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

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Heart failure with preserved ejection fraction and iron deficiency (n=65). Intervention: Ferric derisomaltose vs. Placebo. Primary outcome: Change in peak oxygen uptake from baseline to 12 weeks (p=<0.001).

Q: What does this research mean for the field?

Intravenous ferric derisomaltose improves peak oxygen uptake and other measures of exercise capacity at 12 weeks compared with placebo in patients with heart failure with preserved ejection fraction and iron deficiency. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Gregory D. Lewis; Nora Horick; Fabely Moreno; Kenneth Lim; Diane Cocca-Spofford; Takenori Ikoma; Paridhi Gupta; Carly Camphausen; Laura Caccamo; Charounipha Soydara; Shaina McGinnis; Chloe Newlands; Skyler Williams; Alexandra Minasian; Nicholas Iskenderian; Isabela Landsteiner; Bhavani Iyer; Justin Joseph; Alvaro Delgado; Helena Tattersfield; Elizabeth Moore; Veronica Platt; Sujin Lee; Rajeev Kumar Malhotra

doi:10.1161/circulationaha.126.084009

What happened

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.

Discussion

Author’s perspective

Gregory D. Lewis21h ago

Heart Failure · Harvard University

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.

IRONMET-HFpEF co-author

Expert perspectives 9

Federica Fogacci

Endpoint critiqueGeneral / 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.

X post ↗

Robert J. Mentz

Practice takeHeart 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.

X post ↗

C. Michael Gibson

Results readoutInterventional / Structural Cardiology · Beth Israel Deaconess Medical Center

Gibson noted that one infusion of ferric derisomaltose was well tolerated and improved peak oxygen uptake at 12 weeks.

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Show 6 more perspectives

Henry Han

Results readoutBaylor University

Han pointed out that 98.5% of the 65 patients completed the 12-week follow-up, alongside a peak VO₂ difference of +1.1 mL/kg/min.

X post ↗

Expert perspective

Rajeev Malhotra14h ago

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

t.coIRONMET-HFpEF co-author

Expert perspective

Gregory D. Lewis21h ago

Heart Failure · Harvard University

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.

IRONMET-HFpEF co-author

Expert perspective

Rajeev Malhotra21h ago

The next step is to determine whether IV iron can improve long-term clinical outcomes in patients with HFpEF.

IRONMET-HFpEF co-author

Expert perspective

오

오창명12h ago

🫀🔥 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

t.coIRONMET-HFpEF

Expert perspective

Martha Gulati22h ago

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

t.co t.coIRONMET-HFpEF

Outstanding questions

Open questions from this trial that would benefit from expert input.

Ask about this paper

Answers are grounded in this paper and cite their sources.

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 at 12 weeks compared with placebo in patients with heart failure with preserved ejection fraction and iron deficiency?

Structured PICO

Does intravenous ferric derisomaltose improve peak oxygen uptake at 12 weeks compared with placebo in patients with heart failure with preserved ejection fraction and iron deficiency?

Population

65 patients with heart failure with preserved ejection fraction and iron deficiency (ferritin <100 ng/mL or <300 ng/mL with transferrin saturation <20%), followed for 12 weeks

Intervention

Single-dose ferric derisomaltose 1000 mg administered once intravenously

Comparator

Placebo administered once intravenously

Outcome

Change in peak oxygen uptake from baseline to 12 weekssurrogate endpoint

Main Result

p-valuep=<0.001

In the largest trial to date of iron repletion in HFpEF with iron deficiency, single-dose intravenous ferric derisomaltose improved multiple measures of exercise capacity without serious treatment-related adverse events.

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 ([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.

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 was evaluated on Change in peak oxygen uptake from baseline to 12 weeks (p=<0.001).

synapsesocial.com/papers/6aeca9cbbf0cce6e83e4c801 https://doi.org/10.1161/circulationaha.126.084009

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.

Implication

Supports considering IV iron repletion to improve exercise capacity in iron-deficient HFpEF; extends HFrEF repletion benefits to preserved ejection fraction.

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

Key points