IRONMAN – Randomized Trial of Intravenous Ferric Derisomaltose in Heart Failure with Reduced Ejection Fraction

Presented at the AHA Scientific Sessions 2022 by: Paul R. Kalra, MD- Portsmouth, UK

Introduction and methods

Iron deficiency is rather common in patients with HF, with incidences ranging from 30%-50% in ambulatory outpatients to ~75% in decompensated HF patients who are hospitalized. Patients with iron deficiency have a worse quality of life, impaired exercise capacity, and a higher risk of HF hospitalization or death, independent of anemia or hemoglobin levels. It has been shown that intravenous (IV) administration of ferric carboxymaltose improves quality of life and exercise capacity. In the previous AFFIRM-AHF trial, ferric carboxymaltose treatment reduced 1-year HF rehospitalization in patients hospitalized for HF.

The IRONMAN (Effectiveness of Intravenous Iron Treatment vs. Standard Care in Patients With Heart Failure and Iron Deficiency) trial was a prospective, randomized, open-label, blinded-endpoint, investigator-initiated, event-driven study that used a different iron compound and included mortality as an endpoint. For this trial, 1137 HF patients (LVEF ≤45%; NYHA class II-IV) with iron deficiency (ferritin<100 µg/L or transferrin saturation <20%) were randomized to treatment with IV ferric derisomaltose or standard of care. Patients were recruited at 70 UK sites between August 2016 and October 2021 and followed until April 2022.

The primary endpoint was a composite outcome of recurrent HF hospitalizations and CV death. Key secondary endpoints were recurrent HF hospitalizations; CV death; CV death or hospitalization for HF, MI, or CVA; all-cause mortality; and overall Minnesota Living with Heart Failure Questionnaire (MLWHQ) score at 4 and 20 months. The primary safety endpoint included hospitalization or death due to infection. A prespecified COVID-19 sensitivity analysis, which included all patients randomized until March 31, 2020 (start of first UK lockdown), and a post-hoc COVID-19 analysis (censored at 1 year), were also performed.

Main results

• During a mean follow-up duration of 2.7 years, the incidence rate of the primary endpoint was 22.4 per 100 patient-years in the group treated with ferric derisomaltose and 27.5 per 100 patient-years in the standard-care group (rate ratio (RR): 0.82; 95%CI: 0.66–1.02; P=0.07).
• As for the key secondary endpoints, only CV death or hospitalization for HF, MI, or CVA (hazard ratio (HR): 0.83; 95%CI: 0.69–1.00; P=0.045) and overall MLWHQ score at 4 months (estimated mean difference: –3.33 per 100 patient-years; 95%CI: –6.67 to 0.00; P=0.05) showed a slight difference between the treatment groups.
• In the prespecified COVID-19 sensitivity analysis, the RR for the primary endpoint was 0.76 (95%CI: 0.58–1.00; P=0.047).
• The post-hoc COVID-19 analysis showed an RR for the primary endpoint of 0.66 (95%CI: 0.48–0.91; P=0.011).
• With regard to the primary safety endpoint, there were no differences in the incidence rates of hospitalizations due to infection (RR: 0.82; 95%CI: 0.62–1.08; P=0.16) or deaths due to infection (HR: 1.22; 95%CI: 0.74–2.02; P=0.43).
• There was also no difference in the incidence rate of all serious adverse events (estimated mean difference: –3.2; 95%: –8.3 to 1.8; P=0.21), although the incidence rate of serious cardiac adverse events was numerically lower in the ferric derisomaltose group (estimated mean difference: –7.0; 95%: –12.7 to –1.3; P=0.016).

Conclusion

In HF patients with LVEF ≤ 45% and iron deficiency, IV administration of ferric derisomaltose was associated with a lower risk of HF hospitalization and CV death compared with standard of care but only in analyses that reduced the impact of the COVID-19 pandemic. The iron treatment improved patients’ well-being, was well tolerated, and did not lead to safety concerns.

-Our reporting is based on the information provided at the AHA Scientific Sessions-

The results of this study were simultaneously published in The Lancet.