Review
Iron Deficiency in Heart Failure: Looking Beyond Anaemia

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Iron is an essential micronutrient in many cellular processes. Iron deficiency, with or without anaemia, is common in patients with chronic heart failure. Observational studies have shown iron deficiency to be associated with worse clinical outcomes and mortality. The treatment of iron deficiency in chronic heart failure patients using intravenous iron alone has shown promise in several clinical trials, although further studies which include larger populations and longer follow-up times are needed.

Introduction

Chronic heart failure (CHF) is an increasingly common condition in Australia, with a prevalence of 1.3% and an incidence of 30,000 cases per year [1]. It is associated with significant mortality, with five-year survival ranging from 50-75% [2]. Chronic heart failure also causes significant morbidity with approximately 22,000 hospital admissions in one year [3]. The Australian Institute of Health and Welfare estimated that CHF led to healthcare costs of $411 million in 1993-1994 [4], while a more recent study concluded that current healthcare expenditure on CHF was closer to $1 billion per annum [3]. Over the last decade, iron deficiency (ID) has been increasingly recognised as both a poor prognostic marker and a potential therapeutic target in CHF patients. This review article aims to provide a summary of the current evidence that exists for the treatment of ID in CHF.

Section snippets

Overview of Iron Turnover

Dietary iron is reduced to Fe2+ by duodenal cytochrome B in the lumen of the duodenum and proximal jejunum, where it enters the enterocyte via the divalent metal transporter-1 (DMT-1). Iron is then exported into the circulation by ferroportin, which is located on the basolateral membrane of the enterocyte. Exported iron is subsequently oxidised to Fe3+ by hephaestin and bound to plasma transferrin. The transferrin-iron complex is eventually taken up by target cells expressing transferrin

Definition and Diagnosis of Iron Deficiency in Chronic Heart Failure

Iron deficiency can be classified as absolute or functional [11]. Absolute ID reflects depleted body stores caused by poor dietary intake, impaired gastrointestinal (GI) absorption, and chronic blood loss. Functional ID is thought to be caused by increased hepcidin production and subsequent inhibition of the iron exporter ferroportin, leading to impaired absorption and utilisation of iron [7], [8]. Chronic heart failure patients are susceptible to both forms of ID [8].

The diagnosis of ID in

Aetiology of Iron Deficiency in Chronic Heart Failure

The aetiology of ID in CHF is multifactorial and complex. Aside from reduced dietary intake [21] and chronic GI blood loss, it is believed that CHF causes an inflammatory state which leads to increased hepcidin levels and subsequent ID due to reduced iron absorption and enhanced reticuloendothelial block [8], [17], [22], [23]. However, multiple studies have provided conflicting evidence on the exact cause of ID in CHF. An experimental model found that rats with heart failure and anaemia had

Prevalence of Iron Deficiency in Chronic Heart Failure

Iron deficiency is common in CHF patients. However, the reported prevalence rates of ID in CHF patients vary widely, ranging from 37% to 61%, due to differences in the definitions of ID and the studies’ inclusion criteria (Table 1) [28], [29], [30], [31], [32]. It is also recognised that patients do not necessarily have to be anaemic for ID to be present [28]. Nanas et al. [15] showed that in a group of patients with advanced CHF (NYHA IV) and anaemia, ID (diagnosed on bone marrow aspiration)

Iron Deficiency, Cardiac Function, Exercise Capacity and Quality of Life

Aside from its well-recognised role in erythropoiesis, iron is also a critical component in many important cellular processes such as oxygen transport, electron transfer reactions, mitochondrial respiration, gene regulation, and cellular immunity [33], [34]. The maintenance of iron homeostasis is particularly important in cells with high energy demands such as skeletal and cardiac myocytes [35]. Willis et al. [36] found that rats with ID anaemia had a threefold improvement in exercise endurance

Iron Deficiency and Mortality in Chronic Heart Failure

Multiple observational studies have now shown that ID is associated with increased mortality in CHF. Jankowska et al. [28] found in a large cohort of patients with CHF that the presence of ID is a strong predictor for poor outcomes including hospitalisation and death, with three-year survival rates of 59% for patients with ID versus 71% for those without (p=0.0006). The authors also showed that ID alone led to an adverse prognosis that was independent of the presence of anaemia [28]. Okonko et

Clinical Trials of IV Iron Supplementation

Given the prevalence of ID and its associated negative impact in patients with CHF, there has been interest in treating ID in CHF with IV iron supplementation. To date, there have been nine published clinical trials using IV iron supplementation in patients with CHF. These consist of three open-labelled, uncontrolled studies [42], [43], [44]; one observer-blinded, randomised controlled study [45]; and five double-blinded, randomised, placebo-controlled studies [19], [46], [47], [48], [49].

Is Intravenous Iron Treatment Cost Effective and Can We Do More?

A cost effectiveness analysis in the UK found the use of IV FCM in CHF patients with ID to be cost effective, with an incremental cost effectiveness ratio of €4,414 per quality-adjusted-life-year (QALY). This was much lower than the National Institute for Health and Clinical Excellence threshold of €22,200 to €33,300 per QALY gained, with the result mainly due to improved symptoms and QoL [50]. Use of IV FCM in CHF patients has also been shown to be cost effective in other countries [51], [52],

Conclusion

Iron is an essential micronutrient and has many important physiological roles in the body beyond erythropoiesis. Iron deficiency is common in patients suffering from chronic heart failure regardless of the presence of anaemia, and is associated with worse clinical outcomes. Intravenous iron therapy is safe, cost effective, and improves exercise capacity and quality of life in patients with chronic heart failure. The impact of iron repletion on mortality in chronic heart failure remains

Acknowledgements

This work was financially supported by an unrestricted grant from Biotronik. However, the sponsor had no role in the writing of this article.

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