Heart, Lung and Circulation

Iron Deficiency in Heart Failure Patients and Benefits of Iron Replacement on Clinical Outcomes Including Comorbid Depression

Published:November 19, 2021DOI:


      Iron deficiency and depression are prevalent comorbidities in the setting of heart failure. Both conditions are associated with poorer patient outcomes including mortality, hospitalisation and quality of life. Iron replacement has come to the fore as a means to improve patient outcomes. This review aims to assess the current literature regarding the benefits of iron supplementation for iron deficient heart failure patients including potential improvements in depression.

      Methods and Results

      The databases of Medline, EMBASE, the Cochrane library of systematic reviews, Central Register of Controlled Trials, PubMed, Web of Science and were searched for studies with relevant patient outcomes. A total of 18 studies were identified and included in the review. In essence, intravenous iron was found to be beneficial for New York Heart Association (NYHA) classification, quality of life measures, heart failure (HF) hospitalisation and aerobic capacity. Oral iron however was not beneficial. Research surrounding intravenous iron improving cardiovascular mortality, time to first hospitalisation and changes in depression status is lacking.


      Further research is required to elucidate the advantages of intravenous iron for iron deficient heart failure patients on their depression, mortality and first admission to hospital. Consensus is required regarding which form of iron and the treatment regime that should be adopted for future clinical guidelines.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Klip I.T.
        • Comin-Colet J.
        • Voors A.A.
        • Ponikowski P.
        • Enjuanes C.
        • Banasiak W.
        • et al.
        Iron deficiency in chronic heart failure: an international pooled analysis.
        Am Heart J. 2013; 165: 575-582.e3
        • Felker G.M.
        • Adams Jr., K.F.
        • Gattis W.A.
        • O'Connor C.M.
        Anemia as a risk factor and therapeutic target in heart failure.
        J Am Coll Cardiol. 2004; 44: 959-966
        • Rutledge T.
        • Reis V.A.
        • Linke S.E.
        • Greenberg B.H.
        • Mills P.J.
        Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes.
        J Am Coll Cardiol. 2006; 48: 1527-1537
        • Anand I.S.
        • Gupta P.
        Anemia and iron deficiency in heart failure: current concepts and emerging therapies.
        Circulation. 2018; 138: 80-98
        • Jiang W.A.J.
        • Christopher E.
        • Kuchibhatla M.
        • Gaulden L.H.
        • Cuffe M.S.
        • Blazing M.A.
        • et al.
        Relationship of depression to increased risk of mortality and rehospitalisation in patients with congestive heart failure.
        Arch Intern Med. 2001; 161: 1849-1856
        • Yohannes A.M.
        • Willgoss T.G.
        • Baldwin R.C.
        • Connolly M.J.
        Depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease: prevalence, relevance, clinical implications and management principles.
        Int J Geriatr Psychiatry. 2010; 25: 1209-1221
        • Jankowska E.A.
        • Von Haehling S.
        • Anker S.D.
        • MacDougall I.C.
        • Ponikowski P.
        Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives.
        Eur Heart J. 2013; 34: 816-826c
        • Bolger A.P.
        • Bartlett F.R.
        • Penston H.S.
        • O’Leary J.
        • Pollock N.
        • Kaprielian R.
        • et al.
        Intravenous iron alone for the treatment of anemia in patients with chronic heart failure.
        J Am Coll Cardiol. 2006; 48: 1225-1227
        • Jankowska E.A.
        • Rozentryt P.
        • Witkowska A.
        • Nowak J.
        • Hartmann O.
        • Ponikowska B.
        • et al.
        Iron deficiency: an ominous sign in patients with systolic chronic heart failure.
        Eur Heart J. 2010; 31: 1872-1880
        • Charles-Edwards G.
        • Amaral N.
        • Sleigh A.
        • Ayis S.
        • Catibog N.
        • McDonagh T.
        • et al.
        Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency.
        Circulation. 2019; 139: 2386-2398
        • Avni T.
        • Leibovici L.
        • Gafter-Gvili A.
        Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta-analysis.
        Eur J Heart Fail. 2012; 14: 423-429
        • Bekelman D.B.
        • Havranek E.P.
        • Becker D.M.
        • Kutner J.S.
        • Peterson P.N.
        • Wittstein I.S.
        • et al.
        Symptoms, depression, and quality of life in patients with heart failure.
        J Card Fail. 2007; 13: 643-648
        • Byrne C.J.
        • Toukhsati S.R.
        • Toia D.
        • O'Halloran P.D.
        • Hare D.L.
        Hopelessness and cognitive impairment are risk markers for mortality in systolic heart failure patients.
        J Psychosom Res. 2018; 109: 12-18
        • Blumenthal J.A.
        • Babyak M.A.
        • O’Connor C.
        • Keteyian S.
        • Landzberg J.
        • Howlett J.
        • et al.
        Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial.
        JAMA. 2012; 308: 465-474
        • O’Connor C.M.
        • Jiang W.
        • Kuchibhatla M.
        • Silva S.G.
        • Cuffe M.S.
        • Callwood D.D.
        • et al.
        Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial.
        J Am Coll Cardiol. 2010; 56: 692-699
        • Angermann C.E.
        • Gelbrich G.
        • Stork S.
        • Gunold H.
        • Edelmann F.
        • Wachter R.
        • et al.
        Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: the MOOD-HF randomized clinical trial.
        JAMA. 2016; 315: 2683-2693
        • Maes M.
        • Van de Vyvere J.
        • Vandoolaeghe E.
        • Bril T.
        • Demedts P.
        • Wauters A.
        • et al.
        Alterations in iron metabolism and the erythron in major depression: further evidence for a chronic inflammatory process.
        J Affect Disord. 1996; 40: 23-33
        • Vahdat Shariatpanaahi M.
        • Vahdat Shariatpanaahi Z.
        • Moshtaaghi M.
        • Shahbaazi S.H.
        • Abadi A.
        The relationship between depression and serum ferritin level.
        Eur J Clin Nutr. 2007; 61: 532-535
        • Stewart R.
        • Hirani V.
        Relationship between depressive symptoms, anemia, and iron status in older residents from a national survey population.
        Psychosom Med. 2012; 74: 208-213
        • Kim J.
        • Wessling-Resnick M.
        Iron and mechanisms of emotional behavior.
        J Nutr Biochem. 2014; 25: 1101-1107
        • Ponikowski P.
        • Kirwan B.-A.
        • Anker S.D.
        • McDonagh T.
        • Dorobantu M.
        • Drozdz J.
        • et al.
        • AFFIRM-AHF investigators
        Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.
        Lancet. 2020; 396: 1895-1904
        • Bailly H.
        • Beunardeau M.
        • Cohen A.
        • Harle L.
        • Hernandorena I.
        • Vidal J.S.
        • et al.
        The determinants of iron deficiency: study from the PREDICT cohort.
        Eur Geriatr Med. 2019; 10: S8
        • Boman K.
        • Olofsson M.
        • Bergman A.C.R.
        • Brannstrom M.
        Anaemia, but not iron deficiency, is associated with clinical symptoms and quality of life in patients with severe heart failure and palliative home care: a substudy of the PREFER trial.
        Eur J Intern Med. 2017; 46: 35-40
        • Jankowska E.A.
        • Witkowska A.
        • Von Haehling S.
        • Doehner W.
        • Majda J.
        • Banasiak W.
        • et al.
        Iron deficiency predisposes to depression in men with stable systolic heartfailure.
        Eur J Heart Fail, Supplement. 2011; 10: S180
        • Beck-da-Silva L.
        • Piardi D.
        • Soder S.
        • Rohde L.E.
        • Pereira-Barretto A.C.
        • de Albuquerque D.
        • et al.
        IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia.
        Int J Cardiol. 2013; 168: 3439-3442
        • Karavidas A.
        • Trogkanis E.
        • Farmakis D.
        • Papingiotis G.
        • Matzaraki V.
        • Perpinia A.
        • et al.
        Oral sucrosomial iron improves quality of life in heart failure patients with iron deficiency: A preliminary proof-of-concept study.
        Blood Transfus. 2019; 17: s11
        • Lewis G.D.
        • Malhotra R.
        • Hernandez A.F.
        • McNulty S.E.
        • Smith A.
        • Felker G.M.
        • 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: 1958-1966
        • Zdravkovic S.C.
        • Nagorni S.P.
        • Cojbasic I.
        • Mitic V.
        • Cvetkovic P.
        • Nagorni I.
        • et al.
        Effects of 6-months of oral ferrous and ferric supplement therapy in patients who were hospitalized for decompensated chronic heart failure.
        J Int Med Res. 2019; 47: 3179-3189
        • Anker S.D.
        • Comin Colet J.
        • Filippatos G.
        • Willenheimer R.
        • Dickstein K.
        • Drexler H.
        • et al.
        Ferric carboxymaltose in patients with heart failure and iron deficiency.
        N Engl J Med. 2009; 361: 2436-2448
        • Okonko D.O.
        • Grzeslo A.
        • Witkowski T.
        • Mandal A.K.
        • Slater R.M.
        • Roughton M.
        • et al.
        Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial.
        J Am Coll Cardiol. 2008; 51: 103-112
        • Ponikowski P.
        • van Veldhuisen D.J.
        • Comin-Colet J.
        • Ertl G.
        • Komajda M.
        • Mareev V.
        • et al.
        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: 657-668
        • Toblli J.E.
        • Lombrana A.
        • Duarte P.
        • Di Gennaro F.
        Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency.
        J Am Coll Cardiol. 2007; 50: 1657-1665
        • van Veldhuisen D.J.
        • Ponikowski P.
        • van der Meer P.
        • Metra M.
        • Bohm M.
        • Doletsky A.
        • et al.
        Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency.
        Circulation. 2017; 136: 1374-1383
        • Yeo T.J.
        • Yeo P.S.D.
        • Hadi F.A.
        • Cushway T.
        • Lee K.Y.
        • Yin F.F.
        • et al.
        Single-dose intravenous iron in Southeast Asian heart failure patients: a pilot randomized placebo-controlled study (PRACTICE-ASIA-HF).
        ESC Heart Fail. 2018; 5: 344-353
        • Comin-Colet J.
        • Lainscak M.
        • Dickstein K.
        • Filippatos G.S.
        • Johnson P.
        • Luscher T.F.
        • et al.
        The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: A subanalysis of the FAIR-HF study.
        Eur Heart J. 2013; 34: 30-38
        • Kaminsky B.M.
        • Pogue K.T.
        • Hanigan S.
        • Koelling T.M.
        • Dorsch M.P.
        Effects of total dose infusion of iron intravenously in patients with acute heart failure and anemia (hemoglobin < 13 g/dl).
        Am J Cardiol. 2016; 117: 1942-1946
        • Dalal J.
        • Katekhaye V.
        • Jain R.
        Effect of ferric carboxymaltose on hospitalization and mortality outcomes in chronic heart failure: A meta-analysis.
        Indian Heart J. 2017; 69: 736-741
        • Jankowska E.A.
        • Tkaczyszyn M.
        • Suchocki T.
        • Drozd M.
        • von Haehling S.
        • Doehner W.
        • et al.
        Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials.
        Eur J Heart Fail. 2016; 18: 786-795
        • Atherton J.J.
        • Sindone A.
        • De Pasquale C.G.
        • Driscoll A.
        • MacDonald P.S.
        • Hopper I.
        • et al.
        National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of heart failure 2018.
        Med J Aust. 2018; 209: 363-369
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • Bueno H.
        • Cleland J.F.
        • Coats A.J.S.
        • 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: 891-975
        • Cunha G.J.L.
        • Rocha B.M.L.
        • Menezes Falcao L.
        Iron deficiency in chronic and acute heart failure: A contemporary review on intertwined conditions.
        Eur J Intern Med. 2018; 52: 1-7
        • Zhang S.
        • Zhang F.
        • Du M.
        • Huang K.
        • Wang C.
        Efficacy and safety of iron supplementation in patients with heart failure and iron deficiency: A meta-analysis.
        Br J Nutr. 2019; 121: 841-848
        • Zhou X.
        • Xu W.
        • Xu Y.
        • Qian Z.
        Iron supplementation improves cardiovascular outcomes in patients with heart failure.
        Am J Med. 2019; 132: 955-963
        • Anker S.D.
        • Kirwan B.A.
        • van Veldhuisen D.J.
        • Filippatos G.
        • Comin-Colet J.
        • Ruschitzka F.
        • et al.
        Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis.
        Eur J Heart Fail. 2018; 20: 125-133
        • Friedmann E.
        • Thomas S.A.
        • Liu F.
        • Morton P.G.
        • Chapa D.
        • Gottlieb S.S.
        • et al.
        Relationship of depression, anxiety, and social isolation to chronic heart failure outpatient mortality.
        Am Heart J. 2006; 152: 940.e1-940.e8
        • Haworth J.E.
        • Moniz-Cook E.
        • Clark A.L.
        • Wang M.
        • Waddington R.
        • Cleland J.G.
        Prevalence and predictors of anxiety and depression in a sample of chronic heart failure patients with left ventricular systolic dysfunction.
        Eur J Heart Fail. 2005; 7: 803-808
        • Hare D.L.
        • Davis C.R.
        Cardiac Depression Scale: validation of a new depression scale for cardiac patients.
        J Psychosom Res. 1996; 40: 379-386