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Intravenous Iron for Heart Failure, Iron Deficiency Definitions, and Clinical Response
TAKE-HOME MESSAGE
- In this secondary analysis of the IRONMAN trial, severe anemia or a transferrin saturation <20% (especially with serum ferritin levels ≥100 μg/L) among individuals with heart failure and an LVEF ≤45% were associated with a potentially greater benefit from intravenous ferric derisomaltose.
- These findings provide further insight into the patient-level factors most predictive of response to intravenous ferric derisomaltose. Prospective efforts are needed to ascertain whether this phenotyping strategy could guide patient selection for intravenous iron.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND 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.
Additional Info
Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial
Eur Heart J 2024 Mar 06;[EPub Ahead of Print], JGF Cleland, PA Kalra, P Pellicori, FJ Graham, PWX Foley, IB Squire, PJ Cowburn, A Seed, AL Clark, B Szwejkowski, P Banerjee, J Cooke, M Francis, P Clifford, A Wong, C Petrie, JJV McMurray, EA Thomson, K Wetherall, M Robertson, I Ford, PR KalraFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Most patients with heart failure and anemia are thought to have iron deficiency, and many even in the absence of anemia.1 For randomized trials of heart failure, iron deficiency was defined as having a serum ferritin level <100 µg/L or, provided that ferritin level was <300 µg/L, a transferrin saturation (TSAT) <20%, which was not based on scientific evidence but borrowed from guidelines encouraging intravenous (IV) iron for patients on hemodialysis.2-4 Trials will underestimate the therapeutic potential of iron if the definition of iron deficiency is wrong. Iron deficiency might be best defined by favorable responses to iron supplements, including increased hemoglobin, improved symptoms and exercise capacity, reduced hospitalization rates, and lower mortality risks.5
The IRONMAN randomized trial6 showed that, overall, for patients with heart failure who fulfilled the above definition of iron deficiency, IV iron increased hemoglobin levels, improved quality of life, and reduced the rates of hospitalization for heart failure but did not improve walking distance or reduce mortality. Anemia was strongly associated with low TSAT and poor prognosis.5,7 Administering IV iron to patients with anemia, increased hemoglobin level and improved quality of life, with strong trends to greater reductions in hospitalizations for heart failure and mortality, with little evidence of benefit in the absence of anemia. A TSAT <20% was associated with poor prognosis but greater benefit from IV iron.5 A TSAT ≥20% was associated with better prognosis but no benefit, and possible harm, from IV iron.5,8,9 A serum ferritin level ≤30 µg/L was associated with lower risk and did not predict greater benefit with IV iron.5 If the serum ferritin level was 100 to 299 µg/L and the TSAT <20% (’functional’ iron deficiency), prognosis was poor and the benefits of IV iron were large.5 In summary, the presence of either anemia or a TSAT <20% (or both) may best guide the therapeutic benefits of IV iron for heart failure. Measuring serum ferritin might cause more confusion than clarity.
References