PREFER-HF: Is iron therapy helpful in HFpEF with iron deficiency?

Iron therapy was not associated with functional or quality-of-life improvements in patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency. However, there was a signal suggesting that iron could reduce hospitalisations, with oral and intravenous iron therapy displaying similar results.

The phase 3 PREFER-HF trial (NCT03833336) randomised 72 participants with HF and a left ventricular ejection fraction >45% 1:1:1:1 to intravenous iron therapy, oral ferroglycine sulfate, oral sucrosomial iron, or a placebo [1]. The primary endpoint was improvement in the 6-minute walk test (6MWT) at 24 weeks.

Iron therapy did not improve the distance achieved in the 6MWT compared with placebo in this population (change from baseline -1.51 m vs +5.97 m; P=0.80). Iron therapy also did not improve quality-of-life in these participants. Although the primary endpoint was not met, Dr José Morales-Rull (University Hospital Arnau de Vilanova, Spain) discussed the findings of secondary endpoints and noted that there appeared to be an improvement in transferrin saturation index with iron therapy (Δ6.51; 95% CI 1.86–11.16). Furthermore, time to first hospitalisation or death appeared to be shorter in participants treated with iron (HR 0.46; 95% CI 0.23–0.94). “Oral iron did not seem to perform worse than intravenous iron for these endpoints,” added Dr Morales-Rull. “Sucrosomial iron was somewhat better tolerated than ferroglycine sulfate, with fewer cases of abdominal pain [22.2% vs 38.9%] or constipation [5.5% vs 27.8%].”

The PREFER-HF trial did not meet its primary endpoint. Exploring the other outcomes of the study, it was observed that treating iron deficiency in the HFpEF population may reduce the risk for hospitalisation and that oral iron therapy was not associated with worse outcomes than intravenous iron therapy. However, these findings need to be tested in adequately powered studies.

1. Morales-Rull JL, et al. PREFER-HF: effects of iron therapy in heart failure with preserved ejection fraction and iron deficiency. Hottest trials and trial updates (2), Heart Failure 2025, 17–20 May, Belgrade, Serbia.

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Posted on 17 July 202521 July 2025