Specialist Care

Anaemia has long been recognised as a common comorbidity of chronic heart failure (CHF) with a significant impact on patient outcomes. Iron deficiency, without anaemia, has more recently been acknowledged as an independent risk factor in CHF patients.1 Patients with CHF are more susceptible to iron deficiency with or without anaemia for a variety of reasons. The main factors contributing to anaemia include:

  • Renal dysfunction: Impaired kidney function is common in patients with CHF and can lead to reduced erythropoietin secretion.2
  • Haemodilution: An increased plasma volume caused by CHF can lead to reduced haematocrit.3
  • Bone marrow dysfunction: A reduced blood supply to the bone marrow as a result of CHF can cause bone marrow dysfunction, limiting haemoglobin and progenitor cell production.2
  • Haematinic deficiencies: Any deficiency in the molecules needed for haematopoeisis can lead to anaemia. These include vitamin B12, folate and, particularly, iron deficiency.4
  • Iron deficiency: Iron deficiency anaemia can result from absolute or functional iron deficiency, and a tendency towards iron deficiency in patients with CHF also has a variety of causes:
    • Inflammation and malabsorption: CHF affects many organs, including the gastrointestinal tract.5 A generalised state of inflammation, characteristic of heart failure, causes hepcidin release, blocking intestinal absorption.6 Reduced blood flow to the gut also acts to reduce the ability to absorb iron.5
    • Medication: Chronic use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) in patients with heart failure can trigger blood loss via the intestinal tract, leading to iron deficiency.2 Drug-induced anorexia may also be caused by angiotensin-converting enzyme inhibitors, reducing iron intake.7
    • Reduced dietary intake: CHF patients may reduce their diet, and consequently their iron intake, because of a loss of appetite resulting from oedema in the stomach and intestines; nausea or reduced strength/breathlessness.7

Prevalence of iron deficiency and anaemia by NYHA class

Figure 1: An international pooled analysis showed the increasing prevalence of iron deficiency with worsening disease. Iron deficiency and/or anemia stratified by NYHA functional class. Prevalence of ID and/or anemia per NYHA functional class.1

THE IMPACT OF IRON DEFICIENCY IN CHRONIC HEART FAILURE

Patients with CHF and iron deficiency will experience a reduced quality of life, including feeling worried, fatigued and out of breath, and reduced exercise tolerability compared to iron replete patients.9,10 Not only that, they will also be more likely to need a heart transplant and have an increased risk of death than those patients without iron deficiency. 11

Event-free survival in patients with chronic heart failure with and without iron deficiency

chf event graphFigure 2: Event-free, 8-year survival for patients with chronic heart failure with and without iron deficiency. Differences in mortality rates were significant at 6 months, and remained so through-out follow-up (p<0.001).1

THE IMPACT OF IRON DEFICIENCY IN CHRONIC HEART FAILURE

The prevalence of anaemia is higher in hospitalised patients than those with stable heart disease; several studies looking at the prevalence of anaemia and associated mortality risk are summarised in Table 1.2

Study (N) Patient characteristics Definition of anaemia Prevalence of anaemia Adjusted relative risk of mortality
Kosiborod 2005 (NHC Project)N=50,405 Discharge diagnosis of heart failure Haematocrit:
M: <40%
F: <37%
Men: 61.2%
Women: 52.1%
Haematocrit ≤24% vs >40-44%: 1.02 (0.86-1.19)
Baggish 2007 (ICON) Acute heart failure Hb:
M:<13.0 g/dl
F:<12.0 g/dl
44% 1.72 (1.05-2.80)*
Garty 2007 (HFSIS 2003) Heart failure Hb ≤12.0 g/dl 49% 1.50 (1.29-1.75)*
Kawashiro 2008(HIJC Registry) Heart failure Hb:
M: ≤14.0 g/dl
F: ≤12.0 g/dl
44.2% 1.46 (1.18-1.80)*
Young 2008 (OPTIMIZE-HF Registry) Heart failure Hb in quartiles: quartile 1 (Hb 5.0-10.7 g/dl) and 2 (>10.7-12.1 g/dl) were mildly or severely anaemic 50% Hb ≤12.1 g/dl
25% Hb ≤ 10.7 g/dl
In-hospital mortality: per 1 g/dl
Harjola 2010 (EHFS II) Acute heart failure Hb:
M:< 13.0 g/dl
F:< 12.0 g/dl
39.4% 1.37 (1.07-1.76)*
von Haehling 2010 Acute heart failure Hb:
M:< 13.0 g/dl
F:< 12.0 g/dl
29% Hb< 12 in men or < 11 g/dl in women: 1.47 (1.09-1.98)*
Tarantini 2011 (IS-AHF) Acute heart failure Hb< 12 g/dl 31% In-hospital mortality rate: 5.3% (non-anaemic) vs 12.1% (anaemic)

*hazard ratio for anaemia vs no anaemia
Table 1: Anaemia in selected large-scale studies of patients hospitalised for or with heart failure.2

Patients with anaemia and CHF have an increased risk of hospitalisation of 43% compared to non-anaemic patients12

CHF patients with anaemia are 1.5 times more likely to die than those without13

Survival rates in anaemic and non-anaemic CHF patients

Figure 3: Event-free, 8-year survival rates in iron-deficient and non-iron-deficient CHF patients with or without anaemia.1

TREATING IRON DEFICIENCY AND ANAEMIA IN CHRONIC HEART FAILURE

The European Society of Cardiology guidelines recommend evaluation of iron status in all patients suspected of having heart failure. The underlying cause of iron deficiency and/or anaemia should be identified and treated where necessary; for example, renal disease, occult bleeding or deficiencies other than iron.14 Once the extent and cause of the patient’s iron deficiency has been established treatment options can be considered.


Figure 4: Suggested algorithm for diagnosis of iron deficiency in patients with heart failure.15

  • Dietary changes: Patients with CHF may have a poor or restricted diet caused by loss of appetite or dietary recommendations for a comorbidity such as renal disease.14 Advice on how to increase their intake of iron-rich foods, and coordinating foods to get maximum absorption, could help manage low levels of iron deficiency.
  • Oral iron supplements: Oral iron is inexpensive and widely used to treat iron deficiency despite its low bioavailability – in heart failure patients approximately only 5% of each dose is absorbed.14 Gastrointestinal side-effects are common, reported in up to 60% of patients, and often lead to poor compliance. Oral iron is generally considered unsuitable for patients with impaired gastrointestinal absorption, as is the case in heart failure. Studies of oral iron in heart failure patients have found no changes in haemoglobin, symptom severity and exercise tolerance for patients receiving iron, however, the evidence is limited.14
  • Erythropoiesis-stimulating agents (ESAs): ESAs such as darbepoetin alfa and epoetin are used to treat anaemia, often in patients with chronic kidney disease. However, as erythropoiesis requires iron, treatment is only useful if iron stores are replete. Epoetin can negatively affect iron absorption from the gut, a process already aggravated in CHF patients; therefore, intravenous iron is recommended as the best route for iron administration to support epoetin use.2
  • Intravenous iron: Original formulations include iron sucrose, low and high molecular weight iron dextran and ferric gluconate. More recent products such as ferric carboxymaltose, iron isomaltoside 1000, and ferumoxytol are more stable and allow rapid replenishment of iron levels, without formation of large amounts of non-transferrin-bound iron (NTBI). Delivering iron intravenously also avoids any absorption disorders in the gut.14

BENEFITS OF TREATING IRON DEFICIENCY IN CHRONIC HEART FAILURE

A recent meta-analysis of individual patient data from trials of ferric carboxymaltose compared with placebo in patients with chronic heart failure showed a significant reduction in the risk of recurrent hospitalisations or death due to cardiovascular events in the ferric carboxymaltose group.16

Another meta-analysis of trials of intravenous iron (ferric carboxymaltose or iron sucrose) in heart failure patients with iron deficiency reported a significant reduction in cardiovascular death or hospitalisation for worsening heart failure, improvements in NYHA class, 6-minute walking test distance and quality of life.17 These benefits were seen regardless of anaemia status.17


Table 3: Treating iron deficiency with intravenous iron alleviates heart failure symptoms17