Background and aims Heart failure and chronic kidney disease (CKD) are closely linked, with iron deficiency being highly prevalent in both conditions. Yet, major cardiovascular and nephrology guidelines offer contrasting recommendations on the use of iron. We evaluated the effects of iron versus usual care/placebo on clinical outcomes in patients with CKD. Methods We conducted a systematic review and meta-analysis of randomised trials of intravenous or oral iron in CKD (PROSPERO CRD42023453468). We searched Medline, Embase and the Cochrane Register from database inception until February 1, 2024 to identify eligible trials. We determined results overall and stratified by dialysis- and non-dialysis-requiring CKD using random effects models, with certainty of evidence assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary composite endpoint was heart failure hospitalisation or cardiovascular death. Results We identified 45 trials that met our inclusion criteria. Compared to usual care/placebo, iron reduced the risk of the primary composite endpoint (1659 events; RR 0.84, 95% CI 0.75-0.94; moderate certainty) an effect consistent across dialysis and non-dialysis requiring CKD (P-heterogeneity=0.70). The effect on the primary endpoint appeared driven by both components of hospitalisation for heart failure (RR 0.77; 95% CI 0.61-0.96; moderate certainty) and cardiovascular death (RR 0.81; 95% CI 0.65-1.02; low certainty). The incidence of serious adverse events was lower for iron compared to usual care/placebo (RR 0.90, 95% CI 0.82-0.98; moderate certainty; P-heterogeneity=0.09). Conclusion Iron therapies may reduce the risk of heart failure or cardiovascular death in patients with CKD. Randomised rials evaluating effects of iron on clinical outcomes are needed, especially in non-dialysis CKD, with or without anaemia.

ACKNOWLEDGEMENTS BLN is supported by an Australian National Health and Medical Research Council Emerging Leader Investigator Grant (grant number 2026621) and a Ramaciotti Foundation Health Investment Grant (grant number 2023HIG69). The funders had no role in the writing of the manuscript or decision to submit for publication. DISCLOSURES SVB reports consulting fees from Bayer, AstraZeneca, GSK and Vifor Pharma; speaking fees from Bayer, AstraZeneca, Pfizer and Vifor Pharma (all honoraria paid to his institution); and non-financial research support from Bayer. RPF is an employee of Arbor Research Collaborative for Health, which receives global support for the ongoing DOPPS Programs (provided without restriction on publications by a variety of funders; for details see https://www.dopps.org/AboutUs/Support.aspx) and has received research grants from Fresenius Medical Care; consulting fees (paid to the employer) from AstraZeneca, Akebia, Novo Nordisk and Fresenius, Bayer, Boehringer, Novo Nordisk and Akebia. GMC has served on the Board of Directors of Satellite Healthcare, a non-profit dialysis provider. He has served as Chair or Co-Chair of Trial Steering Committees with Akebia, AstraZeneca, CSL Behring, Sanifit, and Vertex. He has served as an Advisor to Applaud, CloudCath, Durect, Eliaz Therapeutics, Miromatrix, Outset, Physiowave, Renibus, and Unicycive. He has served on Data Safety Monitoring Boards with Bayer, Mineralys, and ReCor. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Puretech Health. MV has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics BLN has received fees for travel support, advisory boards, scientific presentations and steering committee roles from AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, the Limbic, Janssen, Medscape and Travere with all honoraria paid to The George Institute for Global Health. All other authors have nothing to disclose.

PROSPERO (CRD42023453468)

This study did not receive any funding

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