Iron Repletion in Heart Failure With Preserved Ejection Fraction: The IRONMET-HFpEF Randomized Trial

BACKGROUND: Iron deficiency is present in >50% of patients with heart failure with preserved ejection fraction and is associated with reduced exercise capacity and survival. Whether iron repletion improves exercise capacity as objectively measured by peak oxygen uptake ([Formula: see text]) is unknown. The IRONMET-HFpEF trial (Impact of Intravenous Iron Repletion on Mechanisms of Exercise Intolerance in HFpEF) sought to determine whether ferric derisomaltose (FDI) compared with placebo improves peak [Formula: see text] in heart failure with preserved ejection fraction with iron deficiency. METHODS: This was a double-blind, placebo-controlled randomized clinical trial of patients with heart failure with preserved ejection fraction and iron deficiency, defined as ferritin <100 ng/mL or <300 ng/mL with transferrin saturation <20%. Participants were enrolled between December 2021 and April 2026. Single-dose ferric derisomaltose (1000 mg; n=44) or placebo (n=21) was administered once intravenously. The primary end point was the change in peak [Formula: see text] from baseline to 12 weeks with an analysis of covariance model including terms for treatment group, baseline peak [Formula: see text], and sex. Secondary end points included changes in [Formula: see text] at the anaerobic threshold, 6-minute walk test distance, New York Heart Association class, health status assessed by the Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and iron biomarkers at 12 weeks. RESULTS: <0.001 for both). There were no serious adverse events related to FDI administration. CONCLUSIONS: In the largest trial to date of iron repletion in heart failure with preserved ejection fraction with iron deficiency, FDI improved multiple measures of exercise capacity. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04945707.