FAIR-HF2: The value of intravenous iron in patients with HF and iron deficiency

Intravenous iron with ferric carboxymaltose was well-tolerated and improved quality-of-life in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency, but did not reduce HF hospitalisation, compared with placebo. However, a meta-analysis performed by the research group did demonstrate a clinical benefit of this therapy.

Prof. Stefan Anker (Charité University, Germany) presented the primary results of the investigator-initiated, phase 4 FAIR-HF2 study (NCT03036462) [1]. The study enrolled 1,105 participants with symptomatic chronic HF and iron deficiency from 70 clinics in 6 countries and randomised them 1:1 to intravenous iron or a placebo. The 3 primary endpoints were time to cardiovascular death or hospitalisation for HF; composite rate of first and recurring hospitalisation for HF; and time to cardiovascular death or hospitalisation for HF in the subgroup of participants with a transferrin saturation (TSAT) of <20%. Based on multiple comparisons, an alpha of 0.02 was the threshold for statistical significance.

At 3 years of follow-up, the trial did not meet its primary endpoints and was neutral. Specifically, cardiovascular death or hospitalisation for HF was numerically more common in the placebo arm than in the intravenous iron arm (HR 0.79; 95% CI 0.63–0.99; P=0.04). “After 12 months, we did see a significant benefit of intravenous iron on this endpoint,” said Dr Anker (HR 0.71; 95% CI 0.53–0.94; P=0.015). “After the first year, we reduced the dose, which tells me that we may need to increase the dose after the first year to gain the optimal treatment outcome.”

Next, hospitalisation for HF was numerically more common in the intravenous iron arm than in the placebo arm (RR 0.80; 95% CI 0.60–1.06; P=0.12). The results in the subgroup of participants with TSAT <20 were similar to those of the general study population, illustrating that TSAT is a useful biomarker for iron deficiency but not necessarily better than the standard.

“The findings of the FAIR-HF2 trial are highly consistent with those of AFFIRM-AHF and IRONMAN with respect to morbidity and mortality outcomes, but did not reach statistical significance within the trial,” Prof. Anker summarised.

Following these results, the investigators performed a Bayesian meta-analysis including 7,175 participants from FAIR-HF, CONFIRM-HF, AFFIRM-AHF, IRONMAN, HEART-FID, and FAIR-HF2, to assess the effect of intravenous iron on the primary outcome of hospitalisation for HF or cardiovascular death at 1 year of follow-up. This analysis showed that administering intravenous iron to patients with HF and iron deficiency was associated with a lower rate of the primary endpoint events by 19% (see Figure).

Figure: Recurrent events of HF hospitalisations or cardiovascular death by Bayesian random effects meta-analysis [1]



CI, confidence interval; RR, rate ratio.

1. Anker SD, et al. Intravenous iron in patients with systolic heart failure and iron deficiency to improve morbidity and mortality. Late-breaking Clinical Trials IV, ACC 2025 Scientific Session, 29–31 March, Chicago, USA.

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Posted on 22 May 202522 May 2025