Effects of iron on cardiovascular, kidney and safety outcomes in patients with chronic kidney disease: a systematic review and meta-analysis

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 trials evaluating effects of iron on clinical outcomes are needed, especially in non-dialysis CKD, with or without anaemia.