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

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.

Conflict of interest statement

Declaration of interests PRK reports research grants from British Heart Foundation and Pharmacosmos; consulting fees from Ackea, Amgen, Boehringer Ingelheim, Pharmacosmos, Servier, and Vifor Pharma; payment for lectures from AstraZeneca, Bayer, Novartis, Pfizer, Pharmacosmos, and Vifor Pharma; support for attending meetings from Pharmacosmos; is a data safety monitoring board member for the STOP-ACE trial; and has served as Chair of the British Society for Heart Failure. JGFC reports research grants from Amgen, Bayer, Bristol Myers Squibb, British Heart Foundation, Johnson & Johnson, Medtronic, Myokardia, Pharmacosmos, Pharma Nord, and Vifor Pharma; payment for lectures from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Innolife, NI Medical, Novartis, Servier, and Torrent; support for attending meetings from Boehringer Ingelheim and Pharmacosmos; is a data safety monitoring board member for Idorsia and Medtronic; has stock with Heartfelt Limited; and has been provided with equipment by Heartfelt Limited and NI Medical. MCP reports research grants from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Roche, and SQ Innovations; consulting fees from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Novartis, Novo Nordisk, Pharmacosmos, Siemens, and Takeda; payment for lectures from AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Pharmacosmos, Siemens, and Vifor Pharma; support for attending meetings from AstraZeneca; is a data safety monitoring board or advisory board member for AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Pharmacosmos, Teikoku, and Vifor Pharma; and is a director of Global Clinical Trials Partners. EAT, MR, and IF report research grants from British Heart Foundation and Pharmacosmos. PAK reports research grant support from Astellas, Evotec, Pharmacosmos, Unicyte, and Vifor Pharma; consulting fees from AstraZeneca, UCB, Unicyte, and Vifor Pharma; payment for lectures from AstraZeneca, Bayer, Napp, Pfizer, Pharmacosmos, and Vifor Pharma; and support for attending meetings from Pharmacosmos and Vifor Pharma. IBS reports a research grant from British Heart Foundation. FZA reports a research grant from Medtronic; consulting fees and payment for lectures from Abbott, AstraZeneca, Medtronic, Pfizer, Pharmacosmos, Servier, and Vifor Pharma; and support for attending meetings from AstraZeneca, Medtronic, and Pharmacosmos. AA-M reports payment for lectures from AstraZeneca, Janssen, Pharmacosmos, and Takeda; is on a data safety monitoring board or advisory board for AstraZeneca, Novartis, and Pharmacosmos; and reports a grant for equipment from AstraZeneca. PWXF reports a research grant, consulting fees, and other support from Medtronic; payment for lectures from Pharmacosmos and Vifor Pharma; and is a council member of British Heart Rhythm Society charity. FJG reports a research grant from British Heart Foundation. AGJ reports payment for lectures from AstraZeneca, Novartis, and Vifor Pharma; and is the clinical lead of the Scottish Heart Failure Hub. REL reports consulting fees from Abbott. NNL reports research grants from AstraZeneca, Boehringer Ingelheim, British Heart Foundation, and Roche Diagnostics; consulting fees from AstraZeneca; payment for lectures from Novartis and Roche Pharma; and is on a data safety monitoring board or advisory board for Pharmacosmos. AJL reports payment for lectures from AstraZeneca; support for attending meetings from Daiichi Sankyo; is on an advisory board for Daiichi Sankyo and Vifor Pharma; and is Chair of the British Cardiovascular Society Guidelines and Practice Committee. ICM reports consulting fees from GlaxoSmithKline and Vifor Pharma. PP reports consulting fees from Pharmacosmos and Vifor Pharma; and support for attending meetings from Bristol Myers Squibb, Pharmacosmos, and Vifor Pharma. RR reports consulting fees from Pharmacosmos; payment for lectures from Pfizer; is on the data monitoring committee for the Lift study; and has a leadership role in the HFA Education Committee. All other authors declare no competing interests.

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