Clinical perspective: iron replacement therapy in chronic heart failure (2011)

Anaemia is common in patients with chronic heart failure (HF), particularly if there is concomitant renal dysfunction. It is part of a cardio-renal-anaemia syndrome, in which each component impacts on the other in a vicious cycle. Prevalence varies according to the definition used, but a recent meta-analysis reported anaemia in more than one-third of patients with chronic HF (1). The majority of studies in this meta-analysis used the WHO definition of anaemia (haemoglobin < 12 g/dl in women and < 13 g/dl in men). Anaemia prevalence increases with age and with HF severity, but averaged 37% in the studies included in the meta-analysis (1). Anaemia in patients with HF is associated with worse symptoms and decreased exercise capacity (2). It has also been shown to be independently associated with increased risk of hospitalisation and mortality (3), both in patients with left ventricular systolic dysfunction and in those with preserved ejection fraction (1). Outcome studies have not yet established that anaemia is a cause of HF progression rather than simply a marker of disease severity. Nonetheless, evidence is accumulating that there is benefit from correction of anaemia. The multiple causes of anaemia in HF include haemodilution, chronic inflammation, chronic kidney disease (CKD) and iron deficiency (for example, from NSAID-induced gastrointestinal bleeding). ACE inhibitors and angiotensin receptor blockers might also play a part by reducing erythropoietin (EPO) activity. When other causes of anaemia have been excluded, HF anaemia is generally labelled as anaemia of chronic disease. Renal dysfunction and pro-inflammatory cytokine activation appear to contribute to this anaemia in the majority of patients (4), resulting in reduced EPO production or EPO resistance and defective iron utilisation, the latter via increased hepatic production of hepcidin protein (Figure 1). Possible mechanisms involved in the genesis of anaemia in the heart failure Iron deficiency appears to be more important than previously thought as a contributor to anaemia in HF. Although absolute iron deficiency is reported in a minority of cases (< 30%) (3), functional iron deficiency may be more common. Poor utilisation of seemingly adequate iron stores was identified in one study as an important factor associated with anaemia in HF (5). Over the past decade, several studies have been undertaken to assess the benefit of correcting anaemia in HF (Table 1). Initial small single-centre studies reported some improvement in functional capacity and quality of life with use of EPO or its analogues together with supplementary iron (6, 7), although a small multicentre study showed no significant effect on exercise tolerance (8) and the larger STAMINA-HeFT randomised trial of 319 patients found no significant clinical benefits from darbepoetin (9). A meta-analysis of seven randomised trials of erythropoiesis-stimulating agents (ESAs) in HF (10) reported reduced risk of HF hospitalisation. However, no HF trial has yet shown ESA benefit on mortality. Furthermore, the long-term safety of treatment is not proven. This is important in view of adverse cardiovascular effects (thrombotic risk and hypertension) associated with high haemoglobin levels after ESA treatment in CKD patients. Most recently, the TREAT trial in CKD patients with diabetes reported that treatment with darbepoetin (target haemoglobin 13 g/dl) was associated with increased risk of stroke (11). The risk of cardiovascular side effects has led to guideline recommendations not to aim for normalisation of haemoglobin levels when using ESAs in CKD (12, 13). Meta-analysis of the HF trials reported no increased mortality or adverse events with ESAs (10), but the experience in CKD has led to caution among cardiologists and use of ESAs in HF anaemia (an unlicensed indication in Europe) has declined. Ongoing trials, including the large RED-HF trial of darbepoetin, which has all-cause mortality or HF hospitalisation as its primary endpoint, should provide useful data. Meanwhile, the evidence base is moving on and there is increasing interest in the idea of iron replacement on its own for correcting anaemia in HF, with data suggesting that using i.v. iron alone to increase haemoglobin levels can improve cardiac and renal function. Some HF studies have also investigated iron replacement in patients with iron deficiency in the absence of anaemia. The iron replacement studies in HF anaemia have used i.v. iron. Oral iron is often poorly tolerated and so may not be taken reliably; in addition, it may not increase iron stores because of hepcidin-induced reduction in duodenal iron absorption (4) as well as malabsorption associated with gut oedema. Intravenous iron is more effective and there are no compliance issues. Several small studies assessing this new strategy in HF anaemia suggested that treatment can increase haemoglobin, improve exercise capacity and symptoms (14), reduce NTproBNP level and inflammatory status (C-reactive protein level) and reduce hospitalisations (15). In the FERRIC-HF trial (16), in which i.v. iron was given to HF patients with iron deficiency with or without anaemia, treatment was associated with improved exercise capacity (mean of 60 s greater treadmill duration, p = 0.08, and 2.2 ml/kg/min of peak oxygen consumption, p = 0.01) and was well tolerated. The largest iron study to date is the FAIR-HF trial (17) in which 459 patients with HF due to LV systolic dysfunction and iron deficiency (with or without anaemia) received i.v. iron or placebo. Active treatment was associated with improvement at week 24 in the Patient Global Assessment (odds ratio for improvement 2.5) and in the New York Heart Association functional class (odds ratio for improvement by one class 2.4). A new FAIR-HF sub-analysis suggests that treatment might also improve renal function (Ponikowski P. et al., reported at the 2010 Annual Scientific Meeting of the Heart Failure Association of the European Society of Cardiology, Berlin). As with the ESA trials, none of the iron studies so far has had hard endpoints and further randomised studies are needed. IRON-HF is one ongoing trial of iron therapy that includes HF hospitalisations and mortality among the secondary endpoints (18). There has, in the past, been concern about use of i.v. iron because of the history of anaphylaxis with iron dextran. The HF trials used newer non-dextran-containing formulations (iron sucrose or ferric carboxymaltose) with reduced risk of producing hypersensitivity reactions. Ferric carboxymaltose has the additional advantage that higher doses can be given: the total iron requirement can be given in one dose, avoiding the need for patients to make repeated visits for treatment. Also, unlike the other i.v. iron products, it does not require an initial test dose. At our centre, we have audited our use of i.v. iron (ferric carboxymaltose) in patients with HF and anaemia. In a 12-month period, we have given single dose i.v. iron replacement in 30 patients, without any adverse effect. The patients had moderate-to-severe symptoms (mostly NYHA Class III) despite optimal medical management with ACE inhibitors, beta-blockers and aldosterone antagonists and 40% had cardiac resynchronisation therapy also. Median Hb prior to i.v. iron therapy was 10.5 g/dl, with median-estimated GFR of 44 ml/min/1.72 m2, serum iron 6.8 μmol/l (normal range: 12.6–26), ferritin 46 μg/l (normal range: 32–284) and transferrin saturation 9.5% (normal range: 20–45%). The change in mean Hb was 1 g/dl after i.v. iron therapy, with no change in estimated GFR. Serum iron rose to 11.3 μmol/l, ferritin to 274 μg/l and transferrin saturation to 22%. Correction of anaemia is not yet established as routine therapy in HF guidelines (19, 20), but anaemia is common in HF and its cause and correction should be considered. Specific causes should be investigated and iron status checked. In many cases, anaemia is likely to be related to the cardio-renal-anaemia syndrome and treatment with i.v. iron can be considered. Clinical trials to date and practical experience indicate that with the modern formulations i.v. iron replacement is useful and well tolerated. However, we need trial data on clinical outcomes to assess the true value of treating HF anaemia, and further investigation of iron replacement in patients who are iron-deficient, but do not have anaemia. None. None. None.