Anaemia in heart failure: intravenous iron therapy

Background

Anaemia, although common in heart failure patients, reduces functional status, quality of life and is an independent risk factor for hospital admissions and mortality (1,2). Intravenous iron therapy benefits these patients and provides cardiologists with a means for more accurate management.
Prevalence of anaemia in heart failure (HF) patients depending on the defining criteria that is used, ranges from 7 to over 50% (3). Indeed, the World Health Organisation holds a haemoglobin (Hb) concentration under 13 g/dl in men and 12 g/dl in women as aneamia whereas the National Kidney Foundation defines anaemia as Hb < 12 g/dl in men and postmenopausal women. Anaemia is always more frequent in older patients, advanced HF, chronic renal failure, in females and African-Americans (3) - regardless or whether heart failure is systolic or diastolic. Multiple mechanisms have been identified as causes (Fig. 1) (4). Iron deficiency (ID) appears most important, followed by gastrointestinal absorption, increased macrophage iron storage and gastrointestinal bleeding. These factors may contribute to ID and ultimately, lead to anaemia.

Figure 1: Causes and mechanisms of anaemia in heart failure. Figure legend: ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker, ASA: acetylsalicylic acid, EPO: epoetin.

I - Diagnostic testing

Routine diagnostic evaluation (1,5) includes:

• Complete blood count with reticulocyte count and index
• Serum iron and total iron binding capacity
• Transferrin saturation
• Ferritin
• Serum B12 and folate
• Thyroid stimulating hormone
• Fecal occult blood test

Red blood cell distribution width is a numerical measure of the variability in the size of circulating erythrocytes, taken during a standard blood count test. Ineffective erythropoiesis causes heterogeneity in erythrocytes size and a higher RDW. RDW has recently emerged as a new prognostic marker of HF, regardless of Hb levels (6).

Table 1:  Most common laboratory findings suggesting iron deficiency anaemia (7)

Laboratory parameter / Result

Haemoglobin : < 13 g/dl (men)

Hematocrite : < 12 g/dl (women)

< 31-32 %

Mean corpuscular volume: -

Mean corpuscular hemoglobin : -

RBW : > 14 %

Serum iron concentration : -

Transferrin saturation : < 10-15%

Ferritin concentration : < 100 ng/ml
100-300 ng/ml and transferrin saturation < 20%

¯: decreased, RDW: red blood cell distribution width

II - Prognostic implications 

Many studies have shown anaemia to increase mortality and morbidity in HF patients (1, 5, 8, 9) and to cause the following:

• Higher NYHA functional class
• Decreased exercise capacity (shorter distance covered during 6-minute walking test, lower peak-oxygen consumption during cardiopulmonary exercise testing)
• Decreased renal function
• Lower quality of life
• Increased HF admissions

III - Management options 

Current HF guidelines (1,2) have not fully established specific routine treatment. Blood transfusion is useful in critically ill patients with chronic cardiac disease and Hb less than 7 g/dl (10). However, blood transfusion is not recommended as long-term therapy because of associated risks, such as infection, HLA sensibilisation and iron overload (11). As figure 1 shows, impaired erythropoiesis is one of the mechanisms of anaemia in HF. Erythropoietin-stimulating agents (ESA) have been studied in the past decade in combined heart failure and anemia patients and it was found that ESA are associated with a reduction in HF hospitalisations and improvement in exercise tolerance, quality of life, brain-natriuretic peptide levels and left ventricular ejection fraction (12). Recently, intravenous iron therapy has been successfully incorporated into management of patients with HF, as well. Oral iron formulation are used for ID treatment. Nevertheless, poor absortion and gastrointestinal intolerance are common. Intravenous iron preparations used in these patients mainly are 1) iron sucrose (alone or combined with ESA) and 2) iron carboxymaltose.

Intravenous iron sucrose

Two studies showed improvement in Hb level, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score and 6-minute walk test distance (13, 14). In the very recent FERRIC-HF trial (15), 35 HF patients (NYHA class II or III) with ID treated with iron sucrose (200 mg weekly until ferritin > 500 ng/ml, 200 mg monthly thereafter) improved their exercise capacity and symptom status. These benefits were more evident in anaemic patients.
Intravenous iron sucrose can be administered either as slow injection (over 10 minutes) or by infusion (11). Total iron dose required for iron repletion is calculated using the Ganzoni formula (body weight (kg) x 2.4 x [15 – patient's Hb (g/dl)] + 500 mg for stores). This treatment is usually well tolerated. Main side effects are taste disturbances, while less common side effects are nausea, vomiting, abdominal pain, diarrhoea, flushing, bronchospasm, fever, myalgia and injection site reactions.

Intravenous iron carboxymaltose 

Ferric carboxymaltose (FCM) consists of a ferric hydroxide core stabilised by a carbohydrate shell (16) that allows for controlled delivery of iron to target tissues. Several randomised trials have shown that intravenous FCM rapidly improves Hb levels and replenishes depleted iron stores in patients with ID anaemia, including, for example, those with chronic kidney disease (17). FCM is administered via drip infusion (up to a maximum single dose of 1000 mg of iron, but not exceeding 15 mg/kg or the calculated cumulative dose) or bolus injection - at a maximum single dose of up to 200 mg of iron up to three times per week (16).
Anker et al (18) studied the effects of intravenous FCM versus placebo in 459 HF patients (left ventricular ejection fraction of 45 % or less, NYHA class II or III) with ID. Self-Reported Patient Global Assessment, NYHA class, 6-minute walk test distance and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score improved in the group treated with FCM.
FCM is well tolerated. Most adverse effects associated with this treatment are mild to moderate in severity, and include gastrointestinal disturbances, dizziness, rash and injection-site reactions (16).

IV - Intravenous iron therapy in non-anaemic heart failure patients

A large, recent study (19) found that ID (ferritin <100 μg/l, or ferritin 100–300 μg/l with transferrin saturation <20%) is present in 37% of stable chronic systolic HF patients. Iron deficiency was more prevalent in women, mostly with NYHA class IV, higher N-terminal pro-type B natriuretic peptide and C-reactive protein levels. Regarding outcome, a multivariable analysis showed that ID was associated with increased risk of death or heart transplantation, irrespective of the presence of anaemia. Authors suggest that iron supplementation could be considered to improve prognosis of all HF patients with ID. Benefit of iron supplementation was later analysed in the FERRIC-HF trial which found that non-anaemic iron-deficient HF patients had less benefit from intravenous iron sucrose than anaemic patients (15) whereas in the FAIR-HF trial, the patients receiving ferric carboxymaltose showed similar symptoms, 6-minute walk test distance, and quality of life improvements whether anaemic or non-anaemic HF patients (18).

Conclusion:

Anaemia is a common and multifactorial condition associated with poor outcome in HF patients. One of the main causes of anaemia is ID. Iron deficiency can be easily detected with simple laboratory tests. Intravenous iron has emerged as a well tolerated and effective therapy to improve symptoms and quality of life in both anaemic and non-anaemic HF patients with iron deficiency. Nevertheless, larger-scale and longer-term studies are necessary to confirm the safety and efficacy of this therapy in HF patients, especially in those without anaemia.