Background: Managing comorbidities alongside guideline-directed medical therapy is essential in heart failure (HF) treatment. Intravenous (IV) iron therapy is recommended
for HF patients with left ventricular ejection fraction (LVEF) <50% to correct iron deficiency. Traditional markers such as ferritin and transferrin saturation (TSAT) are affected by inflammation and have delayed responses, limiting their clinical utility. This study aimed to evaluate early response to IV iron therapy by monitoring reticulocyte counts, a parameter unaffected by inflammation.

Methods: Hospitalized HF patients with LVEF <50% meeting CONFIRM-HF criteria for IV iron therapy were included. Reticulocyte counts were measured at admission and 72-120 hours post treatment. Associations with hemoglobin (Hb) increase at 1 month, hospital stay duration, emergency department (ED) readmissions, and mortality were assessed.

Results: Patients with ≥1 g/dL Hb increase at 1 month had higher reticulocyte levels at admission (2.0% vs. 1.5%, P = .04) and 72-120 hours post treatment (2.2% vs. 1.3%, P = .004). A ≥9% reticulocyte increase at 72-120 hours predicted Hb rise ≥1 g/dL with 90% specificity (area under the curve: 0.79, P = .002). Those with higher reticulocyte increases had shorter hospital stays (7 vs. 10 days, P = .023) and fewer ED readmissions (24% vs. 66%, P = .004). Higher reticulocyte and Hb levels correlated with reduced mortality over 2 years.

Conclusion: Reticulocyte increase within 72-120 hours after IV iron therapy offers an early, inflammation-independent marker of treatment response in HF patients, outperforming ferritin and TSAT. Elevated baseline reticulocytes may indicate active bone marrow and predict therapeutic benefit.