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Randomized Controlled Trial
. 2024 Oct 29;84(18):1704-1717.
doi: 10.1016/j.jacc.2024.08.052.

Adjudication of Hospitalizations and Deaths in the IRONMAN Trial of Intravenous Iron for Heart Failure

John G F Cleland  1 , Pierpaolo Pellicori  2 , Fraser J Graham  2 , Rebecca Lane  3 , Mark C Petrie  2 , Fozia Ahmed  4 , Iain B Squire  5 , Andrew Ludman  6 , Alan Japp  7 , Abdallah Al-Mohammad  8 , Andrew L Clark  9 , Ben Szwejkowski  10 , Chris Critoph  11 , Victor Chong  12 , Rebekah Schiff  13 , Thuraia Nageh  14 , Jason Glover  15 , John J V McMurray  2 , Elizabeth A Thomson  16 , Michele Robertson  16 , Ian Ford  16 , Philip A Kalra  17 , Paul R Kalra  18 ; IRONMAN Study Group
Affiliations
Randomized Controlled Trial

Adjudication of Hospitalizations and Deaths in the IRONMAN Trial of Intravenous Iron for Heart Failure

John G F Cleland et al. J Am Coll Cardiol. .

Abstract

Background: Patients with heart failure and iron deficiency have diverse causes for hospitalization and death that might be affected by iron repletion.

Objectives: The purpose of this study was to explore causes of hospitalizations and deaths in a randomized trial (IRONMAN) of heart failure comparing intravenous ferric derisomaltose (FDI) (n = 568) and usual care (n = 569).

Methods: Patients with heart failure, left ventricular ejection fraction ≤45%, and either transferrin saturation <20% or serum ferritin <100 μg/L were enrolled. Median follow-up was 2.7 years (Q1-Q3: 1.8-3.6 years). A committee adjudicated the main and contributory causes of unplanned hospitalizations and deaths. RRs (rate ratios) for selected recurrent events with 95% CIs are also reported.

Results: Compared with usual care, patients randomized to FDI had fewer unplanned hospitalizations (RR: 0.83; 95% CI: 0.71-0.97; P = 0.02), with similar reductions in cardiovascular (RR: 0.83; 95% CI: 0.69-1.01) and noncardiovascular (RR: 0.83; 95% CI: 0.67-1.03) hospitalizations, as well as hospitalizations for heart failure (RR: 0.78; 95% CI: 0.60-1.00), respiratory disease (RR: 0.70; 95% CI: 0.53-0.97), or infection (RR: 0.82; 95% CI: 0.66-1.03). Heart failure was the main cause for 26% of hospitalizations and contributed to or complicated a further 12%. Infection caused or contributed to 38% of all hospitalizations, including 27% of heart failure hospitalizations. Patterns of cardiovascular and all-cause mortality were similar for patients assigned to FDI or usual care.

Conclusions: In IRONMAN, FDI exerted similar reductions in cardiovascular and noncardiovascular hospitalizations, suggesting that correcting iron deficiency might increase resistance or resilience to a broad range of problems that cause hospitalizations in patients with heart failure. (Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency; NCT02642562).

Keywords: heart failure; hospitalizations; intravenous iron; iron deficiency; randomized trial.

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Conflict of interest statement

Funding Support and Author Disclosures The IRONMAN trial was funded by the British Heart Foundation (grant CS/15/1/31175). Pharmacosmos supplied FDI and gave additional financial support. Dr Cleland has received funding paid to University of Glasgow for other clinical trials and registries from Bristol Myers Squibb and CSL-Vifor; has received consulting fees paid to University of Glasgow from Pharmacosmos, CSL-Vifor, and Biopeutics; has received honoraria for lectures and support for attending meetings paid to University of Glasgow from Pharmacosmos; is chairperson for data monitoring committees for ADAPT-CRT, CMR-Guide, and PROTECT-HF; and has shares or stock options in HeartFelt (noninvasive monitoring) and Viscardia (synchronous diaphragmatic pacing). Dr Pellicori has received consulting fees from Pharmacosmos, Vifor, and Caption Health; has received honoraria for lectures from AstraZeneca; and has received support for attending meetings from Pharmacosmos. Dr Graham has received personal consulting fees from Vifor; and has received personal support for attending meetings from Pharmacosmos. Dr Petrie has received grants/contracts from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; has received consulting fees from Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences; and has participated on data safety monitoring boards for Moderna and Teikoku. Dr Ahmed has received honoraria for lectures from Pharmacosmos. Dr Squire has received grants/contracts from the British Heart Foundation. Dr Ludman has received honoraria for lectures from AstraZeneca; and is chairperson for the British Cardiovascular Society Guidelines and Practice Committee. Dr Japp has received personal consulting fees from Pharmacosmos; has received honoraria for educational events from Novartis and AstraZeneca; has received support for attending meetings from Novartis; has participated on an advisory board for Pharmacosmos; and is Clinical Lead and Chair for Heart Failure Hub Scotland. Dr Al-Mohammad has received personal honoraria for lectures from AstraZeneca, Janssen, Takeda, and Pharmacosmos; has participated on advisory boards for Novartis, Pharmacosmos, AstraZeneca, Boehringer Ingelheim, and Lilly; is a safety monitoring board member for the REACH-HFpEF Study and a UK-HFpEF registry Executive Steering Committee member; and has received equipment from AstraZeneca. Dr Clark is Chair of the Programme Committee for BCS. Dr Szwejkowski has received support for attending meetings from AstraZeneca. Dr McMurray has received personal consulting fees from Alynylam Pharmaceuticals, Bayer, BMS, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; is a director of Global Clinical Trial Partners; has received personal honoraria for lectures from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; has participated on a data safety monitoring board for George Clinical PTY; and has received funding paid to University of Glasgow for involvement with the following companies/trials: AstraZeneca (DAPA-HF, DELIVER, DETERMINE, DAPA-Resist, DAPA-CKD), Amgen (ATOMIC-HF, COSMIC-HF, GALACTIC-HF), Bayer (FINEARTS), Cardurion (company advisory board), Cytokinetics (GALACTIC-HF), GlaxoSmithKline (ASCEND-D, ASCEND-ND), KBP Biosciences (scientific advisor), and Novartis (PARAGON-HF, PARADISE-MI, PERSPECTIVE, PARACHUTE-HF). Drs Thomson and Robertson have received grants paid to University of Glasgow from the British Heart Foundation and Pharmacosmos. Dr Ford has received grants paid to University of Glasgow from the British Heart Foundation and Pharmacosmos and study drug from Pharmacosmos. Dr Philip Kalra has received funding from Pharmacosmos; has received grants from CSL Vifor, Astellas, Evotec, Pharmacosmos, and Unicyte; has received consulting fees from AstraZeneca, CSL Vifor, Unicyte, and UCB; has received honoraria for lectures from CSL Vifor, AstraZeneca, Pfizer, Pharmacosmos, Napp, and Bayer; and has received support for attending meetings from Pharmacosmos and CSL Vifor. Dr Paul Kalra has received grants paid to University of Glasgow from the British Heart Foundation and Pharmacosmos and to Portsmouth Hospitals University NHS Trust from Pharmacosmos; has received personal consulting fees from Amgen, Boehringer Ingelheim, Pharmacosmos, Servier, and CSL Vifor; has received personal honoraria for lectures from AstraZeneca, Bayer, Novartis, Pfizer, Pharmacosmos, CSL Vifor, and Amgen; has received support for attending meetings from Pharmacosmos; has participated on data safety monitoring boards for the STOP-ACE and EMPRESS-MI trials; and has been Chair-Elect, Chair, and Past Chair for the British Society for Heart Failure. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Central Illustration
Central Illustration
IRONMAN Trial Design and the Effects of FDI on Hospitalizations Design of the IRONMAN trial and effect of FDI on all-cause and cause-specific hospitalizations (recurrent events analysis) for patients with chronic heart failure with a reduced left ventricular ejection fraction (LVEF) and markers of iron deficiency. CV = cardiovascular; IV = intravenous; RR = rate ratio; TSAT = transferrin saturation.
Figure 1
Figure 1
Cumulative Incidence Curves for All-Cause, Cardiovascular, and Noncardiovascular Hospitalizations (Recurrent Events) Graphic presentations of cumulative events for patients assigned to usual care or ferric derisomaltose (FDI), including (A) all-cause hospitalizations and hospitalizations where the main cause was (B) cardiovascular or (C) noncardiovascular based on the method of Ghosh and Lin, adjusting for the competing risk of death. Reductions in event rates were similar for each type of hospitalization.
Figure 2
Figure 2
Causes of Hospitalizations Numbers of hospitalizations for noncardiovascular (non-CV) and cardiovascular (CV) causes and for heart failure (HF) as the main cause or as a main cause or contributory to another CV or non-CV cause according to randomized group, ie, usual care or ferric derisomaltose (FDI). Recurrent event rates between treatment arms were compared according to the method of Lin et al.
Figure 3
Figure 3
Main or Contributory Causes for Cardiovascular Hospitalizations Number of cardiovascular hospitalizations as a main or contributory cause according to randomized group, ie, usual care or ferric derisomaltose (FDI). ¶¶The algorithm did not classify the type of arrhythmia when contributory, but most arrhythmias as a contributory cause were considered to be AF/SVT. Any = main or contributory cause for admission. ACS = acute coronary syndrome; AF/SVT = atrial fibrillation or supraventricular tachycardia; AKI = acute kidney injury; VT/VF = ventricular tachycardia or ventricular fibrillation or cardiac arrest. The y-axis scale is the same as in Figures 2 and 3 to allow comparisons.
Figure 4
Figure 4
Main or Contributory Causes for Noncardiovascular Hospitalizations Legend: Numbers of noncardiovascular hospitalizations as a main or contributory cause according to randomized group, ie, usual care or ferric derisomaltose (FDI). Any = main or contributory cause for admission. The y-axis scale is the same as in Figures 2 and 3 to allow comparisons.
Figure 5
Figure 5
All-Cause Mortality All-cause mortality for patients assigned to usual care or ferric derisomaltose (FDI). HRs (with 95% CIs) were adjusted for the baseline stratification variable of recruitment context (current or recent hospital hospitalization for heart failure or as an outpatient with increased plasma concentrations of natriuretic peptides).
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