IRONMAN: Which marker of iron deficiency best predicts response to intravenous iron in patients with heart failure?

Presented at the ESC Heart Failure 2023 by: John Cleland, MD, PhD - Glasgow, UK

Introduction and methods

At the moment there are variations in the definition of iron deficiency (ID) according to different clinical organizations. The WHO defines ID as serum ferritin<15 µg/L, whereas many clinical laboratories use a cut-off of <30 µg/L. The ESC guidelines, however, define ID as serum ferritin <100 µg/L or between 100-299 µg/L and a TSAT <20%.

There are paradoxical data with regard to the clinical prognosis and ID in patients with HFrEF. Data suggest that in patients with HFrEF serum ferritin<100 µg/L is associated with better prognosis, whereas a TSAT <20% is associated with a worse prognosis. In this analysis of IRONMAN, it was determined which marker of ID (TSAT, ferritin or anemia) best predicts clinical prognosis and response to intravenous iron in patients with HFrEF.

IRONMAN was a prospective, randomized, open-label trial with 1137 patients with HFrEF. Patients were randomized to ferric derisomaltose (FDI) or usual care. Eligible patients had ferritin<100 µg/L or TSAT <20%. Exclusion criteria were: ferritin >400 µg/L; Hb <9.0 g/dL or >13 g/dL in women or >14 g/dL in men; and eGFR <15 ml/min/1.73m². The primary endpoint was a composite of recurrent HF hospitalizations or CV death.

Main results

• When comparing baseline characteristics of patients stratified by anemia, patients with moderate anemia (n=423) had the worst prognosis compared to mild anemia (n=348) or no anemia (n=366).
• When comparing baseline characteristics of patients stratified by serum ferritin, patients with serum ferritin ≥100 µg/L with TSAT<20% (n=210) had a worse prognosis than patients with serum ferritin ≤30 µg/dL (n=297) or >30 to <100 µg/dL (n=627).
• When stratification was done by TSAT at baseline, patients with TSAT ≤10% (n=272) had a worse prognosis than patients with TSAT >10-15% (n=298), >15-<20% (n=271) or ≥20% and serum ferritin <100 µg/dL (n=269). Patients with a TSAT of ≤10% more often had anemia.
• Response to FDI at month 4 as determined by change in Hb was best predicted by TSAT values compared to serum ferritin or anemia (P for interaction<0.001; P for interaction=0.028; P for interaction=0.014, respectively). The largest change in Hb values after FDI was observed in patients with TSAT <10%.
• The incidence rate of the primary endpoint was lower in the FDI group compared to control group in patients with serum ferritin between 100-400 µg/dL and TSAT <20% (HR: 0.66; 95%CI: 0.41-1.06) and in patients with TSAT 15-20% (HR: 0.65; 95%CI: 0.42-1.01). The other markers (anemia status and other values for serum ferritin and TSAT) did not predict response to FDI.
• The risk of CV events in the study cohort was lowest in patients with low serum ferritin (<30 µg/L).

Conclusion

Using data from IRONMAN, it was shown that the risk of events is higher in patients with anemia or TSAT<20%, but lower in patients with serum ferritin <100 µg/L. The effect of FDI on CV events was best predicted by TSAT <20%, especially in patients with serum ferritin of 100-400 µg/dL.

John Cleland concludes his presentation by saying that ‘TSAT could certainly simplify the inclusion criteria and stop confusion if we moved to a new definition [of ID]’.

-Our reporting is based on the information provided at ESC Heart Failure 2023 –