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
Paul R. Kalra, John G.F. Cleland, Mark C. Petrie, Elizabeth Thomson, Philip A. Kalra, Iain Squire, Fozia Ahmed, Abdallah Al‐Mohammad, Peter J. Cowburn, Paul W X Foley, Fraser J Graham, Alan G. Japp, Rebecca Lane, Ninian N. Lang, Andrew Ludman, Iain C. Macdougall, Pierpaolo Pellicori, Robin Ray, Michele Robertson, Alison Seed, Ian Ford, Paul R. Kalra, John G.F. Cleland, Mark C. Petrie, Elizabeth Thomson, Philip A. Kalra, Iain Squire, Fozia Ahmed, Abdallah Al‐Mohammad, Peter J. Cowburn, Paul W X Foley, Fraser J Graham, Alan G. Japp, Rebecca Lane, Ninian N. Lang, Andrew Ludman, Iain C. Macdougall, Pierpaolo Pellicori, Robin Ray, Michele Robertson, Alison Seed, Ian Ford, Nicholas A. Boon, Shannon Amoils, Callum Chapman, Thomas G Diness, John McMurray, Richard Mindham, Pamela Sandu, Claes Christian Strom, Maureen Travers, Robert Wilcox, Allan D. Struthers, Patrick B. Mark, Christopher J. Weir, Elena Cowan, Charlotte Turner, Rosalynn Austin, Paula Rogers, Badri Chandrasekaran, E Fraile, Lynsey Kyeremeh, Lorraine McGregor, Joanna Osmanska, Barbara Meyer, Faheem Ahmad, Jude Fisher, Christina Summersgill, Katarzyna Adeniji, Rajkumar Chinnadurai, Lisa Massimo, Clare S. Hardman, Daisy Sykes, Sarah Frank, Simon Smith, Mohamed Anwar, Beth Whittington, Vennessa Sookhoo, Sinéad Lyons, Janet Middle, Kay Housley, Andrew L. Clark, Jeanne Bulemfu, Christopher Critoph, Victor Chong, Stephen J. Wood, Benjamin R. Szwejkowski, Chim C. Lang, Jackie Duff, Susan M. MacDonald, Rebekah Schiff, Patrick Donnelly, Thuraia Nageh, Swapna Kunhunny, Roy S. Gardner, Marion McAdam, Elizabeth McPherson, Prithwish Banerjee, Eleanor Sear, Nigel Edwards
Abstract
BACKGROUND: For 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. METHODS: IRONMAN 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. FINDINGS: Between 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). INTERPRETATION: For 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. FUNDING: British Heart Foundation and Pharmacosmos.