Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial
Authors: Cleland John G F , Kalra Philip A , Pellicori Pierpaolo , Graham Fraser J , Foley Paul W X , Squire Iain B , Cowburn Peter J , Seed Alison , Clark Andrew L , Szwejkowski Ben , Banerjee Prithwish , Cooke Justin , Francis Mark , Clifford Piers , Wong Aaron , Petrie Colin , McMurray John J V , Thomson Elizabeth A , Wetherall Kirsty , Robertson Michele , Ford Ian , Kalra Paul R ,   the IRONMAN Study Group, Kalra Paul , Cowan Elena , Turner Charlotte , Austin Rosalynn , Lane Rebeca , Rogers Paula , Foley Paul , Chandrasekaran Badri , Fraile Eva , Kyeremeh Lynsey , Ahmed Fozia , Petrie Mark , McGregor Lorraine , Osmanska Joanna , Graham Fraser , Lang Ninian , Meyer Barbara , Ahmad Faheem , Osmanska Joanna , Squire Iain , Fisher Jude , Kalra Philip , Summersgill Christina , Adeniji Katarzyna , Chinnadurai Rajkumar , Ludman Andrew , Massimo Lisa , Hardman Clare , Sykes Daisy , Cowburn Peter , Frank Sarah , Smith Simon , Japp Alan , Anwar Mohamed , Whittington Beth , Seed Alison , Ray Robin , Sookhoo Vennessa , Lyons Sinead , Al-Mohammad Abdallah , Middle Janet , Housley Kay , Clark Andrew , Bulemfu Jeanne , Critoph Christopher , Chong Victor , Wood Stephen , Szwejkowski Benjamin , Lang Chim , Duff Jackie , MacDonald Susan , Schiff Rebekah , Donnelly Patrick , Nageh Thuraia , Kunhunny Swapna , Petrie Mark , Gardner Roy , McAdam Marion , McPherson Elizabeth , Banerjee Prithwish , Sear Eleanor , Edwards Nigel , Glover Jason , Pellicori Pierpaolo , Murphy Clare , Cooke Justin , Spencer Charles , Francis Mark , Matthews Iain , McKie Hayley , Marshall Andrew , Large Janet , Stratford Jenny , Clifford Piers , Boos Christopher , Keeling Philip , Wong Aaron , Jones Deborah , James Alex , Williams Rhys , Leslie Stephen , Finlayson Jim , Clifford Piers , Hannah Andrew , Campbell Philip , Walsh John , Quinn Jane , Chapman Callum , Piper Susan , Patale Sheetal , Gupta Preeti , Sim Victor , Knibbs Lucy , Lyons Kristopher , Dixon Lana , Petrie Colin , Wong Yuk-ki , Labinjoh Catherine , Duckett Simon , Massey Ian , Savage Henry , Matias Sofia , Ramirez Jonaifah , Manisty Charlotte , Hussain Ifza , Sankaranarayanan Rajiv , Davis Gershan , McClure Samuel , Baxter John , Wicks Eleanor , Sobolewska Jolanta , Murphy Jerry , Elzayat Ahmed , Wright Jay , Williams Simon , Muthumala Amal , Chaggar Parminder , Webber Sue , Ellis Gethin , Welch Mandie , Bulugahapitiya Sudantha , Jackson Thomas , Pakrashi Tapesh , Bakhai Ameet , Krishnamurthy Vinodh , Gamma Reto , Ellery Susan , Manisty Charlotte , Jenkins Geraint , Nightingale Angus , Thomson Elizabeth , Ford Ian , Robertson Michele , Greenlaw Nicola , Wetherall Kirsty , Clarke Ross , Graham Christopher , Kean Sharon , Stevenson Alan , Wilson Robbie , Boyle Sarah , McHugh John , Hall Lisa , Woollard Joanne , Brunton Claire , Dinnett Eleanor , Reid Amanda , Howe Serena , Nicholls Jill , Cunnington Anna , Douglas Elizabeth , Fegen Margaret , Jones Marc , McGowan Sheila , Ross Barbara , Sandu Pamela , Surtees Pamela , Stuart Debra , Boon Nicholas , Amoils Shannon , Chapman Callum , Cleland John , Diness Thomas Goldin , Ford Ian , Kalra Paul , Kalra Philip , Macdougall Iain , McMurray John , Mindham Richard , Petrie Mark , Sandu Pamela , Squire Iain , Strom Claes Christian , Thomson Elizabeth , Travers Maureen , Wilcox Robert , Struthers Allan , Mark Patrick , Weir Christopher , Cleland John , Graham Fraser , Pellicori Pierpaolo 
Published: March 2024

Abstract

Background and Aims
What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?

Methods
In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin &lt; 100 µg/L or transferrin saturation (TSAT) &lt; 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death.

Results
The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction &lt; .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT &lt; 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant.

Conclusions
This hypothesis-generating analysis suggests that anaemia or TSAT &lt; 20% with ferritin &gt; 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.