• Paul R Kalra, ClelandJohn G FJGFSchool of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK., Mark C Petrie, Elizabeth A Thomson, Philip A Kalra, Iain B Squire, Fozia Z Ahmed, Abdallah Al-Mohammad, Peter J Cowburn, FoleyPaul W XPWXWiltshire Cardiac Centre, Great Western Hospitals NHS Foundation Trust, Swindon, UK., Fraser J Graham, Alan G Japp, Rebecca E Lane, Ninian N Lang, Andrew J Ludman, Iain C Macdougall, Pierpaolo Pellicori, Robin Ray, Michele Robertson, Alison Seed, Ian Ford, and IRONMAN Study Group.
• Department of Cardiology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK; College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Faculty of Science and Health, University of Portsmouth, Portsmouth, UK.
• Lancet. 2022 Dec 17; 400 (10369): 219922092199-2209.

BackgroundFor patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure.MethodsIRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562.FindingsBetween Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016).InterpretationFor a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population.FundingBritish Heart Foundation and Pharmacosmos.Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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