Administration of ferric derisomaltose for iron deficiency and heart failure during hospital admission or at the clinic – insights from the IRONMAN trial

Large clinical trials of intravenous iron for patients with heart failure have studied hospitalized patients immediately prior to discharge (AFFIRM-HF) and outpatients (HEART-FID)1-3; efficacy might differ by enrolment setting. IRONMAN (NCT02642562) was a prospective, randomized, open-label, blinded-endpoint trial comparing intravenous ferric derisomaltose (FDI) with usual care in patients with left ventricular ejection fraction (LVEF) ≤45% and either a serum ferritin <100 μg/L or transferrin saturation (TSAT) <20%.4-6 Patients were grouped according to recruitment settings: (i) hospitalized; (ii) recently hospitalized (within 6 months); and (iii) outpatients without recent hospitalization with elevated plasma concentrations of natriuretic peptides. The primary outcome was heart failure hospitalization (HFH) (recurrent events) or cardiovascular (CV) death. Secondary outcomes included: (i) HFH (first event) or CV death; (ii) CV death; (iii) myocardial infarction, stroke, HFH (first event) or CV death; (iv) all-cause hospitalization; (v) CV hospitalization; (vi) all-cause death; (vii) unplanned hospitalization or all-cause death; and (viii) hospitalization for infection. In this pre-specified subgroup analysis, the effect of FDI on the primary and secondary endpoints compared to usual care was investigated according to enrolment setting. Of 1137 patients randomized, 164 were enrolled in hospital, 208 had been recently hospitalized, and 765 were more stable outpatients. The median follow-up duration was 2.7 years. Patients enrolled in hospital had lowest concentrations of haemoglobin compared to the other groups (median 11.5 vs. 12.0 and 12.3 g/dL), lowest TSAT (medians 10% vs. 14% and 16%), highest proportion with TSAT <20% (90% vs. 76% and 73%), highest ferritin (median 65 vs. 50 and 47 μg/L), lowest estimated glomerular filtration rate (eGFR) (median 45 vs. 48 and 53 mL/min/1.73 m2), lowest systolic blood pressure (median 113 vs. 117 and 121 mmHg), lowest LVEF (median 30% vs. 32% and 35%), were least likely to have ischaemic aetiology (41% vs. 51% and 62%), least likely to have prior acute coronary syndrome (37% vs. 42% and 56%), and had the worst (highest) Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores (physical score median 30 vs. 24 and 22). Other baseline characteristics, including age and sex were similar across groups. Patients enrolled in hospital were more likely on loop diuretics and less likely on renin–angiotensin system inhibitors (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, sacubitril/valsartan) at baseline. Similar proportions across groups were on beta-blockers, mineralocorticoid receptor antagonists, sodium–glucose cotransporter 2 (SGLT2) inhibitors, and digoxin. Investigators were encouraged to optimize treatment per international clinical practice guidelines at all visits7; therefore, heart failure treatments may have changed over follow-up. Patients enrolled in hospital in the usual care arm had double the rate of primary endpoints compared to outpatients (rate/100 patient-years of 44 in the hospitalized group vs. 22 in the outpatient group). The effect of FDI on the primary and secondary endpoints was similar, in terms of relative risk, irrespective of enrolment setting (Figure 1). The effect of FDI on the change in haemoglobin from baseline to month 4 was consistent across different enrolment settings (pinteraction = 0.16). Enrolment in the outpatient setting was associated with a greater effect of FDI compared to usual care on MLHFQ physical scores at 4 months (difference [95% confidence interval] −3 [−5, −1]) compared to hospitalized (−2 [−6, 2]) and recently hospitalized (2 [−2, 5]) patients (pinteraction = 0.043). IRONMAN is the first heart failure outcome trial to provide within-trial comparisons on the effect of intravenous iron by enrolment setting. As anticipated, patients enrolled in hospital had a higher risk profile compared to outpatients and generally demonstrated higher rates of primary and secondary endpoints. The consistent benefits, in relative terms, between FDI and usual care regardless of whether treatment was initiated in the inpatient or outpatient setting suggest that intravenous iron therapy may be beneficial for a broad range of patients with heart failure throughout their disease trajectory. Hospital admission provides an opportune window for optimizing medical therapy, including correction of iron deficiency. Indeed, if the relative benefits are the same regardless of risk profile, the absolute benefit will be greater amongst patients at higher risk. Compared to those enrolled in outpatient settings, hospitalized patients had features of more severe heart failure (including lower eGFR, systolic blood pressure, and LVEF) which itself may underpin the lower haemoglobin. Haemodilution may also contribute. Lower TSAT, indicating worse iron deficiency, may reflect heart failure severity including inflammation, potentially contributing to hospitalization and lower haemoglobin. Higher ferritin levels seen in hospitalized patients are consistent with greater inflammation due to various causes. In AFFIRM-AHF, intravenous iron was given immediately prior to discharge; in clinical practice it may be challenging to coordinate this. In contrast, in IRONMAN, patients could receive intravenous iron at any time during the inpatient stay, which allows resources to be used more flexibly, helping to mitigate 'therapeutic inertia' and potential delays in treatment initiation. Reassuringly, there was no suggestion of an increased rate of severe infection or an increase in other hazards in patients enrolled in hospital settings. In IRONMAN, there was no difference in the risk of hospitalization due to infection across the three enrolment settings (Figure 1). SGLT2 inhibitors are foundational therapy for heart failure, necessitating understanding their interactions with intravenous iron. In a post-hoc analysis of IRONMAN, there was a trend towards greater increase in haemoglobin with FDI in iron-deficient patients on SGLT2 inhibitors at baseline compared to those not on one.8 This analysis has several limitations that should be acknowledged. The trial was not powered to investigate the effects of treatment in subgroups. Patient characteristics differed in many ways according to recruitment context, which may account for any observed trends or lack thereof. Patients were enrolled solely in the UK, and most were White and men, therefore the results should be extrapolated to other populations with caution. In conclusion, hospitalized patients exhibited a higher rate of the primary outcome compared to outpatients, but the relative risk reduction of FDI was consistent regardless of whether patients were enrolled in hospital wards or outpatient clinics. These findings suggest that intravenous iron therapy may offer benefits across the breadth of clinical settings in the management of heart failure. We thank Public Health Scotland and NHS Digital for the provision of data linkage. We also thank all the participants, physicians, nurses, and other staff who contributed to the IRONMAN study. The study was funded by the British Heart Foundation (grant award CS/15/1/31175) and Pharmacosmos. Pharmacosmos provided supplies of ferric derisomaltose and supported the trial with an additional unrestricted grant. M.C.P. is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217). Conflict of interest: none declared.