A “Negative” Trial of Intravenous Iron Replacement in Heart Failure with Reduced Ejection Fraction

Previous trials of intravenous iron for the treatment of iron deficiency among individuals with heart failure and reduced ejection fraction (HFrEF) have culminated in a level IIa recommendation in the ACC/AHA practice guideline to improve functional status and quality of life (NEJM JW Cardiol May 12 2023 and Lancet 2022; 400:2199; Circulation 2023;147:1640). However, whether this therapy affects a broad range of clinical outcomes remains unclear.

The manufacturer-sponsored HEART-FID trial (NCT03037931) randomized 3065 ambulatory individuals (mean age, 69 years; 34% women; 11% Black; mean left ventricular ejection fraction, 31%) with HFrEF and documented iron deficiency to receive two doses of intravenous ferric carboxymaltose within a week, followed by readministration every 6 months if iron deficiency persisted, or placebo. The primary endpoint was a “win ratio” based upon a hierarchical composite of death and heart failure hospitalizations at 12 months and change in 6-minute walk distance between baseline and 6 months.

Among those treated with iron replacement, there was a nominally lower risk of death at 1 year (8.6% vs. 10.3%), fewer total hospitalizations (297 vs. 332), and a greater improvement in 6-minute walk distance at 6 months (8 meters vs. 4 meters). However, the difference in the win ratio was not statistically significant. Notably, the proportions of patients hospitalized for HF were nearly identical between the two groups (22.9% vs. 23.0%). There was no difference in the rates of treatment-emergent serious adverse events.