Iron deficiency definitions and their clinical and prognostic associations across the spectrum of left ventricular ejection fraction in heart failure

AIMS: Iron deficiency (ID) is prevalent in heart failure (HF). While the impact of ID is well-documented in those with left ventricular ejection fraction (LVEF) < 50 (HFrEF and HFmrEF), its role in those with LVEF ≥50 (HFpEF) is uncertain. We aimed to elucidate and compare the clinical relevance of ID across the LVEF spectrum using multiple definitions. METHODS: Patients with known LVEF and iron parameters from the index and validation cohort of The BIOSTAT-CHF study were pooled (n = 3642). Iron deficiency was defined using three criteria: (i) IDTSAT: transferrin saturation (TSAT) < 20%, (ii) IDSI: serum iron ≤13 μmol/l, and (iii) IDESC: the ESC guideline definition (ferritin <100 µg/l or 100-299 µg/l with TSAT <20%). RESULTS: The prevalence of ID ranged from 57% to 75% depending on definition and LVEF, with the highest rates in HFpEF and in very low LVEF. More than half of patients met all three definitions, but nearly one-third were classified discordantly. Iron deficiency was consistently associated with lower quality of life and greater physical limitations (both P < .01) across all definitions and LVEF categories. Independent associates of ID included female sex, higher heart rate, proton pump inhibitor use, anaemia, hypoalbuminemia, worse renal function, and fluid retention. Iron deficiency was associated with increased CV and non-CV death, all-cause mortality, HF hospitalizations, and their composite in patients with LVEF <50% across all definitions (P < .05). In HFpEF, no definition showed consistent prognostic significance, though interactions with LVEF group were observed for IDTSAT and IDESC (P_interaction <.05). CONCLUSION: Iron deficiency is common and clinically relevant across the HF spectrum, irrespective of definition, and is associated with impaired quality of life and adverse outcomes in patients with LVEF <50%. In HFpEF, however, the prognostic impact of ID appears less pronounced and may depend on the definition applied, highlighting the need for refined diagnostic criteria in this group.