In 65 patients with heart failure with preserved ejection fraction and iron deficiency, single-dose intravenous ferric derisomaltose (1000 mg) significantly improved 12-week peak VO2 compared with placebo (+1.2 vs +0.1 mL/kg/min; least-squares mean difference 1.1 mL/kg/min, 95% CI 0.2–1.9; P=0.02), 6-minute walk distance (+41.1 m; P=0.012), and NYHA class (P=0.013).
Key points
Context & question:Although iron deficiency is present in over half of patients with heart failure with preserved ejection fraction (HFpEF) and is linked to reduced survival and exercise capacity, it was unknown whether iron repletion improves objectively measured peak oxygen uptake (VO2). The IRONMET-HFpEF trial evaluated whether intravenous ferric derisomaltose improves peak VO2 compared with placebo in this patient population.
Methods & population:Study design, patient population, and sample size are not yet reported.
Finding & limits:In 65 patients with heart failure with preserved ejection fraction and iron deficiency, single-dose intravenous ferric derisomaltose (1000 mg) significantly improved 12-week peak VO2 compared with placebo (+1.2 vs +0.1 mL/kg/min; least-squares mean difference 1.1 mL/kg/min, 95% CI 0.2–1.9; P=0.02), 6-minute walk distance (+41.1 m; P=0.012), and NYHA class (P=0.013). Whether IV iron improves long-term clinical outcomes in HFpEF is untested, and experts point to ICONIC and INFUSE as the trials that still need to finish. The small size of this trial also limits how far the result can be taken.
In the largest trial to date of iron repletion in HFpEF, a single dose of ferric derisomaltose (1,000mg) increased peak oxygen uptake at week 12 (primary endpoint) by 1.1ml/kg/min compared to placebo, while also improving several other measures of exercise capacity.
Endpoint critique·General / Preventive / Lipids · University of Bologna
Iron repletion may partly reverse exercise intolerance, but lasting clinical benefit is still unproven.
Read full perspective
Fogacci noted that IV iron improved peak VO₂ by 1.1 mL/kg/min vs placebo at 12 weeks in 65 patients with iron-deficient HFpEF. She read this as evidence that exercise intolerance may be partly reversible through iron repletion, but said evidence of lasting clinical benefit is still needed.
Practice take·Heart Failure / Cardiomyopathy · Duke University
An important study on patient-centered endpoints, but ICONIC and INFUSE still need to finish.
Read full perspective
Mentz, who wrote the accompanying editorial, called this an important study of IV iron with FDI in HFpEF that improved peak VO2 and other patient-centered endpoints. He said the field now needs to finish the ICONIC and INFUSE trials.
Results readout·Director of Heart Failure, Mass General Brigham
The first study to fully map exercise responses to iron repletion found gains across several measures.
Read full perspective
Lewis described the trial as the first study to comprehensively evaluate how patients with HFpEF and iron deficiency respond during exercise after iron repletion. He said ferric derisomaltose improved multiple measures of exercise capacity.
Excited to share the results of our clinical trial #IRONMET-HFpEF. IV ferric derisomaltose vs placebo in HFpEF with iron deficiency showing a 1.1 ml/kg/min improvement in peak VO2 and improved 6MWT & NYHA. @GLewisCardiol @CircAHA @MGBResearchNews @mghcvrc
In the first study to comprehensively evaluate exercise response patterns to iron repletion in patients with HFpEF and iron deficiency, we found that ferric derisomaltose improved multiple measures of exercise capacity.
🫀🔥 What if correcting iron deficiency could restore exercise capacity in HFpEF—even without directly targeting cardiac filling pressures?
A new randomized trial in Circulation demonstrates that a single intravenous dose of ferric derisomaltose significantly improves peak
IRONMET-HFpEF
👥 65 with HFpEF + iron deficiency; 72.3% women
⚖️ IV iron 🆚 placebo
📊 12wk peak VO₂: +1.1 mL/kg/min (95% CI 0.2–1.9)
✅ Promising functional benefit; small trial
🔗
#AHA26 #ScientificSessions26 #CVPrev
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Full evidence
Why the trial, tables, limitations, PICO, abstract, media & sources
Why the trial?
Although iron deficiency is present in over half of patients with heart failure with preserved ejection fraction (HFpEF) and is linked to reduced survival and exercise capacity, it was unknown whether iron repletion improves objectively measured peak oxygen uptake (VO2). The IRONMET-HFpEF trial evaluated whether intravenous ferric derisomaltose improves peak VO2 compared with placebo in this patient population.
Does intravenous ferric derisomaltose improve peak oxygen uptake (peak VO2) compared with placebo in patients with heart failure with preserved ejection fraction and iron deficiency?
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Structured PICO
Does intravenous ferric derisomaltose improve peak oxygen uptake (peak VO2) compared with placebo in patients with heart failure with preserved ejection fraction and iron deficiency?
PPopulation
65 adults with heart failure with preserved ejection fraction and iron deficiency (median age 68 years, 72% women) followed for 12 weeks.
IIntervention
Single-dose ferric derisomaltose (1000 mg; n=44) administered once intravenously, followed for 12 weeks.
CComparator
Placebo (n=21) administered once intravenously, followed for 12 weeks.
OOutcome
Change in peak oxygen uptake (peak VO2) from baseline to 12 weeks, analyzed with an analysis of covariance model including terms for treatment group, baseline peak VO2, and sex.surrogate endpoint
Main Result
Mean Difference1.1 (95% CI 0.2–1.9)
Absolute Event Rate1.2% vs 0.1%
p-valuep=0.02
In patients with HFpEF and iron deficiency, single-dose intravenous ferric derisomaltose significantly improved peak VO2, 6-minute walk distance, and NYHA class at 12 weeks compared with placebo.
Where experts stand
Heart failure evidence still forming
Experts see this small trial as an encouraging sign that a single iron infusion can improve exercise capacity in iron-deficient heart failure with preserved ejection fraction, but not yet as practice-changing without outcome data.
The reaction is positive and one-sided. Investigators and outside heart failure specialists agree that correcting iron deficiency improved how well these patients could exercise. The live question is whether that functional gain turns into lasting clinical benefit, which larger ongoing trials will need to answer.
Agreement
Clinicians agree the exercise benefit is encouraging but that the trial does not show lasting clinical benefit. The next step they name is testing whether IV iron improves long-term outcomes.
2 clinicians say this directly
Still unclear
Whether IV iron improves long-term clinical outcomes in HFpEF is untested, and experts point to ICONIC and INFUSE as the trials that still need to finish. The small size of this trial also limits how far the result can be taken.
Implication
Supports considering IV iron repletion to improve exercise capacity in iron-deficient HFpEF; extends HFrEF repletion benefits to preserved ejection fraction.
Abstract
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 (peak VO2) 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 VO2 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 VO2 from baseline to 12 weeks with an analysis of covariance model including terms for treatment group, baseline peak VO2 , and sex. Secondary end points included changes in VO2 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: Among 65 randomized participants (median age, 68 years [interquartile range, 58–76 years], 72% women, transferrin saturation 16.0±7.4%, ferritin 57.8±48.9 ng/mL), 64 (98.5%) completed the study. The median baseline peak VO2 was 12.7 mL·kg −1 ·min −1 (interquartile range, 10.6–15.8 mL·kg −1 ·min −1 ) in the FDI group and 12.2 mL·kg −1 ·min −1 (11.6–14.6 mL·kg −1 ·min −1 ) in the placebo group. At 12 weeks, peak VO2 improved by 1.2 mL·kg −1 ·min −1 (95% CI, 0.6–1.7) in the FDI group and was unchanged (0.1 mL·kg −1 ·min −1 [95% CI, −0.7 to 0.9]) in the placebo group (least-squares mean difference, 1.1 mL·kg −1 ·min −1 [95% CI, 0.2–1.9]; P =0.02). VO2 at the anaerobic threshold, 6-minute walk test distance, and New York Heart Association class also improved in the FDI compared with the placebo group (all P <0.05), whereas the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score did not differ significantly between groups (FDI group, +4.4 [95% CI, −2.4 to 11.2]; P =0.20). FDI increased transferrin saturation (9.4% [95% CI, 4.9%–13.9%]) and ferritin (183 ng/mL [95% CI, 128–238]) compared with the placebo group ( P LSMD <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
Cite This Study
Lewis et al. (2026) conducted an RCT in Heart failure with preserved ejection fraction and iron deficiency (n=65). Ferric derisomaltose vs. Placebo administered once intravenously was evaluated on Change in peak oxygen uptake (peak VO2) from baseline to 12 weeks (MD 1.1 mL·kg−1·min−1, 95% CI 0.2-1.9, p=0.02).
