Clinical question: Does IV ferric carboxymaltose improve clinical outcomes in patients with heart failure (HF) and iron deficiency?
Background: Iron deficiency affects up to half of patients with HF and is associated with worse symptoms, reduced exercise capacity, and increased mortality compared with those without iron deficiency. Although intravenous iron supplementation has been investigated as a therapeutic strategy, its clinical benefit remains uncertain due to mixed results from prior trials. Transferrin saturation below 20% has emerged as a potentially more specific marker of iron deficiency than serum ferritin alone. The FAIR-HF2 trial was conducted to evaluate the effects of intensive and consistent intravenous iron supplementation in this population.
Study design: Randomized, double-blinded, placebo-controlled, clinical trial in 70 clinic sites across six European countries
Synopsis: This trial enrolled 1,105 patients with HF with reduced ejection fraction (left ventricular ejection fraction 45% or less) and iron deficiency (serum ferritin level under 100 ng/mL; or if transferrin saturation was under 20%, a serum ferritin level between 100 and 299 ng/mL) between 2017 and 2023. Participants were randomized to receive either IV ferric carboxymaltose (n=558), with an initial dose of up to 2,000 mg followed by 500 mg every four months, or placebo (n=547). The primary outcomes were: time to cardiovascular death or first HF hospitalization; total HF hospitalizations; and time to cardiovascular death or first HF hospitalization in patients with transferrin saturation under 20%. At a median follow-up of 16.6 months, the first outcome occurred in 141 patients in the treatment group versus 166 in the placebo group (HR, 0.79; 95% CI, 0.63–0.99; P=.04). Total heart failure hospitalizations were 264 versus 320 (rate ratio, 0.80; 95% CI, 0.60–1.06; P=.12), and in the transferrin saturation under 20% subgroup, 103 versus 128 events occurred (HR, 0.79; 95% CI, 0.61–1.02; P=.07). Ferric carboxymaltose was well tolerated, with similar rates of adverse events in both groups.
Bottom line: In patients with HF and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20% or reduce the total number of heart failure hospitalizations versus placebo. Despite the P value of 0.04 for time to cardiovascular death or first heart failure exacerbation, the authors did not consider this statistically significant, given that they used more stringent criteria to control for multiple primary outcomes (Hochberg procedure).
Citation: Anker SD, et al. Intravenous ferric carboxymaltose in heart failure with iron deficiency: the FAIR-HF2 DZHK05 randomized clinical trial. JAMA. 2025;333(22):1965-1976. doi:10.1001/jama.2025.3833.
Dr. Abraham is an academic hospitalist at UT Health San Antonio and an assistant clinical professor in the division of internal medicine at the Joe R. & Teresa Long School of Medicine in San Antonio.