Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial

Abstract

Background and aims: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?

Methods: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death.

Results: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant.

Conclusions: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Keywords: Anaemia; Ferric derisomaltose; Ferritin; Heart failure; Iron deficiency; Morbidity; Mortality; Quality of life; Randomized clinical trial; Transferrin saturation.

Structured Graphical Abstract

The IRONMAN trial main inclusion criteria, design, and blood markers of iron deficiency, including haemoglobin, transferrin saturation (TSAT), and serum ferritin, used to predict response to intravenous ferric derisomaltose (FDI). Markers of response including increase in haemoglobin, symptoms (Minnesota Living with Heart Failure questionnaire) and 6-minute walk test distance at 4 months and incidence of clinical events, including heart failure hospitalization (HFH) and cardiovascular (CV) death, for the duration of the trial with or without COVID-sensitivity analyses. CI, confidence interval; LVEF, left ventricular ejection fraction; RR, rate ratio. #Serum ferritin < 30 µg/L predicted a marked increase in haemoglobin only when associated with a TSAT < 20%. *Patients with a TSAT < 20% but serum ferritin ≥ 100 µg/L obtained the greatest benefit in terms of improvement in the primary endpoint. ^The benefit of FDI was similar in relative terms for patients with and without anaemia but because those with anaemia were at greater risk, they obtained greater absolute benefit.

Figure 1

Change in haemoglobin (ΔHb) for patients randomized to usual care (control) or ferric derisomaltose (FDI) according to anaemia status, serum ferritin, and transferrin saturation (TSAT). Mean changes are shown. See Tables 2, 3, 5, and 6 for standard deviations of change and mean differences with 95% confidence intervals

Figure 2

Differences in Minnesota Living with Heart Failure questionnaire score (lower is better) at 4 months for patients randomized to usual care (control) or ferric derisomaltose (FDI) according to anaemia status, serum, ferritin and transferrin saturation (TSAT). Mean values are shown. See Tables 2, 3, 5, and 6 for standard deviations of change and mean differences with 95% confidence intervals

Figure 3

Primary endpoint (recurrent events) according to anaemia classification (none, mild, or moderate). No statistically significant interaction was observed between anaemia severity and treatment effect (P_interaction = .95). FDI, ferric derisomaltose; RR, rate ratio. See Table 1 for definition of anaemia classes and Table 2 for event rates

Figure 4

Primary endpoint (recurrent events) according to serum ferritin < 100 or ≥100 µg/L (with TSAT < 20%). No statistically significant interaction was observed between serum ferritin classification and treatment effect. FDI, ferric derisomaltose; RR, rate ratio. See Table 3 for event rates

Figure 5

Primary endpoint (recurrent events) according to transferrin saturation (TSAT) < 20% or ≥20% (with serum ferritin < 100 µg/L). No statistically significant interaction was observed between TSAT classification and treatment effect. FDI, ferric derisomaltose; RR, rate ratio. See Table 5 for event rates