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Intravenous Iron Therapy in Heart Failure With Reduced Ejection Fraction: Tackling the Deficiency

2021; Lippincott Williams & Wilkins; Volume: 144; Issue: 4 Linguagem: Inglês

10.1161/circulationaha.121.054271

1524-4539

Konrad Teodor Sawicki, Hossein Ardehali,

Iron Metabolism and Disorders

HomeCirculationVol. 144, No. 4Intravenous Iron Therapy in Heart Failure With Reduced Ejection Fraction: Tackling the Deficiency Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBIntravenous Iron Therapy in Heart Failure With Reduced Ejection Fraction: Tackling the Deficiency Konrad Teodor Sawicki, MD, PhD and Hossein Ardehali, MD, PhD Konrad Teodor SawickiKonrad Teodor Sawicki https://orcid.org/0000-0003-2124-0081 Feinberg Cardiovascular Research Institute (K.T.S., H.A.), Northwestern University, Chicago, IL. Division of Cardiology, Department of Medicine, Feinberg School of Medicine (K.T.S., H.A.), Northwestern University, Chicago, IL. and Hossein ArdehaliHossein Ardehali Correspondence to: Hossein Ardehali, MD, PhD, Northwestern University Feinberg School of Medicine, 303 East Superior Ave, Chicago, IL 60611. Email E-mail Address: [email protected] https://orcid.org/0000-0002-7662-0551 Feinberg Cardiovascular Research Institute (K.T.S., H.A.), Northwestern University, Chicago, IL. Division of Cardiology, Department of Medicine, Feinberg School of Medicine (K.T.S., H.A.), Northwestern University, Chicago, IL. Originally published26 Jul 2021https://doi.org/10.1161/CIRCULATIONAHA.121.054271Circulation. 2021;144:253–255Over the past decade, there has been significant interest in the treatment of iron deficiency (ID) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). With the recent AFFIRM-AHF trial (Ferric Carboxymaltose for Iron Deficiency at Discharge After Acute Heart Failure), there are now 4 randomized, controlled trials that have demonstrated symptomatic benefit in treating patients with ID and HFrEF patients with intravenous ferric carboxymaltose (FCM). Although systemic ID is an important comorbidity that can occur in patients with HFrEF and should be appropriately treated, excess iron is cardiotoxic and overtreatment of patients with HFrEF with intravenous iron may have detrimental effects.This Perspective discusses the major clinical trials of intravenous iron supplementation in patients with HFrEF, addresses potential safety concerns of intravenous iron, provides new insights on oral iron repletion, and proposes future directions.Trials of Intravenous Iron Supplementation in HFIron is an essential nutrient that is necessary for oxygen delivery and metabolic homeostasis, and patients with HFrEF are at risk of developing absolute and functional ID. There are now 4 randomized clinical trials that have evaluated the effect of intravenous FCM in patients with ID and HFrEF. All 4 trials were relatively small and short-term, and the majority of patients were White and European. The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials collectively demonstrated that intravenous FCM in ambulatory patients with HFrEF and ID improves symptoms, as measured by functional capacity (6-minute walk test), New York Heart Association classification, and subjective assessment. The most recent trial, AFFIRM-AHF, demonstrated that intravenous FCM modestly reduces total HF hospitalizations in a high-risk population of patients with ID admitted for acute HF. No effect on cardiovascular death was seen in pre– or post–coronavirus disease 2019 (COVID-19) analyses.All 4 trials defined ID in HFrEF using the criteria of serum ferritin <100 ng/mL (absolute ID) or serum ferritin 100 to 300 ng/mL with serum transferrin saturation <20% (functional ID), regardless of the presence or absence of anemia. It is interesting that these criteria were not derived from patients with HFrEF but rather adopted from patients with ID and chronic kidney disease (CKD). However, CKD is associated with uremia-mediated inflammation, increased levels of hepcidin, and decreased renal production of erythropoietin requiring erythropoiesis-stimulating agents, none of which are seen in HFrEF. Given the differences in ID pathophysiology between CKD and HFrEF, it is unclear whether these serum markers accurately diagnose ID in HFrEF patients, particularly functional ID. In addition, patients with HFrEF and coexisting CKD have complex iron metabolism, which requires additional study. Indeed, in FAIR-HF and CONFIRM-HF, the median ferritin levels were 39 ng/mL and 46 ng/mL respectively, both significantly lower than the ferritin cutoff of 100 ng/mL. In AFFIRM-AHF, the benefits of intravenous FCM were also more pronounced in patients with ferritin <100 ng/mL.These trials demonstrate that ID is an important comorbidity in HFrEF and that treatment of true ID in HFrEF improves symptoms and modestly reduces hospitalizations. Although these are important end points, HFrEF therapies are most impactful when the therapy improves survival and significantly reduces nonfatal HF events. In addition, it remains to be seen whether intravenous iron improves myocardial function or alters the natural history of HFrEF.Potential Safety Concerns with Intravenous Iron TherapiesThe symptomatic benefits of intravenous iron supplementation in patients with HFrEF with true ID should be balanced with the potential safety concerns associated with iron excess. Although oral iron absorption is tightly regulated by the effects of hepcidin and rarely leads to iron excess, intravenous iron introduces large amounts of non–transferrin-bound iron, which bypasses regulatory mechanisms and can cause iron overload.The accumulation of unbound iron can be detrimental to cells and tissues by catalyzing reactive oxygen species. In rodent models, intravenous iron infusions were associated with increased oxidative stress and progression of atherosclerosis.1 In healthy human volunteers, intravenous iron resulted in transient endothelial dysfunction and biomarkers of oxidative stress.2 The toxic effects of intravenous iron may be particularly important to consider in the setting of (1) infection, because many infectious agents thrive on iron, and (2) patients with coronary artery disease with vulnerable or high-risk plaques, in whom the pro-oxidative effects of iron may theoretically promote plaque rupture.It is also important to note that although certain patients with HFrEF may be systemically ID, they may simultaneously have increased myocardial iron. Reductions in myocardial iron reduce oxidative stress and cardiotoxicity in rodent models of cardiac injury, suggesting that targeted therapies that replenish systemic iron yet specifically reduce myocardial iron may be beneficial.3 Questions also remain about the long-term safety of intravenous iron in HFrEF, particularly in patients who receive repeated intravenous iron infusions. The follow-up periods of the 4 trials mentioned ranged from only 16 to 52 weeks, and data are lacking on the long-term effects of intravenous iron on ventricular remodeling, inflammation, and survival.Alternative Strategies: Oral Iron SupplementationAn understudied alternative to intravenous iron is oral iron supplementation. Oral iron is inexpensive and widely available, and newer agents like oral sucrosomial iron are better absorbed with fewer gastrointestinal side effects. In fact, the Food and Drug Administration and European Medicines Agency recommend a trial of oral iron before the use of intravenous FCM (except in CKD).The only study to compare intravenous versus oral iron in patients with HFrEF and ID was terminated prematurely because of insufficient funding, but preliminary results showed increases in serum ferritin and transferrin saturation in both iron groups.4 In addition, the IRONOUT-HF trial suggested that a subset of patients with HFrEF and ID defined by low hepcidin (<6.6 ng/mL) may benefit from oral iron polysaccharide through improvement in iron indices.Most recently, a prospective pilot study showed that 3-month therapy with low-dose oral sucrosomial iron in patients with ID and HFrEF was associated with higher iron indices and improved exercise capacity and quality of life at 3 months, which persisted at 6 months. There was also a trend toward reduced B-type natriuretic peptide with oral sucrosomial iron compared with control.5 These encouraging results are being further investigated in the IVOFER-HF trial (2017-005053-37), which is comparing the effect of intravenous FCM versus oral sucrosomial iron on functional capacity in patients with ID and HFrEF.Conclusions and Future DirectionsIntravenous FCM provides systemic metabolic benefits in patients with ID and HFrEF through improvement in symptoms and reduction in hospitalizations. However, important questions remain about the effect of intravenous iron on myocardial and endothelial function, mortality, and long-term safety, especially in the setting of infection and inflammation. These questions will hopefully be answered in ongoing well-powered trials: HEART-FID (NCT03037931), FAIR-HF2 (NCT03036462), and IRON-MAN (NCT02642562).Additional research is also needed in several key aspects of the field. First, more accurate criteria for defining true systemic ID in HFrEF are needed using novel biomarkers like hepcidin and soluble transferrin receptor, including validation with bone marrow iron stores. Second, large randomized trials in diverse populations should assess the head-to-head efficacy of intravenous iron versus novel low-dose oral iron formulations. Third, novel targeted iron agents that replenish systemic iron stores yet prevent myocardial iron overload may hold promise in the treatment of HFrEF. Last, mechanistic studies are required to assess the effects of intravenous iron on biological outcomes, including oxidative stress, endothelial function, and plaque stability, particularly in high-risk settings such as infection.Sources of FundingNone.Disclosures Dr Ardehali is supported by National Institutes of Health grants R01 HL127646, R01 HL140973, and R01 HL138982. Dr Sawicki declares no competing interests.Footnoteshttps://www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 255.Correspondence to: Hossein Ardehali, MD, PhD, Northwestern University Feinberg School of Medicine, 303 East Superior Ave, Chicago, IL 60611. Email [email protected]eduReferences1. Kuo KL, Hung SC, Lee TS, Tarng DC. Iron sucrose accelerates early atherogenesis by increasing superoxide production and upregulating adhesion molecules in CKD.J Am Soc Nephrol. 2014; 25:2596–2606. doi: 10.1681/ASN.2013080838CrossrefMedlineGoogle Scholar2. Rooyakkers TM, Stroes ES, Kooistra MP, van Faassen EE, Hider RC, Rabelink TJ, Marx JJ. Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo.Eur J Clin Invest. 2002; 32(suppl 1):9–16. doi: 10.1046/j.1365-2362.2002.0320s1009.xCrossrefMedlineGoogle Scholar3. Chang HC, Wu R, Shang M, Sato T, Chen C, Shapiro JS, Liu T, Thakur A, Sawicki KT, Prasad SV, et al.. Reduction in mitochondrial iron alleviates cardiac damage during injury.EMBO Mol Med. 2016; 8:247–267. doi: 10.15252/emmm.201505748CrossrefMedlineGoogle Scholar4. Beck-da-Silva L, Piardi D, Soder S, Rohde LE, Pereira-Barretto AC, de Albuquerque D, Bocchi E, Vilas-Boas F, Moura LZ, Montera MW, 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. doi: 10.1016/j.ijcard.2013.04.181CrossrefMedlineGoogle Scholar5. Karavidas A, Troganis E, Lazaros G, Balta D, Karavidas IN, Polyzogopoulou E, Parissis J, Farmakis D. Oral sucrosomial iron improves exercise capacity and quality of life in heart failure with reduced ejection fraction and iron deficiency: a non-randomized, open-label, proof-of-concept study [published online January 9, 2021].Eur J Heart Fail. https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2092. doi: 10.1002/ejhf.2092Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By SAWICKI K and AMBROSY A (2022) Heart Failure With Iron Deficiency Across the Left Ventricular Ejection Fraction Continuum: Need to Redefine?, Journal of Cardiac Failure, 10.1016/j.cardfail.2022.01.018, Online publication date: 1-Feb-2022. Wong C, Lau K, Tang E, Lee C, Lee C, Woo Y, Au I, Tan K and Lui D (2022) Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study, Cardiovascular Diabetology, 10.1186/s12933-022-01520-w, 21:1, Online publication date: 1-Dec-2022. Brautaset Englund K, Østby C, Broch K, Ueland T, Aukrust P, Gude E, Andreassen A and Gullestad L (2022) Iron homeostasis in heart transplant recipients randomized to ferric derisomaltose or placebo, Clinical Transplantation, 10.1111/ctr.14695 July 27, 2021Vol 144, Issue 4Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.054271PMID: 34310166 Originally publishedJuly 26, 2021 Keywordscardiotoxicityironheart failurecardiomyopathiesmetabolismPDF download Advertisement SubjectsCardiomyopathyCardiotoxicityHeart FailureMetabolism