{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:58:53Z","timestamp":1760147933554,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T00:00:00Z","timestamp":1678492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute for Health and Care Research (NIHR)","award":["CL-2019-15-001","CL-NIHR-20-05"],"award-info":[{"award-number":["CL-2019-15-001","CL-NIHR-20-05"]}]},{"name":"NIHR","award":["CL-2019-15-001","CL-NIHR-20-05"],"award-info":[{"award-number":["CL-2019-15-001","CL-NIHR-20-05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>(1) Background: Iron deficiency (ID) is an important adverse prognostic marker in patients with heart failure (HF); however, it is unclear whether intravenous iron replacement reduces cardiovascular mortality in this patient group. Here, we estimate the effect of intravenous iron replacement therapy on hard clinical outcomes following the publication of IRONMAN, the largest trial in this field. (2) Methods: In this systematic review and meta-analysis, prospectively registered with PROSPERO and reported according to PRISMA guidelines, we searched PubMed and Embase for randomized controlled trials investigating intravenous iron replacement in patients with HF and co-existing ID. The primary outcome was cardiovascular mortality and secondary outcomes were all-cause mortality, hospitalizations for HF and a combination of the primary outcome and hospitalizations for HF. (3) Results: A total of 1671 items were identified and after removal of duplicates we screened titles and abstracts of 1202 records. Some 31 studies were identified for full-text review and 12 studies were included in the final review. The odds ratio (OR) for cardiovascular death using a random effects model was 0.85 (95% CI 0.69 to 1.04) and for all-cause mortality it was 0.83 (95% CI 0.59 to 1.15). There was a significant reduction in hospitalizations for HF (OR 0.49, 95% CI 0.35 to 0.69) and the combination of hospitalizations for HF and cardiovascular death (OR 0.65, 95% CI 0.5 to 0.85). (4) Conclusions: This review supports the use of IV iron replacement reducing hospitalization rates for HF, however more research is required to determine the effect on cardiovascular mortality and to identify the patient population most likely to benefit.<\/jats:p>","DOI":"10.3390\/jcdd10030116","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T02:31:55Z","timestamp":1678674715000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of Intravenous Iron Replacement Therapy on Cardiovascular Outcomes in Patients with Heart Failure: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2412-2574","authenticated-orcid":false,"given":"Johannes","family":"Reinhold","sequence":"first","affiliation":[{"name":"Norwich Medical School, University of East Anglia (UEA), Norwich Research Park, Norwich NR4 7TJ, UK"},{"name":"Department of Cardiology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4472-6791","authenticated-orcid":false,"given":"Vyas","family":"Burra","sequence":"additional","affiliation":[{"name":"Medical School, King\u2019s College London, Strand, London WC2R 2LS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6837-5787","authenticated-orcid":false,"given":"Natasha","family":"Corballis","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia (UEA), Norwich Research Park, Norwich NR4 7TJ, UK"},{"name":"Department of Cardiology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1534-7587","authenticated-orcid":false,"given":"Vasiliki","family":"Tsampasian","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia (UEA), Norwich Research Park, Norwich NR4 7TJ, UK"},{"name":"Department of Cardiology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth","family":"Matthews","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia (UEA), Norwich Research Park, Norwich NR4 7TJ, UK"},{"name":"Department of Cardiology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charikleia","family":"Papadopoulou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"},{"name":"Royal Papworth Hospital, Papworth Rd, Trumpington, Cambridge CB2 0AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4005-7752","authenticated-orcid":false,"given":"Vassilios S.","family":"Vassiliou","sequence":"additional","affiliation":[{"name":"Norwich Medical School, University of East Anglia (UEA), Norwich Research Park, Norwich NR4 7TJ, UK"},{"name":"Department of Cardiology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1056\/NEJM199912233412607","article-title":"Disorders of iron metabolism","volume":"341","author":"Andrews","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1007\/s00018-009-0051-1","article-title":"Mammalian iron transport","volume":"66","author":"Anderson","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1093\/eurheartj\/ehs224","article-title":"Iron deficiency and heart failure: Diagnostic dilemmas and therapeutic perspectives","volume":"34","author":"Jankowska","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrm1620","article-title":"Iron\u2013sulphur cluster biogenesis and mitochondrial iron homeostasis","volume":"6","author":"Rouault","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S568","DOI":"10.1093\/jn\/131.2.568S","article-title":"Iron Biology in Immune Function, Muscle Metabolism and Neuronal Functioning","volume":"131","author":"Beard","year":"2001","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1056\/NEJMoa0908355","article-title":"Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency","volume":"361","author":"Anker","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1093\/eurheartj\/ehu385","article-title":"Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency","volume":"36","author":"Ponikowski","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1161\/CIRCULATIONAHA.117.027497","article-title":"Effect of Ferric Car-boxymaltose on Exercise Capacity in Patients with Chronic Heart Failure and Iron Deficiency","volume":"136","author":"Ponikowski","year":"2017","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e004519","DOI":"10.1161\/CIRCHEARTFAILURE.117.004519","article-title":"Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients","volume":"11","author":"Klip","year":"2018","journal-title":"Circ. Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.jacc.2021.11.039","article-title":"Criteria for Iron Deficiency in Patients with Heart Failure","volume":"79","author":"Masini","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ijcard.2020.12.021","article-title":"Iron deficiency for prognosis in acute coronary syndrome\u2014A systematic review and meta-analysis","volume":"328","author":"Reinhold","year":"2021","journal-title":"Int. J. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/ejhf.236","article-title":"Iron therapy for the treatment of iron deficiency in chronic heart failure: Intrave-nous or oral?","volume":"17","author":"McDonagh","year":"2015","journal-title":"Eur. J. Heart Fail."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.ahj.2013.01.017","article-title":"Iron deficiency in chronic heart failure: An international pooled analysis","volume":"165","author":"Klip","year":"2013","journal-title":"Am. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/nrcardio.2011.77","article-title":"Anemia and iron deficiency in heart failure: Mechanisms and therapeutic approaches","volume":"8","author":"Anker","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1016\/S0140-6736(22)02083-9","article-title":"Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): An investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial","volume":"400","author":"Kalra","year":"2022","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1093\/eurheartj\/ehab368","article-title":"2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_17","first-page":"e895","article-title":"2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"145","author":"Heidenreich","year":"2022","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1161\/CIRCULATIONAHA.118.038516","article-title":"Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients with Chronic Heart Failure and Iron Deficiency","volume":"139","author":"Amaral","year":"2019","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/ejhf.2454","article-title":"Cardiac energetics in patients with chronic heart failure and iron deficiency: An in-vivo 31 P magnetic resonance spectroscopy study","volume":"24","author":"Papalia","year":"2022","journal-title":"Eur. J. Heart Fail."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and Group, P. (2009). Preferred reporting items for systematic reviews and me-ta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1093\/eurheartj\/ehab411","article-title":"The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy\u2014The IRON-CRT trial","volume":"42","author":"Martens","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1016\/S0140-6736(20)32339-4","article-title":"Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: A multicentre, double-blind, randomised, controlled trial","volume":"396","author":"Ponikowski","year":"2020","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/ehf2.12250","article-title":"Single-dose intravenous iron in Southeast Asian heart failure patients: A pilot randomized placebo-controlled study (PRACTICE-ASIA-HF)","volume":"5","author":"Yeo","year":"2018","journal-title":"ESC Heart Fail."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jacc.2007.09.036","article-title":"Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron defi-ciency FERRIC-HF: A randomized, controlled, observer-blinded trial","volume":"51","author":"Okonko","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1097\/FJC.0000000000001287","article-title":"IV Sodium Ferric Gluconate Complex in Patients with Iron Deficiency Hospitalized due to Acute Heart Failure-Investigator Initiated, Randomized Con-trolled Trial","volume":"80","author":"Marcusohn","year":"2022","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_26","first-page":"OC18","article-title":"Long-Term Effect of Intravenous Iron on Overall Survival and Hospitalization in Patients with Heart Failure with Reduced Ejection Fraction, Iron Deficiency and Mild Renal Impairment: An Open-Label 5-Year Follow Up Observation","volume":"11","author":"Toblli","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"ehx493.P5825","DOI":"10.1093\/eurheartj\/ehx493.P5825","article-title":"P5825Intravenous iron therapy in acute decompensated heart failure patients with iron deficiency anaemia","volume":"38","author":"Youssef","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1016\/j.ijcard.2013.04.181","article-title":"IRON-HF study: A randomized trial to assess the effects of iron in heart failure patients with anemia","volume":"168","author":"Piardi","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/ejhf.1154","article-title":"Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function","volume":"20","author":"Hoes","year":"2018","journal-title":"Eur. J. Heart Fail."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Johnson, B.B., Reinhold, J., Holmes, T.L., Moore, J.A., Cowell, V., Bernardo, A.S., Rushworth, S.A., Vassiliou, V., and Smith, J.G.W. (2021). Modelling Metabolic Shifts during Cardiomyocyte Differentiation, Iron Deficiency and Transferrin Rescue Using Human Pluripotent Stem Cells. Metabolites, 12.","DOI":"10.3390\/metabo12010009"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1177\/0163278702025001006","article-title":"To IPD or not to IPD? Advantages and disadvantages of systematic reviews using indi-vidual patient data","volume":"25","author":"Stewart","year":"2002","journal-title":"Eval. Health Prof."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e014254","DOI":"10.1161\/JAHA.119.014254","article-title":"Noninvasive Imaging Estimation of Myocardial Iron Repletion Following Administration of Intravenous Iron: The Myocardial-IRON Trial","volume":"9","author":"Cardells","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12968-015-0207-0","article-title":"T1 at 1.5T and 3T compared with conventional T2* at 1.5T for cardiac siderosis","volume":"17","author":"Alam","year":"2015","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/10\/3\/116\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:52:58Z","timestamp":1760122378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/10\/3\/116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,11]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["jcdd10030116"],"URL":"https:\/\/doi.org\/10.3390\/jcdd10030116","relation":{},"ISSN":["2308-3425"],"issn-type":[{"type":"electronic","value":"2308-3425"}],"subject":[],"published":{"date-parts":[[2023,3,11]]}}}