Management of iron deficiency in chronic heart failure: Practical considerations for clinical use and future directions


      • The pathophysiology of iron deficiency in heart failure is summarized.
      • The major randomized trials of iron replenishment in heart failure are summarized.
      • A proposed algorithm of screening and managing iron deficiency in heart failure patients is proposed.


      Heart Failure (HF) is a global pandemic with rapidly increasing prevalence. In an attempt to maintain patients well being, the therapeutic interest has expanded to the vicious cycles that confer to HF mortality and morbidity and a number of comorbidities have been targeted. Iron deficiency represents a common comorbid condition that affects outcomes in HF. The treatment of iron deficiency is strongly supported by the cardiologic societies all over the world. Intravenous iron, primarily ferric carboxymaltose, has shown clinical benefit in this setting, irrespective of the anemia status. Practical recommendations though are lacking. In this document, we have tried to cover the practical gap and provide useful details for intravenous iron use.


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        • Ponikowski P.
        • Anker S.D.
        • AlHabib K.F.
        • Cowie M.R.
        • Force T.L.
        • Hu S.
        • et al.
        Heart failure: preventing disease and death worldwide.
        ESC Heart Fail. 2014; 1: 4-25
        • Savarese G.
        • Lund L.H.
        Global public health burden of heart failure.
        Cardiac Fail Rev. 2017; 3: 7-11
        • Capellini M.D.
        • Comin-Colet J.
        • de Francisco A.
        • Dignass A.
        • Doehner W.
        • Lam C.S.
        • et al.
        Iron deficiency across chronic inflammatory conditions: international expert opinion on definition, diagnosis, and management.
        Am J Hematol. 2017; 92: 1068-1078
        • Anand I.S.
        • Gupta P.
        Anemia and Iron deficiency in heart failure: current concepts and emerging therapies.
        Circulation. 2018; 138: 80-98
        • Dignass A.
        • Farrag K.
        • Stein J.
        Limitations of serum ferritin in diagnosing iron deficiency in inflammatory conditions.
        Int J Chronic Dis. 2018; 2018: 9394060
        • Weiss G.
        • Goodnough L.T.
        Anemia of chronic disease.
        N Engl J Med. 2005; 352: 1011-1023
        • Knovich M.A.
        • Storey J.A.
        • Coffman L.G.
        • Torti S.V.
        • Torti F.M.
        Ferritin for the clinician.
        Blood Rev. 2009; 23: 95-104
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • Bueno H.
        • Cleland J.G.
        • Coats A.J.
        • 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 Heart J. 2016; 37: 2129-2200
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • Butler J.
        • Casey Jr., D.E.
        • Colvin M.M.
        • 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.
        J Am Coll Cardiol. 2017; 70: 776-803
        • Ezekowitz J.A.
        • O'Meara E.
        • McDonald M.A.
        • Abrams H.
        • Chan M.
        • Ducharme A.
        • et al.
        2017 comprehensive update of the Canadian cardiovascular society guidelines for the Management of Heart Failure.
        Can J Cardiol. 2017; 33: 1342-1433
        • NHFA CSANZ Heart Failure Guidelines Working Group
        • Atherton J.J.
        • Sindone A.
        • De Pasquale C.G.
        • Driscoll A.
        • MacDonald P.S.
        • et al.
        Heart Lung Circ. 2018; 27: 1123-1208
        • Grote Beverborg N.
        • Klip I.T.
        • Meijers W.C.
        • Voors A.A.
        • Vegter E.L.
        • van der Wal H.H.
        • et al.
        Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients.
        Circ Heart Fail. 2018; 11e004519
        • Cohen-Solal A.
        • Leclercq C.
        • Mebazaa A.
        • DeGroote P.
        • Damy T.
        • Isnard R.
        • et al.
        Diagnosis and treatment of iron deficiency in patients with heart failure: expert position paper from French cardiologists.
        Arch Cardiovasc Dis. 2014; 107: 563-571
        • Jankowska E.A.
        • Kasztura M.
        • Sokolski M.
        • Bronisz M.
        • Nawrocka S.
        • Oleśkowska-Florek W.
        • et al.
        Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure.
        Eur Heart J. 2014; 35: 2468-2476
        • Tkaczyszyn M.
        • Comín-Colet J.
        • Voors A.A.
        • van Veldhuisen D.J.
        • Enjuanes C.
        • Moliner-Borja P.
        • et al.
        Iron deficiency and red cell indices in patients with heart failure.
        Eur J Heart Fail. 2017; 20: 114-122
        • Rocha B.M.L.
        • Cunha G.J.L.
        • Menezes Falcão L.F.
        The burden of iron deficiency in heart failure.
        J Am Coll Cardiol. 2018; 71: 782-793
        • Núñez J.
        • Comín-Colet J.
        • Miñana G.
        • Núñez E.
        • Santas E.
        • Mollar A.
        • et al.
        Iron deficiency and risk of early readmission following a hospitalization for acute heart failure.
        Eur J Heart Fail. 2016; 18: 798-802
        • 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
        • 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 (e573): 575-582
        • Bekfani Pellicori P.
        • Morris D.
        • Ebner N.
        • Valentova M.
        • Sandek A.
        • Doehner W.
        • et al.
        Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life.
        Clin Res Cardiol. 2018;
        • Martens Nijst P.
        • Verbrugge F.H.
        • Smeets K.
        • Dupont M.
        • Mullens W.
        Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction.
        Acta Cardiol. 2018; 73: 115-123
        • Mordi I.R.
        • Tee A.
        • Lang C.C.
        Iron therapy in heart failure: ready for primetime?.
        Card Fail Rev. 2018; 4: 28-32
        • Nemeth E.
        • Tuttle M.
        • Powelson J.
        • Vaughn M.B.
        • Donovan A.
        • Ward D.M.
        • et al.
        Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.
        Science. 2004; 306: 2090-2093
        • Jankowska E.A.
        • Malyszko J.
        • Ardehali H.
        • Koc-Zorawska E.
        • Banasiak W.
        • von Haehling S.
        • et al.
        Iron status in patients with chronic heart failure.
        Eur Heart J. 2013; 34: 827-834
        • Stugiewicz M.
        • Tkaczyszyn M.
        • Kasztura M.
        • Banasiak W.
        • Ponikowski P.
        • Jankowska E.A.
        The influence of iron deficiency on the functioning of skeletal muscles: experimental evidence and clinical implications.
        Eur J Heart Fail. 2016; 18: 762-773
        • Dziegala M.
        • Josiak K.
        • Kasztura M.
        • Kobak K.
        • von Haehling S.
        • Banasiak W.
        • et al.
        Iron deficiency as energetic insult to skeletal muscle in chronic diseases.
        J Cachexia Sarcopenia Muscle. 2018; (Sep 4)
        • Xu W.
        • Barrientos T.
        • Mao L.
        • Rockman H.A.
        • Sauve A.A.
        • Andrews N.C.
        Lethal cardiomyopathy in mice lacking transferrin receptor in the heart.
        Cell Rep. 2015; 20: 533-545
        • Kobak K.A.
        • Radwańska M.
        • Dzięgała M.
        • Kasztura M.
        • Josiak K.
        • Banasiak W.
        • et al.
        Structural and functional abnormalities in iron-depleted heart.
        Heart Fail Rev Oct. 2018; 3
        • Nakano H.
        • Nagai T.
        • Sundaram V.
        • Nakai M.
        • Nishimura K.
        • Honda Y.
        • et al.
        Impact of iron deficiency on long-term clinical outcomes of hospitalized patients with heart failure.
        Int J Cardiol. 2018; 261: 114-118
        • 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
        • 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
        • 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 symptomatic heart failure and iron deficiency.
        Eur Heart J. 2015; 36: 657-668
        • van Veldhuisen D.J.
        • Ponikowski P.
        • van der Meer P.
        • Metra M.
        • Böhm 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
        • 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
        • 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: the FERRIC-HF II randomized mechanistic trial.
        Circulation. 2019; (Feb 19)
        • 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
        • McDonagh T.
        • Damy T.
        • Doehner W.
        • Lam C.S.P.
        • Sindone A.
        • van der Meer P.
        • et al.
        Screening, diagnosis and treatment of iron deficiency in chronic heart failure: putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice.
        Eur J Heart Fail. 2018; (Oct 12)