By Dr. Timothy Swinn, edited by Dr. Ahmed El-Medany
Results from the IRONMAN trial1, recently released in the LANCET, have demonstrated a lower rate of hospital admissions due to heart failure and cardiovascular death with intravenous (IV) ferric derisomaltose which didn’t quite reach statistical significance. IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial designed to assess the long-term effects of repeated doses of IV ferric derisomaltose on heart failure hospital admissions and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF). Patients were predominantly recruited from outpatient clinics across 70 UK hospitals with key inclusion criteria of left ventricular ejection fraction less than 45% and iron deficiency (transferrin saturation<20% or ferritin<100 ug/l). 1,137 patients were randomised to receive standard care or IV ferric derisomaltose, a novel iron compound allowing rapid infusion of high iron doses. Median age was 73.4 years, median follow up time 2.3 years and both groups had heart failure medications optimised.
The primary outcome was a composite of hospital admissions due to heart failure and cardiovascular death. This occurred at a rate of 22.4 events per 100 patient years in the ferric derisomaltose group, compared to 27.5 events per 100 patient years in the control group (relative rate 0.82, 95% C.I. 0.66-1.02, p=0.070). Although this did not reach statistical significance, a pre-specified covid-19 analysis (all patients followed up until 30th September 2020, 6 months post first UK lockdown) did (RR 0.76, C.I. 0.58-1.0, p=0.047). There was no significant improvement in heart failure quality of life questionnaires or a 6-minute walk test at 4 or 20 months (Minnesota Living with Heart Failure and EQ-5D scores both used). IV iron did not reduce all-cause mortality (Hazard ratio 0.95, C.I. 0.78-1.17, p=0.64) or all-cause unplanned hospital admissions (HR 0.91, C.I. 0.79-1.05, p=0.21), however it appeared safe, with no increase in adverse events or hospital admissions for infection. Only 1 of the 569 patients receiving IV ferric derisomaltose in this study reported an infusion reaction: with vomiting and back pain which fully resolved. Of note, 17% of the control group received non-protocol IV iron at some stage, which may have reduced the perceived benefit.
IRONMAN returned very similar results to AFFIRM-AHF2, published in 2020. AFFIRM-AHF followed up 1,108 patients for 1 year and used the same primary endpoint for IV ferric carboxymaltose (RR 0.79, C.I. 0.62-1.01, p=0.059). Analysing the results from IRONMAN after 1 year yielded a statistically significant outcome (RR 0.66, C.I. 0.48-0.91, p=0.011).
At first glance, these results appear positive for intravenous ferric derisomaltose. Indeed, the safety profile is certainly reassuring. Looking more in-depth, however, the primary endpoint reduction is driven primarily by fewer heart failure-related admissions rather than lower cardiovascular death and neither all-cause hospital admissions nor all-cause mortality demonstrated significant reductions. Furthermore, IV iron infusions are commonly administered in day-care units and require another trip to hospital for a patient group that is already burdened with relatively frequent health appointments. This leaves clinicians and patients with a decision to make; whether the benefits of serial IV iron merit the repeated trips to hospital.
Regardless, IRONMAN was a well-designed trial about adjunctive heart failure treatment and provides valuable information to guide decision-making on an individual patient basis.
References
- Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. The Lancet [Internet]. 2022 Nov 5 [cited 2022 Nov 24];0(0). Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02083-9/fulltext
- Ponikowski P, Kirwan BA, Anker SD, McDonagh T, Dorobantu M, Drozdz J, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. The Lancet. 2020 Dec 12;396(10266):1895–904.
