Benefit of IV Iron Supplementation Varies in Patients with Heart Failure

Intravenous iron supplementation was safe but did not significantly lower the time to first heart failure (HF) hospitalization or cardiovascular death among patients with reduced ejection fraction (HFrEF) and iron deficiency in new data at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions.1

The FAIR-HF2 trial, enrolling 1105 patients with HFrEF at 70 centers in 6 countries, showed ferric carboxymaltose treatment led to an overall 21% lower risk of CV death or first HF hospitalization, consistent with previous clinical trials that did not reach statistical significance.

“It we take the totality of evidence from this new trial, which is in line with the previous studies, and take all of the data together in a meta-analysis, it confirms what we have in the current guidelines, namely, that intravenous iron for patients with HFrEF is useful,” said Stefan D. Anker, MD, a cardiologist at Charité–Universitätsmedizin Berlin.2 “It has a positive effect on symptoms and quality of life—you feel better, and you function better—and you also get an added bonus in terms of reducing cardiovascular events and heart failure hospitalizations, particularly in the first year after the start of treatment.”

A deficiency of iron in the blood is prevalent among nearly half of people with HF, and has been linked to worse outcomes and fatigue, weakness, and shortness of breath symptoms. The benefits of iron supplementation have not been confirmed for those with HF and iron deficiency. Results from trials, including AFFIRM-HF, IRONMAN, and HEART-FID, did not meet the primary endpoint of total HF hospitalizations and cardiovascular death among patients with worsening HF receiving ferric carboxymaltose.3,4,5

Iron deficiency was primarily defined by serum ferritin level (<100 ng/mL) in previous trials, but Anker and colleagues noted that transferrin saturation (TSAT) <20% has been identified as a more specific marker of iron deficiency. Across a median follow-up of 16.6 months, ferric carboxymaltose (n = 558) was initially given at an intravenous dose of 2000 mg followed by 500 mg every 4 months versus saline placebo (n = 547).1

Participants were 33% women with a mean age of 70 years—most were taking standard HF medications, with multiple cardiovascular risk factors, including high blood pressure, diabetes, or coronary artery disease.

Upon analysis, cardiovascular death or first heart failure hospitalization was identified in 141 of those treated with ferrix carboxymaltose versus 166 in the placebo group (hazard ratio [HR], 0.79 [95% CI, 0.63–0.99]; P =.04). A second primary outcome of total HF hospitalizations occurred 264 and 320 times, respectively (rate ratio [RR], 0.80 [95% CI, 0.60–1.06]; P =.12). A final primary outcome of cardiovascular death or first heart failure hospitalization in pateints with TSAT <20% occured in 103 and 128 patients, respectively (HR, 0.79 [95% CI, 0.61–1.02]; P =.07).

As initial iron supplementation doses were higher than the subsequent doses, average totals of iron received were 2040 mg in the first year, 925 mg in the second year, and 750 mg in the third year. Anker and colleagues suggested the variation in total iron may have impacted the primary endpoints, with a larger between-group difference reported at one year, compared with the two and three-year timepoints.

In a meta-analysis of more than 7000 patients with HFrEF across multiple clinical trials, including the current study, results revealed a significant benefit of intravenous iron supplementation in the first year of therapy, suggesting further research on the optimal strategy beyond the first year.2

“Intravenous iron was particularly useful in the first year, when the highest dose of iron was given. This suggests that there is a meaningful association between the amount of iron given and the benefit,” Anker said.2 “Based on the totality of evidence that is now available, we can with certainty say that intravenous iron therapy at the doses given in FAIR-HF2 and other recent trials is safe.”

References

1. Anker SD, Friede T, Butler J, et al. Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency: The FAIR-HF2 DZHK05 Randomized Clinical Trial. JAMA. Published online March 30, 2025. doi:10.1001/jama.2025.3833
2. Intravenous iron offers some benefits for some patients with heart failure. American College of Cardiology. March 30, 2025. Accessed March 30, 2025. https://www.acc.org/About-ACC/Press-Releases/2025/03/30/12/35/Intravenous-Iron-Offers-Some-Benefits-for-Some-Patients-with-Heart-Failure.
3. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial [published correction appears in Lancet. 2021 Nov 27;398(10315):1964. doi: 10.1016/S0140-6736(21)02492-2.]. Lancet. 2020;396(10266):1895-1904. doi:10.1016/S0140-6736(20)32339-4
4. Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022;400(10369):2199-2209. doi:10.1016/S0140-6736(22)02083-9
5. Mentz RJ, Garg J, Rockhold FW, et al. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. N Engl J Med. 2023;389(11):975-986. doi:10.1056/NEJMoa2304968