Skip to main content
Top
Published in: American Journal of Cardiovascular Drugs 2/2024

01-03-2024 | Heart Failure | Systematic Review

Efficacy of Intravenous Iron in Patients with Heart Failure with Reduced Ejection Fraction and Iron Deficiency: A Systematic Review and Meta-Analysis of Randomized Control Trials

Authors: Andrew Sephien, Denisse Camille Dayto, Tea Reljic, Xavier Prida, Joanna M. Joly, Matthew Tavares, Jason N. Katz, Ambuj Kumar

Published in: American Journal of Cardiovascular Drugs | Issue 2/2024

Login to get access

Abstract

Background

The European Society of Cardiology (ESC) provided a focused update to the 2021 Guideline for the Management of Heart Failure, now providing a 1A recommendation for intravenous iron in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency (ID). However, the findings from randomized controlled trials (RCT) are mixed. This systematic review of RCTs aims to provide an update and synthesize the evidence addressing the association of intravenous iron with patient-based outcomes in patients with HFrEF and ID.

Methods

Any RCT evaluating the effect of intravenous iron in patients with HFrEF and ID was eligible for inclusion. A complete search of the EMBASE and PubMed databases was conducted from inception until 15 September 2023. The primary outcome was the composite of the quality of life (QoL) questionnaires, while the secondary outcomes included first heart failure (HF) hospitalizations and all-cause mortality. Data extraction was performed independently by two reviewers. Data were pooled using a random-effects model.

Results

Of the 1035 references, 15 RCTs enrolling 6649 patients were included in this study. Intravenous iron was associated with significant improvement in the composite of QoL (standardized mean difference − 1.36, 95% confidence interval [CI] − 2.24 to − 0.48; = 0.002), a significant reduction in first HF hospitalizations (hazard ratio [HR] 0.73, 95% CI 0.56–0.95; p = 0.02), and with no change in all-cause mortality (HR 0.90, 95% CI 0.79–1.03; p = 0.12). The certainty of the evidence ranged from moderate to very low.

Conclusion

Intravenous iron is possibly associated with improved QoL and reduced HF hospitalizations, without impacting all-cause mortality. These findings not only support the use of intravenous iron in patients with HFrEF but also emphasize the need for well-designed and executed RCTs with granular outcome reporting and powered sufficiently to address the impact of intravenous iron on mortality in patients with HFrEF and ID.

Registration

PROSPERO identifier number CRD42023389
Appendix
Available only for authorised users
Literature
1.
go back to reference Sindone A, Doehner W, Comin-Colet J. Systematic review and meta-analysis of intravenous iron-carbohydrate complexes in HFrEF patients with iron deficiency. ESC Heart Fail. 2023;10:44–56.CrossRefPubMed Sindone A, Doehner W, Comin-Colet J. Systematic review and meta-analysis of intravenous iron-carbohydrate complexes in HFrEF patients with iron deficiency. ESC Heart Fail. 2023;10:44–56.CrossRefPubMed
2.
go back to reference von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail. 2019;7:36–46.CrossRef von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail. 2019;7:36–46.CrossRef
3.
go back to reference Anand IS, Gupta P. Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation. 2018;138:80–98.CrossRefPubMed Anand IS, Gupta P. Anemia and iron deficiency in heart failure: current concepts and emerging therapies. Circulation. 2018;138:80–98.CrossRefPubMed
4.
go back to reference Rocha BML, Cunha GJL, Menezes Falcao LF. The burden of iron deficiency in heart failure: therapeutic approach. J Am Coll Cardiol. 2018;71:782–93.CrossRefPubMed Rocha BML, Cunha GJL, Menezes Falcao LF. The burden of iron deficiency in heart failure: therapeutic approach. J Am Coll Cardiol. 2018;71:782–93.CrossRefPubMed
5.
go back to reference Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013;34:816–29.CrossRefPubMed Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013;34:816–29.CrossRefPubMed
6.
go back to reference Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(575–82): e3. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(575–82): e3.
7.
go back to reference Graham FJ, Pellicori P, Ford I, Petrie MC, Kalra PR, Cleland JGF. Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials. Clin Res Cardiol. 2021;110:1299–307.CrossRefPubMedPubMedCentral Graham FJ, Pellicori P, Ford I, Petrie MC, Kalra PR, Cleland JGF. Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials. Clin Res Cardiol. 2021;110:1299–307.CrossRefPubMedPubMedCentral
8.
go back to reference 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;317:1958–66.CrossRefPubMedPubMedCentral 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;317:1958–66.CrossRefPubMedPubMedCentral
9.
go back to reference Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48.CrossRefPubMed Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48.CrossRefPubMed
10.
go back to reference Comin-Colet J, Lainscak M, Dickstein K, 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;34:30–8.CrossRefPubMed Comin-Colet J, Lainscak M, Dickstein K, 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;34:30–8.CrossRefPubMed
11.
go back to reference Okonko DO, Grzeslo A, Witkowski T, 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;51:103–12.CrossRefPubMed Okonko DO, Grzeslo A, Witkowski T, 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;51:103–12.CrossRefPubMed
12.
go back to reference Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396:1895–904.CrossRefPubMed Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396:1895–904.CrossRefPubMed
13.
go back to reference van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation. 2017;136:1374–83.CrossRefPubMedPubMedCentral van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation. 2017;136:1374–83.CrossRefPubMedPubMedCentral
14.
go back to reference McDonagh TA, Metra M, Adamo M, et al. Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;28:5168. McDonagh TA, Metra M, Adamo M, et al. Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;28:5168.
15.
go back to reference Kalra PR, Cleland JGF, Petrie MC, et al. 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. Lancet. 2022. Kalra PR, Cleland JGF, Petrie MC, et al. 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. Lancet. 2022.
16.
go back to reference Salah HM, Savarese G, Rosano GMC, Ambrosy AP, Mentz RJ, Fudim M. Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis. ESC Heart Fail. 2023;10:1473.CrossRefPubMedPubMedCentral Salah HM, Savarese G, Rosano GMC, Ambrosy AP, Mentz RJ, Fudim M. Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis. ESC Heart Fail. 2023;10:1473.CrossRefPubMedPubMedCentral
17.
go back to reference Mentz RJ, Garg J, Rockhold FW, et al. Ferric carboxymaltose in heart failure with iron deficiency. N Engl J Med. 2023;389:975.CrossRefPubMed Mentz RJ, Garg J, Rockhold FW, et al. Ferric carboxymaltose in heart failure with iron deficiency. N Engl J Med. 2023;389:975.CrossRefPubMed
18.
go back to reference Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.CrossRef Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.CrossRef
19.
go back to reference Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev 2019;(10):ED000142. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev 2019;(10):ED000142.
20.
21.
go back to reference Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–94.CrossRefPubMed Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–94.CrossRefPubMed
22.
go back to reference Beck-da-Silva L, Piardi D, Soder S, et al. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol. 2013;168:3439–42.CrossRefPubMed Beck-da-Silva L, Piardi D, Soder S, et al. IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol. 2013;168:3439–42.CrossRefPubMed
23.
go back to reference Charles-Edwards G, Amaral N, Sleigh A, et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency. Circulation. 2019;139:2386–98.CrossRefPubMed Charles-Edwards G, Amaral N, Sleigh A, et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency. Circulation. 2019;139:2386–98.CrossRefPubMed
24.
go back to reference Dhoot S, Mittal S, Singh SP, Patel V, Kasliwal RR, Mehta V. Effect of ferric-carboxy maltose on oxygen kinetics and functional status in heart failure patients with iron deficiency. Future Sci OA. 2020;6:Fso467.CrossRefPubMedPubMedCentral Dhoot S, Mittal S, Singh SP, Patel V, Kasliwal RR, Mehta V. Effect of ferric-carboxy maltose on oxygen kinetics and functional status in heart failure patients with iron deficiency. Future Sci OA. 2020;6:Fso467.CrossRefPubMedPubMedCentral
25.
go back to reference Filippatos G, Ponikowski P, Farmakis D, et al. Efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency with and without anaemia: a subgroup analysis of AFFIRM-AHF. Eur Heart J. 2021;42:1053.CrossRef Filippatos G, Ponikowski P, Farmakis D, et al. Efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency with and without anaemia: a subgroup analysis of AFFIRM-AHF. Eur Heart J. 2021;42:1053.CrossRef
26.
go back to reference Jankowska EA, Kirwan BA, Kosiborod M, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J. 2021;42:3011–20.CrossRefPubMed Jankowska EA, Kirwan BA, Kosiborod M, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J. 2021;42:3011–20.CrossRefPubMed
27.
go back to reference Karakas M. Effect of ferric carboxymaltose on LVEF as assessed by cardiac MRI in patients with chronic heart failure and iron deficiency: a randomized, double-blinded, placebo-controlled, dual-center trial. Eur J Heart Fail. 2019;21:176. Karakas M. Effect of ferric carboxymaltose on LVEF as assessed by cardiac MRI in patients with chronic heart failure and iron deficiency: a randomized, double-blinded, placebo-controlled, dual-center trial. Eur J Heart Fail. 2019;21:176.
28.
go back to reference Martens P, Dupont M, Dauw J, et al. The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial. Eur Heart J. 2021;42:4905–14.CrossRefPubMedPubMedCentral Martens P, Dupont M, Dauw J, et al. The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial. Eur Heart J. 2021;42:4905–14.CrossRefPubMedPubMedCentral
29.
go back to reference Nuñez J, Minana G, Cardells I, et al. Noninvasive imaging estimation of myocardial iron repletion following administration of intravenous iron: the myocardial-IRON trial. J Am Heart Assoc. 2020;9: e014254.CrossRefPubMedPubMedCentral Nuñez J, Minana G, Cardells I, et al. Noninvasive imaging estimation of myocardial iron repletion following administration of intravenous iron: the myocardial-IRON trial. J Am Heart Assoc. 2020;9: e014254.CrossRefPubMedPubMedCentral
30.
go back to reference Ponikowski P, Van Veldhuisen DJ, Comin-Colet J, 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;36:657–68.CrossRefPubMed Ponikowski P, Van Veldhuisen DJ, Comin-Colet J, 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;36:657–68.CrossRefPubMed
31.
go back to reference Toblli JE, Lombraña 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;50:1657–65.CrossRefPubMed Toblli JE, Lombraña 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;50:1657–65.CrossRefPubMed
32.
go back to reference Youssef G, Kamal A, Diab R, Abdel HM. Intravenous iron therapy in acute decompensated heart failure patients with iron deficiency anaemia. Eur Heart J. 2017;38:1231.CrossRef Youssef G, Kamal A, Diab R, Abdel HM. Intravenous iron therapy in acute decompensated heart failure patients with iron deficiency anaemia. Eur Heart J. 2017;38:1231.CrossRef
33.
go back to reference Filippatos G, Farmakis D, Colet JC, et al. Intravenous ferric carboxymaltose in iron-Deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial. Eur J Heart Fail. 2013;15:1267–76.CrossRefPubMedPubMedCentral Filippatos G, Farmakis D, Colet JC, et al. Intravenous ferric carboxymaltose in iron-Deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial. Eur J Heart Fail. 2013;15:1267–76.CrossRefPubMedPubMedCentral
34.
go back to reference Zhou X, Xu W, Xu Y, Qian Z. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med. 2019;132:955–63.CrossRefPubMed Zhou X, Xu W, Xu Y, Qian Z. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med. 2019;132:955–63.CrossRefPubMed
35.
go back to reference Ponikowski P, Mentz RJ, Hernandez AF, et al. Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis. Eur Heart J. 2023;44:5077–91.CrossRefPubMedPubMedCentral Ponikowski P, Mentz RJ, Hernandez AF, et al. Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis. Eur Heart J. 2023;44:5077–91.CrossRefPubMedPubMedCentral
Metadata
Title
Efficacy of Intravenous Iron in Patients with Heart Failure with Reduced Ejection Fraction and Iron Deficiency: A Systematic Review and Meta-Analysis of Randomized Control Trials
Authors
Andrew Sephien
Denisse Camille Dayto
Tea Reljic
Xavier Prida
Joanna M. Joly
Matthew Tavares
Jason N. Katz
Ambuj Kumar
Publication date
01-03-2024
Publisher
Springer International Publishing
Published in
American Journal of Cardiovascular Drugs / Issue 2/2024
Print ISSN: 1175-3277
Electronic ISSN: 1179-187X
DOI
https://doi.org/10.1007/s40256-024-00635-7

Other articles of this Issue 2/2024

American Journal of Cardiovascular Drugs 2/2024 Go to the issue