IRONMAN: IV Iron Improves Outcomes in Heart Failure Among Iron Deficient Patients

Paul Kalra, MD

Treatment with intravenous iron in patients with heart failure and iron deficiency was associated with improvements in symptoms and reduced rate of recurrent hospitalizations, according to results of the IRONMAN study.

A randomized trial of intravenous ferric derisomaltose in heart failure with reduced ejection fraction (HFrEF), results of the study indicate long-term use was associated with an 18% relative reduction in rate of recurrent heart failure hospitalizations and cardiovascular death compared to usual care.

“People with heart failure are at risk of developing recurrent iron deficiency if their iron levels are not ‘topped up’ regularly. These results demonstrate that repeated dosing with IV iron is a beneficial, safe and well-tolerated treatment option that may improve the well-being of adults with heart failure and iron deficiency within a few months,” said Paul Kalra, MD, a consultant cardiologist and heart failure specialist at Portsmouth Hospitals University National Health Service Trust and honorary senior lecturer at the University of Glasgow, in a statement. “This study builds on existing evidence such that intravenous iron may benefit a broad range of people with heart failure, including those who are hospitalized, recently discharged or attending office or out-patient clinic appointments.”

Iron deficiency is regarded as one of the most commonly reported issues among patients with HFrEF and, in recent years, a spotlight has been shown on its association with an increased risk of adverse outcomes among this patient population. Citing previous research indicating use of IV ferric derisomaltose was associated with improvements in quality of life and reduction in events up to 12 months, a team led by Karl and colleagues sought to explore the efficacy and safety of IV iron in patients with HFrEF.

Funded by the British Heart Foundation and presented at the American Heart Association 2022 Scientific Sessions, the investigator-initiated, event-driven IRONMAN trial was designed as a prospective, randomized, open-label, blinded endpoint trial with a primary outcome of interest defined as recurrent heart failure hospitalizations and cardiovascular death. Secondary outcomes of interest for the trial included both components of the primary outcome as individual endpoints, all-cause mortality, and change in Minnesota Living with Heart Failure Questionnaire (MLHFQ).

For inclusion in the trial, patients needed to be at least 18 years of age or older, have a left ventricular ejection fraction below 45% and be classified as having NYHA Class II-IV heart failure. As part of study protocol, re-dosing occurred at week 4, month 4, and every 4n months thereafter if either ferritin was below 100 ug/L or TSAT was below 25%.

Overall, 1137 patients from 70 sites in the United Kingdom were enrolled from August 2016 and October 2021. Randomized in a 1:1 ratio to ferric derisomaltose or standard of care, the study’s arms included 569 randomized to ferric derisomaltose or standard of care. These patients had a median follow-up duration of 2.7 (IQR, 1.8-3.6) years. The overall study cohort had mean age of 73 years and 74% of participants were male.

In their analyses, investigators found use of ferric derisomaltose was associated with a reduced rate of recurrent heart failure hospitalizations and cardiovascular death, with a rate of 27.5 per 100 patient-years observed with standard of care and a rate of 22.4 per 100 patient-years observed with ferric derisomaltose (RR, 0.82 [95% CI, 0.66-1.02]). Further analysis of secondary outcomes of interest indicated use of ferric derisomaltose was associated with a reduction in risk or rate of total heart failure hospitalizations (RR, 0.80 [95% CI, 0.62-1.03]), cardiovascular death (HR, 0.86 [95% CI, 0.67-1.10]), and improvements in MLHFQ at 20 months (-2.57 [95% CI, -6.72 to 1.59]). Investigators noted the onset of the COVID-19 pandemic prevented optimal timelines for study visits and may have limited the magnitude of benefit observed in the trial.

“While the trial continued through the COVID-19 pandemic, there were extended periods of time when it was not possible to see patients in-person and administer additional doses of IV iron if needed,” Kalra added. “This impacted the study and is likely to have reduced the magnitude of benefit seen with IV iron.”

This study, “IRONMAN: A Randomized Trial of Intravenous Ferric Derisomaltose in Heart Failure With Reduced Ejection Fraction,” was presented at AHA 22.