Rationale and design of a randomised trial of intravenous iron in patients with heart failure

Abstract

Objectives: For patients with a reduced left ventricular ejection fraction (LVEF) heart failure with reduced ejection fraction (HFrEF) and iron deficiency, administration of intravenous iron improves symptoms, exercise capacity and may in the following 12 months, reduce hospitalisations for heart failure. The Effectiveness of Intravenous iron treatment versus standard care in patients with heart failure and iron deficiency (IRONMAN) trial evaluated whether the benefits of intravenous iron persist in the longer term and impact on morbidity and mortality.

Methods: IRONMAN is a prospective, randomised, open-label, blinded endpoint (PROBE) event-driven trial. Patients aged ≥18 years with HFrEF (LVEF ≤45%) and evidence of iron deficiency (ferritin <100 µg/L and/or TSAT <20%) were enrolled if they had either a current or recent hospitalisation for heart failure or elevated plasma concentrations of a natriuretic peptide. Participants were randomised to receive, or not to receive, intravenous ferric derisomaltose in addition to guideline-recommended therapy for HFrEF. Every 4 months, intravenous iron was administered if either ferritin was <100 µg/L or, provided ferritin was ≤400 µg/L, TSAT was <25%. The primary endpoint is a composite of total hospitalisations for heart failure and cardiovascular death. Hospitalisation and deaths due to infection are safety endpoints.

Results: Trial recruitment was completed across 70 UK hospital sites in October 2021. Participants were followed until the end of March 2022. We plan to report the results by November 2022.

Conclusions: IRONMAN will determine whether repeated doses of intravenous ferric derisomaltose are beneficial and safe for the long-term treatment of a broad range of patients with HFrEF and iron deficiency.

Trial registration number: NCT02642562.

Keywords: Heart Failure; Heart Failure, Systolic.

Conflict of interest statement

Competing interests: PRK: research grant support from British Heart Foundation, Pharmacosmos and Vifor; consultancy fees from Ackea, Amgem, Bayer, Boehringer Ingelheim, Boston Scientific, Napp, Novartis, Pharmacosmos, Servier and Vifor; payment for lectures from AstraZeneca, Bayer, Novartis, Pharmacosmos and Vifor; support for attending meetings from Pharmacosmos; has served as Chair of the British Society for Heart Failure. JGC: research grant support from Amgen, Bayer, Bristol Myers Squibb, Vifor, Pharmacosmos, Cytokinetics, Johnson & Johnson, MyoKardia, Stealth Biopharmaceuticals and Viscardia; honoraria from Abbott, Amgen, Bayer, Bristol Myers Squibb, Novartis, Medtronic, Idorsia, Vifor, Pharmacosmos, Cytokinetics, Servier, Boehringer Ingelheim, AstraZeneca, Innolife, Torrent, Johnson & Johnson, MyoKardia, Respicardia, Stealth Biopharmaceuticals, Viscardia and NI Medical. MCP: research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific and Pharmacosmos. Consultancy, payment for lectures and clinical trials committees: Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Medtronic, Abbvie, Bayer, Takeda, Cardiorentis, Pharmacosmos, Siemens, SQ Innovations and Vifor; MCP is supported by the British Heart Foundation (BHF) Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+). FA: Research funding from Medtronic; consultancy fees from AstraZeneca, Medtronic, Pfizer, Pharmacosmos, Servier and Vifor; support for attending meetings from AstraZeneca, Medtronic, Pharmacosmos and Vifor. PF: payment for lectures from Vifor and Pharmacosmos; support for attending meetings from Pharmacosmos. PAK: research grant support from Pharmacosmos, Vifor, Astellas, Unicyte and Evotec; consultancy fees from Vifor, Pharmacosmos, AstraZeneca, Napp, Pfizer and Bayer; support for attending meetings from Pharmacosmos and Vifor. NNL: research grant support from Roche Diagnostics, British Heart Foundation, AstraZeneca, Tenovus Scotland and Boehringer Ingelheim; consultancy fees from AstraZeneca; payment for lectures from Roche Pharma, Pfizer and Novartis; participation on a DSM/advisory board for Pharmacosmos; Associate Editor of Circulation: Heart Failure. RL: payment for lectures from Boston Scientific. ICM: consultancy fees from GlaxoSmithKline and Vifor; steering committee member for GlaxoSmithKline trials. PP: research grant support from British Heart Foundation; consultancy fees from Pharmacosmos, Novartis, Vifor and AstraZeneca; support for attending meetings from Boehringer Ingelheim and Vifor. MTBP: none. MR: research grant support from British Heart Foundation, Pharmacosmos. IBS: payment for lectures from Novartis, Merck, AstraZeneca and Boehringer Ingelheim; expert advisory role on NICE COVID RAPID Guidelines Committee. EAT: research grant support from British Heart Foundation and Pharmacosmos. IF: research grant support from British Heart Foundation, Pharmacosmos and Vifor.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Overview of the Ironman trial: visit schedule and procedures. *See box 1 for full list of inclusion and exclusion criteria. CRP, C reactive protein; EGFR, estimated glomerular filtration rate; SAE, serious adverse event.