Oral iron in HFrEF with iron deficiency: an overlooked treatment strategy?

Abstract Background Iron deficiency (ID) is associated with poor outcomes in heart failure with reduced ejection fraction (HFrEF). Intravenous iron improves functional capacity and cardiovascular outcomes in HFrEF. Oral iron treatment has been scarcely studied and is not recommended by international guidelines. IRONOUT-HF was a clinical trial including 225 patients with HFrEF and ID, who received oral iron polysaccharide 150mg twice daily or placebo for 16 weeks. Purpose Using IRONOUT-HF data, we sought to assess iron status throughout follow-up and whether ID improvement associated with receiving oral iron and better clinical outcomes. Methods Patient level data from IRONOUT.HF was obtained from the BioLINCC repository of the National Heart, Lung and Blood Institute. Patients were divided according to transferrin saturation (TSat) change between baseline and week 16 as follows: TSat increase="responders"; TSat reduction/neutral="non-responders". We then characterized patients according to TSat change and assessed if receiving oral iron was associated with TSat change and the impact of TSat change on clinical outcomes. Results A total of 186 patients had iron biomarkers available at baseline and end of follow-up. One hundred (53.8%) were TSat responders and 86 (46.2%) TSat non-responders. Compared to non-responders, responders had similar age (61 vs 62 years), sex (61 vs 66 % men), but significantly lower baseline levels of ferritin (75.8 vs 92.0ng/mL, p=0.01), TSat (18.0 vs 24.7%, p0.01) and hepcidin (7.1 vs 10.2ng/mL, p0.01). Receiving oral iron doubled the odds of experiencing TSat response (OR=2.00, 95%CI=1.11-3.59, p0.01) and improved TSat on average by +3.15% (95%CI=0.78-5.52). TSat change from baseline associated with a peak VO2 increase (β=0.64 ml/kg/min; 95%CI=0.05-1.22), but not with improvements in quality of life assessed by KCCQ-CSS (mean absolute difference MAD 2.5, 95% CI -1.3 to 6.3), 6-minute walk distance (MAD 1.8 m, 95% CI of -18.2 to 21.8) and log NT-proBNP (MAD -0.14 log units, 95% CI -0.32 to 0.03). Conclusions Oral iron increased TSat which was associated with peak VO2 improvement. These findings suggest that oral iron may improve iron status in HFrEF with low baseline TSat. Larger trials using different oral iron formulations and doses, focused on patients with decreased baseline TSat should be conducted.