- IRONMET-HFpEF was the first randomized, double-blind, placebo-controlled trial to test whether iron repletion improves peak oxygen uptake in heart failure with preserved ejection fraction (HFpEF) and iron deficiency.
- A 1,000-mg infusion of ferric derisomaltose raised peak oxygen uptake by 1.1 mL/kg/min compared with placebo at 12 weeks, which is higher than the commonly used threshold for a clinically meaningful change.
- Six-minute walk distance improved by 41 m and more patients improved by at least one NYHA class. Health status scores rose by 4.4 points, a difference that was not statistically significant.
Poor exercise tolerance is the defining complaint of patients with heart failure with preserved ejection fraction (HFpEF), and drugs that reduce heart failure hospitalization, such as SGLT2 inhibitors and mineralocorticoid receptor antagonists, have done little to improve it. More than half of patients with HFpEF are iron deficient, a higher share than in heart failure with reduced ejection fraction (HFrEF). Yet nearly all trials of intravenous (IV) iron have enrolled patients with HFrEF, where iron repletion now carries a class 1 guideline recommendation to improve symptoms and exercise capacity.
At the 2026 American Heart Association Scientific Sessions, Dr. Gregory D. Lewis of Mass General Brigham presented the IRONMET-HFpEF trial (NCT04945707), simultaneously published in Circulation. The trial, sponsored by the National Heart, Lung, and Blood Institute, randomized 65 patients with HFpEF and iron deficiency 2:1 to a single 1,000 mg IV infusion of ferric derisomaltose (n=44) or saline placebo (n=21). Iron deficiency was defined as ferritin less than 100 ng/mL, or ferritin less than 300 ng/mL with transferrin saturation less than 20%, the same definition used in HFrEF trials. The primary endpoint was the change in peak oxygen uptake (VO2) on cardiopulmonary exercise testing at 12 weeks, read by an independent core laboratory. Median age was 68 years, 72% of patients were women, and median baseline peak VO2 was 12.4 mL/kg/min. All but one patient completed the trial.
Peak VO2 rose by 1.2 mL/kg/min with iron and was unchanged with placebo, a difference of 1.1 mL/kg/min (95% CI 0.2–1.9; P=0.02). That exceeds the 1.0 mL/kg/min threshold commonly used as the minimal clinically important difference. The increase held for absolute peak VO2 not indexed to body weight so weight change did not explain it.
The functional secondary endpoints moved in the same direction. Compared with placebo, iron improved 6-minute walk distance by 41 m (95% CI 9.5–72.8; P=0.012) and VO2 at the anaerobic threshold by 46 mL/min (95% CI 0.7–92.2; P=0.047). In the iron group, 36% of patients improved by at least one NYHA class compared with 10% on placebo (P=0.013). The Kansas City Cardiomyopathy Questionnaire Overall Summary Score rose by 4.4 points relative to placebo, but the difference was not significant (95% CI –2.4 to 11.2; P=0.20).
The single infusion raised transferrin saturation by 9.4 percentage points, ferritin by 183 ng/mL, and hemoglobin by 1.4 g/dL compared with placebo (all P<0.001). Two patients on iron had mild drug-related symptoms, one with transient flu-like symptoms and one with lip fullness and nausea. None had a drug-related serious adverse event, and no deaths occurred.
Ferric derisomaltose can be given in doses of up to 2 g at once, with no test dose and no FDA boxed warning. Lewis said a single dose typically does not need repeating for 6 to 12 months. “We’re talking about a single therapy,” he said in an interview at the meeting.
The trial was small, outcomes were measured only at 12 weeks, and most participants were white. Secondary endpoints were not adjusted for multiple comparisons. “We have to be mindful of the fact that the clinical trial size was relatively modest,” said Lewis. Two larger trials, ISLE-HFpEF and INFUSE-HFpEF, will test IV iron in broader HFpEF populations and assess long-term clinical outcomes.
Lewis pointed to the experience in HFrEF. Iron deficiency is, if anything, more common in HFpEF, he noted, “and we have no reason to believe that they’re not going to behave similarly to patients with heart failure reduced EF.”