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European Journal of Heart Failure 2003 5(1):3-4; doi:10.1016/S1388-9842(02)00161-7
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© 2002 European Society of Cardiology

Anaemia in heart failure: its diagnosis and management

Anne Parsi and Franz Xaver Kleber*

Department of Internal Medicine, UKB Warener Street 7, D-12683 Berlin, Germany

* Corresponding author. Tel.: +49-30-56-81-36-01; fax: +46-30-56-81-36-03 E-mail address: fxkleber{at}ukb.de

Chronic heart failure (CHF) is a common syndrome [1] affecting more than 20 million people world-wide and approximately 7 million people in the European community. The incidence and prevalence of CHF have been shown to increase sharply with age [2]. Prognosis is poor; 12 week mortality was 14% in the recently reported Euroheart survey [3].

Anaemia as a cofactor in CHF has not been well evaluated and its contribution is ill defined [4,5].

The following factors have to be considered:

  1. There may be reduced intestinal iron uptake associated with cardiac cachexia and malabsorption.
  2. Tumour necrosis factor alpha, which is increased in patients with CHF, can lead to depression of bone marrow and interferes with the action and utilisation of erythropoietin and iron.
  3. CHF activates the renin–angiotensin–aldosterone-system and vasopressin, resulting in sodium and water retention and dilutional anaemia.
  4. CHF can lead to renal dysfunction due to renal vasoconstriction and ischemia resulting in an increase in erythropoietin. Usually renal anaemia develops in chronic renal dysfunction with serum creatinine over 3.5 mg/dl or a creatinine clearance below 30 ml/min.
  5. Diabetes as well as arterial hypertension can contribute to heart failure and are frequent concomitant diseases. Both can also cause further renal dysfunction.
  6. High doses of ACE-inhibitors can impair the response to erythropoietin treatment in hemodialysis patients [6].
  7. Chronic anaemia contributes to CHF because an increased cardiac output is required to deliver oxygen to the tissues. This leads to an increase in myocardial oxygen demands and stimulates volume overload hypertrophy [7].
  8. Treatment of the disease underlying CHF, principally coronary artery disease, with agents such as aspirin and warfarin can contribute to blood loss and anaemia due to gastrointestinal bleeding.
  9. A rightward shift of the oxyhemoglobin dissociation curve on exercise has been shown in patients with CHF [8]. Erythropoietin treatment can further increase 2,3 DPG levels with a further increase in oxygen extraction [9,10].
  10. Renal failure, hypercirculation due to therapeutic arterio-venous shunts and anaemia, hypertension as well as left ventricular hypertrophy interact in various ways and contribute further to heart failure and vice versa to renal failure.

Taking into consideration all of the above mentioned factors, anaemia favours the progression of heart failure.

Anaemia has been recognised to exacerbate pre-existing heart failure [11]. Furthermore recent literature suggests a far more important role of anaemia in the natural course of CHF. In addition, a vicious cycle between anaemia, chronic renal failure and exacerbation of heart failure can be assumed.

Thus it seems logical, that Silverberg et al. [12,13] suggested treatment with a combination of erythropoietin and intravenous iron. This combination has been shown to be safe and effective in patients with CHF before starting dialysis as well as in patients on dialysis. Intravenous iron administration seems to be more effective than oral administration, possibly because of iron absorption disturbances in CHF patients. Intravenous iron therapy can reduce the need for high erythropoietin doses, which it might be preferable to avoid since this can lead to an increase in arterial pressure, which may not be desirable. Improvement of symptoms of CHF and exercise capacity has also been observed [12–14].

These benefits might be more pronounced in the early stages of CHF, than in patients with end stage CHF under dialysis and recombinant erythropoietin therapy [15].

If treatment with erythropoietin and iron is preceded by exclusion of other causes of anaemia, for example intestinal blood loss or fluid overload, it might be quite effective for improvement of symptoms and reduction of left ventricular size [5]. Prognostic benefits are unproven, but cannot be excluded.

Recent studies have investigated a novel erythropoiesis stimulating protein (NESP) which has a three-times longer half-life due to addition of two extra carbohydrate chains [16]. NESP is a hyperglycosylated analogue of recombinant human erythropoietin that was used in 1500 patients for stimulation of erythropoiesis.

In conclusion, moderate and severe anaemia of any origin can exacerbate CHF. Patients with heart failure may benefit from therapy of anaemia. Favourable influences on the long-term course are possible but so far unproven. Further studies are needed.


   References
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  2. Johannson S., Wallander M.A., Ruigomez A., Garcia Rodriguez L.A. Incidence of newly diagnosed heart failure in UK general practice. Eur. J. Heart Failure (2001) 3:225–231.[Abstract/Free Full Text]
  3. Cleland J.G.F., Swedberg K., Cohen-Solal A., et al. The Euro Heart Failure Survey of the EUROHEART survey programme. A survey on the quality of care among patients with heart failure in Europe. Eur Heart J (2002) 2:123–132.
  4. Levin A., Foley R.N. Cardiovascular disease in chronic renal insufficiency. Am. J. Kidney Dis. (2000) 36(Suppl_3):S24–S30.[Web of Science][Medline]
  5. Kausz A.T., Obrador G.T., Pereira B.J. Anemia management in patients with chronic renal insufficiency. Am. J. Kidney Dis. (2000) 36(Suppl 3):S39–S51.[CrossRef][Web of Science][Medline]
  6. Albitar S., Genin R., Fen-Chong M., Serveauz M.O., Bourgeon B. High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol. Dial. Transplant (1998) 13:1206–1210.[Abstract/Free Full Text]
  7. Aessopos A., Farmakis D., Karagiorga M., et al. Cardiac involvement in thalassemia intermedia: a multicenter study. Blood (2001) 97:3411–3416.[Abstract/Free Full Text]
  8. Agostoni P., Wasserman K., Perego G.B., et al. Oxygen transport to muscle during exercise in chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am. J. Cardiol. (1997) 79:1120–1124.[CrossRef][Web of Science][Medline]
  9. Metevier F., Marchais S.J., Guerin A.P., Pannier B., London G.M. Pathophysiology of anaemia: focus on the heart and blood vessels. Nephrol. Dial. Transplant (2000) 15(Suppl 3):14–18.[Abstract/Free Full Text]
  10. Birgegard G., Sandhagen B. Erythropoetin treatment can increase 2,3-diphospho-glycerate levels in red blood cells. Scand. J. Clin. Lab. Invest. (2001) 61:337–340.[Web of Science][Medline]
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  12. Silverberg D.S., Wexler D., Blum M., et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anaemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalisation. JACC (2000) 35:1737–1744.[Abstract/Free Full Text]
  13. Silverberg D.S., Wexler D., Sheps D., et al. The effect of correction of mild anaemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomised controlled study. JACC (2001) 37:1775–1780.[Abstract/Free Full Text]
  14. Cody L., Daly C., Campbell M., et al. Recombinat human erythropoietin for chronic renal failure anaemia in pre-dialysis patients (Cochrane Review). Cochrane Database Syst. Rev. (2001) 4:CD 003266.[Medline]
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  16. Macdougall I.C. Novel erythropoiesis stimulating protein. Semin. Nephrol. (2000) 20:375–381.[Web of Science][Medline]

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