IRON-MET HFpEF RCT: single 1 g IV ferric derisomaltose raised peak VO2 10% at 12 weeks in iron-deficient patients

The double-blind trial randomized 44 participants to active iron and 21 to placebo at Mass General Brigham. Cardiopulmonary exercise testing was performed at baseline and 12 weeks; secondary endpoints included 6-minute walk distance, anaerobic threshold VO2, and NYHA class. Bioavailable iron rose and exercise metrics improved in the intervention arm while patient-reported health status scores showed no between-group difference. Prior HFrEF iron trials such as AFFIRM-AHF and IRONMAN demonstrated reduced hospitalizations with repeated dosing, yet oral iron failed due to absorption barriers. The current 10% VO2 gain matches clinically meaningful thresholds reported in exercise-intervention meta-analyses, but the absence of quality-of-life improvement highlights a dissociation between physiologic and symptomatic response. The study population was small, 72% female, and predominantly white with follow-up limited to 12 weeks. No serious adverse events occurred. These design features limit generalizability and leave open whether gains persist or translate to fewer hospitalizations or deaths in broader HFpEF cohorts. Next required studies are larger, longer, event-driven phase 3 trials enrolling diverse racial and ethnic groups with primary endpoints of cardiovascular death or heart-failure hospitalization rather than surrogate exercise capacity.