IRONMAN: Intravenous Ferric Derisomaltose did not not meet primary endpoint in HFrEF

By Leah Kosyakovsky on

Key Points:

  • Iron deficiency is common and a poor prognostic feature in patients with heart failure. However, while iron infusion has improved symptoms in patients with HFrEF, there has been no association with improved “hard” outcomes such as hospitalization or CV death.
  • In the IRONMAN study, patients with HFrEF and iron deficiency were randomized to Intravenous Ferric Derisomaltose (IV FDI) or placebo. The primary outcome of interest was a composite of recurrent HF hospitalizations and CV death.
  • The observed reduction in primary endpoint with Intravenous Ferric Derisomaltose did not reach statistical significance compared to usual care.

Iron deficiency has been associated with poor outcomes in heart failure patients. While numerous trials have demonstrated that iron infusion in iron-deficient HFrEF patients leads to symptomatic improvement (FAIR-HF, CONFIRM-HF, and AFFIRM-HF), there has been no association with improved hospitalizations or mortality. In a breaking presentation at the 2022 AHA Scientific Sessions today, Dr. Paul Kalra (University of Glasgow) and his team presented their study: “Randomized Trial of Intravenous Ferric Derisomaltose in Heart Failure with Reduced Ejection Fraction,” or the IRONMAN trial.

The IRONMAN study (NCT02642562) was a multi-center randomized clinical trial conducted across 70 sites in the UK which evaluated the effects of IV iron administration vs placebo on patients with HFrEF (EF <45%). The inclusion criteria comprised any adults with EF <45%, NYHA class II-IV, and evidence of iron deficiency (TSAT <20% and/or ferritin < 100ug/L); relevant exclusions included ferritin >400ug/L, eGFR<15, recent type I MI or cardiac surgery, or active infection . A total of 1,137 patients were randomized. The mean age was 73, and 26% of patients were female. Those receiving iron received additional doses at one month and every four months thereafter if they continued to meet criteria.

The primary outcome was a composite of recurrent HF hospitalizations and CV death, which was reduced but did not reach statistically significance in the iron infusion group over an average follow-up of 2.5 years (RR 0.82, 95% CI 0.66-1.02; p=0.07). Secondary outcomes included HF hospitalizations, CV death, time to first event (CV death, HF hospitalizations, MI, or CVA), all-cause mortality, and Minnesota Heart Failure Questionnaire score, none of which were statistically significant between the two groups. The pre-specified COVID-19 sensitivity analysis of patients recruited prior to the start of the pandemic demonstrated a statistically significant reduction in the primary outcome (RR 0.76, 95% CI 0.58-1.00; p=0.047); however the clinical significance of this finding is not clear. Iron infusion was safe and well-tolerated, with no significantly increased incidence of infectious hospitalization or death due to infection.

When discussing the clinical implications of the study at AHA, Dr. Kalra stated: “In a broad range of patients with HF and iron deficiency, administration of IV FDI was associated with a lower risk of recurrent heart failure hospitalizations and CV death, which approached statistical significance…there were fewer serious adverse cardiac events and no increase in serious adverse events related to infection with IV FDI.”