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Anaemia and iron deficiency associated with increased mortality in HF patients

Literature - Cleland JGF et al., JAMA Cardiol. 2016

Cleland JGF, Zhang J, Pellicori P, et al.
JAMA Cardiol. 2016;1(5):539-547


Prognosis of HF patients is worse in the presence of anaemia or iron deficiency [1]. Correction of iron deficiency in these patients does not always improve anaemia, in which case erythropoiesis-stimulating peptides may be administered to stimulate erythrocyte production [2]. In a large trial, darbepoetin alfa treatment only resulted in a modest improvement of quality of life and no reduction of re-hospitalisations or death [3]. On the other hand, intravenous administration of iron has been associated with improvements in symptoms, functional class and morbidity, likely independently of the severity of anaemia [4,5].
It is not clear whether anaemia or iron deficiency is the key driver of worsening the symptoms and prognosis in HF patients. Understanding the relationship between HF, anaemia and iron deficiency, can provide useful information and guide treatment decisions in this context.
In this study, the epidemiology of anaemia and iron deficiency in 4456 patients with suspected HF was evaluated. HF diagnoses were categorised according to 5 cardiac phenotypes based on echocardiography and measurement of NT-proBNP, described in the ESC guidelines of 2008 [5].

Main results

  • The median age was 73 years, 39.5% were women, 40.2% had EF<40%, 15.9% had EF>40% with diastolic dysfunction or NT-proBNP>400 pg/mL (HFnEF type 1), and 10.4% had no substantial echocardiographic abnormality and NT-proBNP>400 pg/mL (HFnEF type 2).
  • Anaemia was present in 27.8% of patients. In 14.4% anaemia was mild, in 7.9% moderate and in 5.4% severe. The prevalence of anaemia was higher in patients with EF<40% (33.3%), as well as in patients with HFnEF type 1 (32.8%) and HFnEF type 2 (34.0%), compared with individuals without HF.
  • Depending on the definition, 43.2% to 68.0% of patients with anaemia had a low serum iron concentration or transferrin saturation, compared with 14.7% to 35.2% of the patients without anaemia.
  • In a multivariable analysis, serum iron was independently and directly associated with haemoglobin concentrations (coefficient: 0.11; 95% CI: 0.10-0.12; P < 0.001), heart rate (coefficient: 0.10; 95% CI: 0. 70-0.13; P < 0.001), serum sodium (coefficient: 0.05; 95% CI: 0.04-0.07; P < 0.001) and eGFR (coefficient: 0.01; 95% CI: 0.005-0.01; P < 0.001)
  • In a multivariable model restricted to hematinic variables and key clinical characteristics, the following factors were associated with higher all-cause mortality: lower haemoglobin (t= -5,07, HR: 0.92, 95%CI: 0.89-0.95, P<0.0001) and serum iron concentrations (t= -2,73, HR: 0.98, 95%CI: 0.97-0.99, P=0.007), the highest quintile of ferritin (t= 1.93, HR: 1.18, 95%CI: 0.99-1.41, P=0.056), and higher serum vitamin B12 concentrations (t= 3,30, HR: 1.03, 95%CI: 1.01-1.05, P=0.001).
  • Associations with all-cause mortality were weaker in an extended model, and the association with serum iron was lost. In the extended model, only serum iron concentrations was associated with CV mortality only.


Anaemia is common in HF patients with or without reduced left ventricular ejection fraction and often associated with iron deficiency. Both anaemia and iron deficiency were associated with an increase in all-cause mortality. The current data may help design and interpret future studies evaluating treatment of these conditions.

Find this article online at JAMA Cardiology


1. Jankowska EA, von Haehling S, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013;34(11):816-829.
2. Silverberg DS. The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome. Heart Fail Rev. 2011;16(6):609-614.
3. Swedberg K, Young JB, Anand IS, et al; RED-HF Committees; RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368(13):1210-1219.
4. Anker SD, Comin Colet J, Filippatos G, et al; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448.
5. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657-668.
6. Dickstein K, Cohen-Solal A, Filippatos G, et al; ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) [published correction appears in Eur J Heart Fail. 2010;12(4):416]. Eur J Heart Fail. 2008;10(10):933-989.

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