Intravenous iron therapy outcomes according to deficiency type in heart failure (IRON-HEART)
E Kaya, E B Erkip, B Kucuk, F Dogru, U Guven, O Furtuna, D A Barlas, F Kahraman, M Demir, G Sonmez, H I Durmus, M A Astarcioglu, T SenAbstract
Background
Intravenous iron is recommended for iron-deficient heart failure (HF), yet clinical benefit varies across patients. Current definitions rely largely on ferritin and do not account for biological heterogeneity or treatment response. Whether mechanistic iron-deficiency phenotypes and functional iron repletion identify differential outcomes remains uncertain.
Purpose
We sought to evaluate whether mechanistic iron-deficiency phenotypes and treatment-induced changes in transferrin saturation identify differential clinical benefit from intravenous iron therapy in heart failure.
Methods
We analyzed a guideline-treated HF cohort (n=146). Patients were classified into mechanistic iron-deficiency phenotypes (Type 1–3). Functional response was quantified as the change in transferrin saturation (ΔTSAT). Multivariable logistic models adjusted for age, sex, left ventricular ejection fraction, NYHA class, and anemia evaluated associations with a composite clinical outcome. Phenotype×ΔTSAT interaction, ferritin-stratified analyses, and decision-analytic metrics (ROC, NRI/IDI, decision curve analysis) assessed heterogeneity, incremental prognostic value, and clinical utility.
Results
Phenotypes were not clinically equivalent. Type 1 (β=1.87, p=0.00041) and Type 3 (β=1.46, p=0.012) were independently associated with the composite outcome, whereas Type 2 was not (p=0.14). Functional response was prognostic: higher ΔTSAT was associated with lower risk (β=−0.0255, p=0.0427). The effect of ΔTSAT differed by phenotype, indicating biology-dependent benefit. In ferritin-based subgroups, ΔTSAT effects were inconsistent (all p>0.12), whereas TSAT dynamics retained directional prognostic value. Adding ΔTSAT improved risk classification (positive NRI/IDI) and yielded higher net benefit across clinically relevant thresholds on decision-curve analysis.
Conclusions
Among HF patients treated according to guidelines, clinical benefit from intravenous iron is biologically heterogeneous. Mechanistic phenotype and functional iron response jointly determine outcomes. This is the first clinical study to validate mechanistic iron-deficiency phenotypes and to demonstrate that treatment-induced TSAT response, rather than ferritin status, determines phenotype-specific clinical benefit from intravenous iron in heart failure. These findings support moving from ferritin-centered eligibility toward a phenotype- and response-guided strategy for selecting and monitoring intravenous iron therapy.Response-Guided Clinical Benefit