Heart failure is a common health condition that is associated with significant morbidity and mortality. The American Heart Association estimates a prevalence of 6.2 million people in the United States between 2013 and 2016.1 In an international pooled analysis of 1506 patients with chronic heart failure, iron deficiency was identified in 50% of patients.2 This is of concern, as disorders of iron hemostasis lead to diminished iron circulation as well as functional iron in the form of hemoglobin.3 In an observational study of 157 patients with congestive heart failure, iron-deficient patients were observed to have decreased exercise tolerance and a 3-fold increased risk of mortality, regardless of anemia status.3 This is likely due to iron being a required component of metalloproteins involved in oxygen storage and oxidative phosphorylation.4,5 Iron deficiency leads to biochemical impairment in oxygen delivery, which likely leads to worse symptoms and outcomes in the setting of the preexisting structural impairment in oxygen delivery in patients with heart failure.
Thus, it seems that supplementation of iron in these patients should improve functional status and outcomes. Patients with iron deficiency anemia are generally treated with oral iron due to its efficacy, safety, and low cost.6 Additionally, intravenous (IV) iron has been shown to be associated with anaphylaxis and infection.6,7 One major disadvantage of oral iron is the increased rate of gastrointestinal side effects compared with IV iron, with one systematic review reporting an odds ratio (OR) of 3.05; 95% CI 2.07-4.48.8 Both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) guidelines recommend testing all patients with heart failure for anemia and iron deficiency, defined as ferritin <100 µg/L or ferritin 100-299 µg/L with transferrin saturation <20%.9,10 Both sets of guidelines recommend treating iron-deficient patients with symptoms of heart failure. The ESC guidelines specifically recommend using IV ferric carboxymaltose; the ACC/AHA/HFSA guidelines recommend using IV iron but no specific formulation.9,10
The evidence for these guidelines stems from a variety of randomized controlled trials (RCT) that have studied iron supplementation in patients with heart failure. The most recent and largest meta-analysis reviewed 10 RCTs with a total of 1404 iron-deficient patients with systolic heart failure who underwent treatment with iron or placebo.11 This analysis showed that iron supplementation reduced hospitalization for worsening heart failure, OR 0.39; 95% CI 0.19-0.80, and the combined endpoint of death and heart failure hospitalization, OR 0.47; 95% CI 0.32-0.69. Zhou and colleagues also found that treatment with iron improved New York Heart Association (NYHA) class, peak oxygen consumption, 6-minute walk distance, and left ventricular ejection fraction. Eight out of the 10 RCTs analyzed in this study used IV iron formulations. Of the two trials that studied oral iron supplementation, IRON 5-HF, published in 2013,was terminated early after recruitment of only 23 patients.12 The second trial, IRONOUT HF, published in 2017, found no significant benefit of oral iron supplementation in patients with heart failure with reduced ejection fraction and iron deficiency.13 The limited follow-up of patients in this study, 16 weeks, may not have been enough to detect a longer-term benefit.
There is clear evidence indicating the significant overlap of heart failure and iron deficiency. Furthermore, supplementation with IV iron appears to improve symptoms and outcomes in these patients. Both the European and American guidelines recommend testing for iron deficiency and IV repletion for those found deficient. While oral iron supplementation is not currently recommended, this is a result of a lack of data on the long-term benefit of oral iron supplementation in iron-deficient patients with heart failure, rather than a proven lack of long-term efficacy. Moving forward, large RCTs with adequate length of follow-up are needed to assess for any potential benefit of oral iron supplementation in heart failure patients.
Dr. Varun Subashchandran is a 4th year medical student at NYU Grossman School of Medicine
Peer reviewed by Dr. Adam Skolnicks, cardiology, NYU Langone Health
Image courtesy of Wikimedia Commons
- Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation. 2020;141(9):E139-E596. doi:10.1161/CIR.0000000000000757 https://www.ahajournals.org/doi/10.1161/CIR.0000000000000757
- Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(4):575-582.e3. doi:10.1016/j.ahj.2013.01.017
- Okonko DO, Mandal AKJ, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol. 2011;58(12):1241-1251. doi:10.1016/j.jacc.2011.04.040 https://pubmed.ncbi.nlm.nih.gov/21903058/
- O’Hagan JE. The iron-protein link in hæmoglobin and myoglobin. Nature. 1959;183(4658):393. doi:10.1038/183393a0
- Oexle H, Gnaiger E, Weiss G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta. 1999;1413(3):99-107. doi:10.1016/S0005-2728(99)00088-2
- Macdougall IC. Strategies for iron supplementation: oral versus intravenous. Kidney Int Suppl. 1999;55(69):S61-S66. doi:10.1046/j.1523-1755.1999.055suppl.69061.x https://pubmed.ncbi.nlm.nih.gov/10084288/
- Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ. 2013;347(7923):f4822. doi:10.1136/bmj.f4822
- Tolkien Z, Stecher L, Mander AP, Pereira DIA, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117383. doi:10.1371/journal.pone.0117383
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975. doi:10.1002/ejhf.592 https://academic.oup.com/eurheartj/article/37/27/2129/1748921
- Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. doi:10.1161/CIR.0000000000000509
- Zhou X, Xu W, Xu Y, Qian Z. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med. 2019;132(8):955-963. doi:10.1016/j.amjmed.2019.02.018
- von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail. 2019;7(1):36-46. doi:10.1016/j.jchf.2018.07.015
- Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency the IRONOUT HF randomized clinical trial. JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427 https://jamanetwork.com/journals/jama/fullarticle/2626574