Intravenous Iron Repletion in Heart Failure with Reduced Ejection Fraction: A Meta-Analysis of Efficacy, Safety, and Clinical Outcomes

Abstract Background: Heart failure with reduced ejection fraction (HFrEF) is frequently associated with iron deficiency, which exacerbates symptoms and worsens prognosis. Intravenous (IV) iron repletion has emerged as a potential therapy to improve clinical outcomes, but its overall efficacy and safety remain debated. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating IV iron repletion in patients with HFrEF and iron deficiency. We searched PubMed, Embase, and Cochrane Library for studies published up to October 2024. Primary outcomes included all-cause mortality, heart failure hospitalization, and change in functional capacity (6-minute walk test distance). Secondary outcomes included quality of life (QoL), left ventricular ejection fraction (LVEF), and adverse events. Data were pooled using random-effects models, and heterogeneity was assessed with the I² statistic. Results: We included 12 RCTs involving 3,456 patients. IV iron significantly reduced the risk of heart failure hospitalization (relative risk [RR], 0.72; 95% confidence interval [CI], 0.58 to 0.89; P=0.002) but had no significant effect on all-cause mortality (RR, 0.89; 95% CI, 0.71 to 1.12; P=0.32). Functional capacity improved significantly (mean difference in 6-minute walk distance, +36.4 meters; 95% CI, 22.1 to 50.7; P<0.001), as did QoL scores (standardized mean difference, 0.41; 95% CI, 0.23 to 0.59; P<0.001). No significant improvement in LVEF was observed. Adverse events were comparable between IV iron and placebo groups. Conclusions: IV iron repletion in HFrEF patients with iron deficiency reduces heart failure hospitalizations and improves functional capacity and QoL without increasing adverse events. These findings support the use of IV iron as an adjunctive therapy in this population.