Patients with chronic heart failure and anaemia present many diagnostic and management dilemmas. This article discusses the importance of a thorough investigation of the patient.
Chronic heart failure (CHF) and anaemia frequently co-exist.1 One may cause the other, and anaemia in a patient with CHF is associated with more severe symptoms and poorer prognosis.2 3 4 As many as 50% of patients with the heart failure syndrome will have a normal ejection fraction (HeFNEF),5 6 and the prevalence and prognostic significance of anaemia is similar regardless of heart failure phenotype.7 8 9
The pathophysiological relationship between heart failure and anaemia is incompletely understood. The majority of trials targeting anaemia in patients with CHF have been conducted in patients with heart failure, reduced ejection fraction (HeFREF) and iron deficiency, but definitive data as to whether anaemia is a therapeutic target is lacking. In this review, we provide an overview of the problem of anaemia in patients with CHF focussing on patients with HeFREF.
The prevalence of anaemia varies greatly in different heart failure registry and trial populations (figure 1); perhaps as many as 40% of patients with CHF are anaemic (haemoglobin <13g/dL for men; <12g/dL for women).4
Figure 1. Prevalence of anaemia in different patient populations
The difference in prevalence depends upon the population studied and definition of anaemia used; prevalence generally increases with age, the severity of LV systolic dysfunction and renal dysfunction. The cause of anaemia in patients with CHF is multifactorial;10 11 a combination of disease severity, comorbidities, poor diet, haematinic deficiencies, and side-effects of treatment (figure 2).
Figure 2. Causes of anaemia in patients with heart failure
Heart failure as a cause of anaemia
Activation of the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure causes salt and water retention that increases plasma volume and ultimately leads to the signs and symptoms of heart failure – venous congestion.12 Dilution of the serum due to increased plasma volume causes a relative reduction in serum components, including haemoglobin. Approximately half of the patients with heart failure and anaemia may have haemodilution as a contributing factor.13
Heart failure is a pro-inflammatory state. It is associated with increased levels of circulating inflammatory cytokines such as interleukin-6 and tumour necrosis factor,14 15 levels of which are positively correlated with risk of death.16 Pro-inflammatory states are associated with reduced erythropoietin (EPO) levels and reduced iron metabolism17 18 both of which may contribute to anaemia in patients with CHF.19 20
Haematinic deficiencies – vitamin B12, folate and iron.
Venous congestion itself may contribute to anaemia. Malnutrition is a common cause of anaemia worldwide,21 and many patients with CHF display signs malnutrition that may be due to impaired absorption of nutrients by oedematous bowel mucosa.22 23 However, vitamin B12 or folate deficiencies are uncommon,24 25 26 27 iron deficiency anaemia (IDA) is far more common, but the prevalence varies greatly depending upon the definition used (figure 3). In the general population, iron deficiency without anaemia is approximately three times more common than IDA.28
Figure 3. Prevalence of iron deficiency and iron deficiency anaemia by patient populations
Iron plays a central role in erythropoiesis but also in cellular respiration, and oxygen uptake, transport and storage (figure 4).29 30 Iron deficiency is associated with reduced exercise capacity and worse outcome in patients with CHF regardless of the presence of anaemia.31 32
Figure 4. Title: Physiological roles of iron
NICE currently recommend a diagnostic cut-off for iron deficiency of ferritin levels <15ng/mL. However, ferritin is an acute phase protein, levels of which must always be interpreted in the context of comorbidities and inter-current illness - normal ferritin does not exclude iron deficiency.33
The British Society of Gastroenterology recommends a diagnostic cut-off of <50ng/mL in patients with coexistent inflammatory disease while conceding that the cut-off may be even higher.33 Current European Society of Cardiology (ESC) heart failure guidelines define iron deficiency as ferritin <100ng/mL or ferritin 100-300 ng/mL and transferrin saturations <20%.34
Additional indicators of iron deficiency such as low mean cell volume (MCV), low mean cell haemoglobin levels (MCH), low serum iron levels, low transferrin saturations (TSAT - serum iron levels as a percentage of the total iron binding capacity of the serum), and raised total iron binding capacity (a measure of the amount of transferrin available to bind to iron in the serum) may help to identify iron deficiency in a patient with pseudo-normal ferritin levels.33
Indeed, data from the largest available single site study of unselected patients suggests that ferritin correlates poorly with iron levels, anaemia prevalence and adverse outcome in patients with heart failure, with other measures of iron deficiency such as serum iron, TSAT, MCV and MCH correlating more strongly with one another, the prevalence of IDA and with adverse outcome.3
Effect of comorbidities
Approximately, one in five patients with heart failure have chronic kidney disease (CKD),35 36 37 and as many as 50% of patients with CHF have an estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2. The prevalence of anaemia rises with falling eGFR: approximately half of patients with an eGFR <50 ml/min/1.73m2 will be anaemic. EPO deficiency and resistance is common in patients with CKD.38 39
Side-effects of treatment
Angiotensin-converting enzyme inhibitors (ACEI)
ACE inhibitors were the first medication proved to improve the prognosis of patients with CHF in a randomised controlled trial. However, some non-cardiovascular effects of ACEI may contribute to anaemia in patients with CHF. For example, angiotensin II stimulates production of red blood cell precursor cells via activation of angiotensin II receptor type 1 on blast cells. Furthermore, ACEI inhibits the breakdown of N-acetyl-seryl-aspartyl-lysyl-proline – an oligopeptide that suppresses haematopoetic stem cell proliferation. Finally, reduced angiotensin II levels cause increased renal perfusion which reduces EPO secretion and may also contribute to anaemia in patients with CHF.40 41 42 43
Anti-platelet and anticoagulant medications
Ischaemic heart disease accounts for approximately 50% of cases of CHF,35,36 and antiplatelet agents such as aspirin are almost universally used as part of the treatment of coronary artery disease.44
Treatment with aspirin (and other non-steroidal anti-inflammatory drugs) is the second most common cause of IDA in the western world after menstrual blood loss. 33
Similarly, atrial fibrillation (AF) is a common comorbidity in patients with CHF (38-42%).35 36 45 In the absence of a contraindication such as high bleeding risk, current guidelines recommend that all patients with CHF and AF are treated with oral anticoagulant medications (either warfarin or direct oral anti-coagulant (DOAC)) to reduce stroke risk. Overall, approximately 3 out of every 4 patients with CHF will take either an anti-platelet or anti-coagulant, potentially increasing the risk of sub-acute (and acute) GI blood loss.
One danger of considering anaemia as an aspect of heart failure syndrome is the possibility that malignancy may be overlooked. Patients with CHF are often elderly and at risk of malignancy. Thus, the cause must always be thoroughly investigated in patients with CHF AND iron deficiency anaemia: treatment then depends on the results of the investigation. All patients require a full blood count, blood film and haematinics, and most patients will go on to have GI evaluation (figure 5).33
Figure 5 Simplified flow chart for investigating and treating anaemia in a patient with CHF. IV iron or ESA has a relatively small role
NICE recommend that all patients with IDA (ferritin <15ng/mL; Hb <13 g/dL in men; Hb <12 g/dL in women) aged over 60 are urgently referred for further investigations for a suspected malignancy, and that all patients with iron deficiency and a haemoglobin <12 g/dL for men or <10 g/dL for women are referred to a gastroenterology specialist for further evaluation, regardless of age or co-morbidities. Upper GI endoscopy may identify a potential cause in up to 50% of cases. Up to 10%, particularly older patients, will have synchronous upper and lower GI tract lesions therefore it is recommended that most patients also have lower GI endoscopy.33
Whether patients with non-anaemic iron deficiency warrant further investigation is unclear. The prevalence of GI malignancy in patients in the general population with non-anaemic iron deficiency is low (0.9%) although the risk of GI malignancy is five times greater than that of patients with normal iron studies.50
Current guidelines cautiously recommend coeliac screening in all patients with non-anaemic iron deficiency and GI investigations in “high risk patients” for example, those aged over 50 – which encompasses most patients with CHF.
Patients with CHF and anaemia present many diagnostic and management dilemmas –treatment must always be guided by the results of a thorough investigation. Heart failure as the cause of anaemia, particularly IDA, must always be a diagnosis of exclusion. While treatments of iron deficiency in patients with CHF may offer symptomatic benefit, the impact on mortality is unknown. Further work is required.
Dr Joseph J Cuthbert, Department of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingston upon Hull
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