Intravenous ferric derisomaltose for patients with heart failure: does iron heart translate into IRONMAN?

Comment on the article ‘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’, which was published in the The Lancet, https://doi.org/10.1016/S0140-6736(22)02083-9. This investigator-initiated, prospective, randomized, open-label, blinded-endpoint trial aimed to test the superiority of intravenous iron supplementation with ferric derisomaltose over usual care in patients with new or established symptomatic heart failure (HF) and left ventricular ejection fraction ≤45% with evidence of iron deficiency (defined as transferrin saturation < 20%, or serum ferritin <100 μg/L). Patients with serum ferritin concentrations >400 μg/L or haemoglobin <9 g/dL were excluded.1 The IRONMAN trial was funded by the British Heart Foundation and Pharmacosmos. From a total of 1869 patients screened at 70 hospitals in the United Kingdom (UK) between 2016 and 2021, 1137 eligible patients (median age, 73 years; 26% female) were randomized 1:1 to either ferric derisomaltose (n = 569) or usual care (n = 568). Most patients (67%) were enrolled from outpatient clinics and had raised NT-proBNP or BNP, and the vast majority had a New York Heart Association (NYHA) class of II (57%) or III (41%). In patients randomized to the ferric derisomaltose group, iron deficiency and repletion therapy dose were decided on the basis of haemoglobin levels and body weight. At trial visit, ferric derisomaltose was administered when ferritin was <100 μg/L, or ≤400 μg/L with a transferrin saturation <25%. Median follow-up was 2.7 years. The primary endpoint was a composite of hospital admissions for HF and cardiovascular death. Secondary endpoints included: recurrent hospital admission for HF, cardiovascular hospital admission (first event), cardiovascular death or hospital admission for HF (first event), cardiovascular death or hospital admission for stroke, myocardial infarction or HF (first event), all-cause mortality, all-cause hospital admission. Other secondary endpoints were indices of quality of life (QoL) and exercise capacity, as assessed by MLHFQ score, EQ-5D index and 6-min walk distance at 4 and 20 months. Safety endpoints were deaths and hospital admissions due to infection. A prespecified COVID-19 sensitivity analysis, including all patients randomly assigned until 31 March 2020 and censoring follow-up on 30 September 2020, was carried out. The primary endpoint occurred in 336 patients in the ferric derisomaltose group (22 per 100 patient-years) and in 411 patients in the usual care group (28 per 100 patient-years) (rate ratio [RR] 0.82; 95% confidence interval [CI], 0.66–1.02; P = 0.070). In the COVID-19 sensitivity analysis, the observed treatment effect was larger and marginally statistically significant (RR, 0.76; 95% CI, 0.58–1.00; P = 0.047). The expanded outcome of cardiovascular death or hospital admission for stroke, myocardial infarction or HF occurred in fewer patients assigned to ferric derisomaltose as compared with those in the usual care group (RR, 0.83; 95% CI, 0.69–1.00; P = 0.045). However, each primary and secondary outcome was analysed sequentially with a requirement that a P value would not be interpreted as meaningful unless the analysis of the previous outcome had a P value <0.05. The incidence of other secondary outcomes was not different in the two groups, except for better physical domain MLHFQ scores in the ferric derisomaltose at 4 months. No difference in the prespecified safety endpoints was observed between the two groups. Iron exerts a pivotal role in cardiac metabolism and function, and its deficiency is a frequent comorbidity in HF.2 Based on circulating biomarkers of depleted body iron stores and reduced systemic iron availability, approximately 40% of patients with chronic HF and 75% of those with acute decompensated HF have iron deficiency, regardless of the presence of anaemia.3 While an ‘absolute’ iron deficiency is often observed in patients with HF, a substantial proportion of them have a ‘functional’ deficiency, which is related to impaired iron absorption from the gastro-intestinal tract or to its sequestration into hepatocytes and macrophages due to a low-grade inflammatory state.4 HF patients with iron deficiency have worse QoL and exercise capacity, as well as higher rehospitalization and mortality rates.3,4 These observations have prompted a number of clinical trials aiming to test intravenous repletion of iron stores as a therapeutic strategy to improve the outcome of patients with HF, including the AFFIRM-AHF trial.5–7 Based on the accumulated evidence, current European Society of Cardiology (ESC) guidelines recommend periodic screening of HF patients for iron deficiency (class I, level of evidence [LoE] C), and intravenous iron supplementation with ferric carboxymaltose in symptomatic HF patients with iron deficiency to improve symptoms and QoL (class IIa, LoE A) and to reduce the risk of HF hospitalization (class IIa, LoE B).8 Unlike AFFIRM-AHF, which enrolled patients hospitalized due to acute HF,6 the IRONMAN trial mostly included outpatients with chronic HF and used a different iron formulation (i.e. ferric derisomaltose), which can be administered as a rapid, high-dose infusion.1 Patients enrolled in the IRONMAN trial were at relatively lower risk than those included in the AFFIRM-AHF,6 extending available data on the effects of intravenous iron supplementation to a broader range of patients with HF. Another strength is the longer follow-up compared to previous trials. The results of the trial showed, however, that ferric derisomaltose infusion is not convincingly superior to usual care among patients with HF and iron deficiency, despite a numerically lower incidence of the primary composite endpoint of HF hospitalizations and cardiovascular death in the experimental group.1 Of note, 17% of patients included in the usual care group received intravenous iron, which might have contributed to diluting the treatment effect. As in the AFFIRM-AHF,6 the results were influenced by the COVID-19 pandemic, which affected both enrolment and on-site follow-up rate, thus preventing systematic blood testing for detection of recurrent iron deficiency and redosing with iron. Interestingly, the pre-specified COVID-19 sensitivity analysis, censoring follow-up after 6 months from the pandemic start, showed a somewhat larger and marginally significant reduction in the incidence of the primary endpoint in patients treated with ferric derisomaltose, largely driven by a reduction in hospitalization for HF. However, no improvement in QoL measures or exercise capacity were observed on long-term follow-up. Importantly, no evident safety issues were noted in relation to ferric derisomaltose infusion, and no differences in the rates of deaths or hospitalization due to infection were detected at follow-up between the two groups.1 A major limitation is that the power calculation was revised during the course of the trial to account for a larger effect size suggested by the AFFIRM-AHF6 and a meta-analysis of published trials. Yet, the event rates and observed treatment effect were lower than expected. Another important drawback is that guideline-directed medical therapy was suboptimal in both groups, and the use of novel drugs such as sodium-glucose cotransporter-2 (SGLT2) inhibitors was quite limited (∼3%). Interestingly, recent studies suggest that SGLT2 inhibitors might dampen the state of inflammation-mediated functional iron deficiency observed in HF by inducing a reduction in circulating hepcidin and ferritin, and increasing the cytosolic pool of ferrous iron.9 Further evidence is needed to explore potential interactions between SGLT2 inhibitors and iron supplementation therapy. In conclusion, the IRONMAN trial integrates the body of evidence on intravenous iron supplementation in patients with HF and iron deficiency, by demonstrating the long-term safety of therapy with ferric derisomaltose infusion, and suggesting a potential reduction in the risk of recurrent hospital admissions, without apparent effects on cardiovascular mortality. While waiting for cost-effectiveness analyses and additional evidence from ongoing trials,10 individual-patient-data meta-analyses of all published and unpublished trials may help addressing the current uncertainties, and identifying subsets of patients with HF who may benefit most from intravenous iron supplementation. No new data were generated or analysed in support of this research. All authors declare no funding for this contribution.