its which in can absorption in the The resulted could bone and lead to the effect of on normal the could be even more in patients with normal kidney compared to those with has also been to in a The above that use of IV iron in HF patients may be associated with could that no of was in CONFIRM-HF or trials. However, serum levels and bone were not measured in these trials. So, the risk of and even to these three trials. the follow-up of these trials have been to effects of IV iron therapy in these patients. Thus, the safety of chronic of IV iron in HF patients to be Although at the to this question may be by a more of the patients with HF receive IV iron on the of ID is highly in patients with and patients with ferritin level < 100 ng/mL or Tsat < 20% would from IV iron of Hb level and without any safety However, the accurate definition and prevalence of ID in HF is still debatable. use of IV iron in HF has not been to major clinical outcomes. in a chronic disease such as HF, in symptoms and are that improve mortality and that improve symptoms more evidence being into clinical This is there is for with those even if research from FAIR-HF and CONFIRM-HF trials that iron therapy in HF is and there is still need to better define the effects of iron therapy with to major endpoints such as outcomes. Additionally, evidence does not oral iron supplementation as a of iron therapy for patients with HF and ID. evidence were it is that with accurate improvement in the and a better a of HF patients response to oral iron. It is also that the for the use of IV iron in patients is of ID anaemia in patients who have or those who have had response to oral So, the use of IV iron in HF patients for treatment of ID without a trial of oral iron is in the have already iron supplementation as a treatment for HF patients who simply have ferritin < 100 ng/mL or Tsat < 20%. the of for the diagnosis and of patients with HF a class (defined as be with level of evidence A (defined as from randomized clinical to the use of IV FCM in symptomatic patients with HFrEF and on the that the class may the beneficial effects of IV iron and does not the and effects of this Thus, in our this should be Since of blood is considered an that could lead to development of treatment with IV iron at is used as an or therapy to blood in anaemic HF patients who are for HF such as heart or ventricular This is of the of iron with response and in of evidence that suggests a for iron in the of the The evidence even suggests that in iron could and risk of heart Several clinical trials attempt to important The trial is with an of In this randomized, placebo-controlled patients with HF and ID be randomized to receive either FCM or placebo with a primary endpoint of hospitalization for HF and is an open-label, randomized clinical trial to the question whether ID with IV iron in HF patients would mortality or hospitalization for HF Patients with LVEF < and NYHA class who are iron-deficient (defined as Tsat < 20% ferritin < 100 and have hospitalization for HF or elevated natriuretic receive IV iron (iron on of standard care in an is participants in the with an of is a randomized, double-blind, placebo-controlled trial to assess the effect of IV FCM compared to placebo on mortality or hospitalization for HF, and the change in the 6MWT distance in patients with HF and ID of is participants in a randomized, double-blind, placebo-controlled trial to assess the effect of IV FCM on hospitalization and mortality in iron-deficient HF patients who are for acute HF of A of patients with HFrEF and ID symptomatic from iron However, more research is needed in to define this to the mechanisms and to the form and of iron in these patients. against in diagnosis of ID in HF and also against the of IV iron in this population. It is that oral iron supplementation be in a subgroup of HF patients with ID. To date, the evidence has not been that the use of IV iron in HF can improve ‘major’ clinical outcomes. studies that iron supplementation indeed HF, this would not be the time in that a is to be beneficial with mechanisms that are still However, at the the of should be continued to the iron improve it does it do HF patients would the most from iron and are the effects of IV who provided and that improved the quality of this of