IRONMAN failed primary endpoint but shows potential long-term benefits of iron repletion in HF patients

The IRONMAN trial narrowly missed its primary endpoint but did appear to suggest long-term benefits of intravenous (IV) iron supplementation for heart failure (HF) patients with an iron deficiency.

Iron deficiency is common in patients with HF and is associated with more severe symptoms and an adverse prognosis. Prof. Paul Kalra (Portsmouth Hospitals University NHS Trust; University of Glasgow, UK) and his team designed the randomised, multicentre, phase 4 IRONMAN trial (NCT02642562) to investigate whether long-term administration of IV iron improves outcomes among adults with HF and iron deficiency compared with the current guideline-recommended care [1,2]. Although the 2021 ESC Guideline recommends IV iron supplementation with ferric carboxymaltose for patients with iron deficiency recently hospitalised for symptomatic HF and with LVEF ≤50% and iron deficiency, the evidence level is IIa and it is not routinely incorporated into patient care [3]. The investigators here wanted to explore the clinical efficacy of IV iron administration when HF patients were in hospital.

The study included 1,137 hospitalised adults with HF and iron deficiency in the UK. The average age of the participants was 73 years and 26% were women. The participants were randomised 1:1 to receive IV iron plus standard care or standard care alone. The intervention group received additional doses at the 1-month review and every 2 months if iron deficiency returned. The participants were followed up for a median duration of ~2.5 years, with follow-up clinic visits every 4 months. The primary endpoint was the composite of hospitalisation for worsening HF or cardiovascular (CV) death.

During the COVID-19 pandemic in 2020 and 2021, recruitment slowed or ceased at many sites. To account for these difficulties and in line with regulatory (FDA, EMA) guidance, a prespecified COVID-19 sensitivity analysis was performed on the data from the 1,063 participants who had joined the trial before 31 March 2020 and whose treatment was not affected by the pandemic.

Without consideration of the impact of COVID-19, participants in the 2 arms showed no significant difference for the primary endpoint of recurrent HF hospitalisation or CV death (HR 0.82; 95% CI 0.66–1.02; P=0.07). In a secondary analysis participants in the intervention group appeared to have a better quality of life after 4 months, and long-term IV iron use was also associated with lower rates of serious adverse cardiac events compared with standard care. The risk of infection did not increase in the IV iron-receiving participants compared with standard care.

The prespecified COVID-19 sensitivity analysis observed a potential benefit of IV iron on the main study outcome, reducing the risk of heart failure hospitalisation and cardiovascular death (RR 0.76; 95% CI 0.58-1.00; P=0.047).

Although the trial was neutral overall, in the context of other data supporting iron, they may be viewed as supportive of iron repletion. “I think, the IRONMAN trial gives us reassurance that correction of iron deficiency by administering high-dose IV iron improves the well-being and prognosis for a broad range of patients with HF,” Prof. Kalra concluded.

1. 
   
   1. Kalra PR. IRONMAN: a randomized trial of intravenous ferric derisomaltose in heart failure with reduced ejection fraction. LBS.02, AHA Scientific Sessions 2022, 05–07 November, Chicago, USA.
   2. Kalra PR, et al. Lancet. 2022;Nov 5. DOI: 10.1016/S0140-6736(22)02083-9.
   3. McDonagh TA, Eur J Heart Fail. 2022;24(1):4–131.

 

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Posted on 11 January, 202311 January, 2023