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. 2025 Jul 31.
doi: 10.1002/ejhf.3742. Online ahead of print.

Intravenous ferric carboxymaltose in heart failure with iron deficiency (FAIR-HF2 DZHK05 trial): Sex-specific outcomes

Mahir Karakas  1   2 , Tim Friede  3   4 , Javed Butler  5   6 , Khawaja M Talha  7 , Marius Placzek  3   4 , Thomas Asendorf  3   4 , Monika Diek  8 , Anna Nosko  1 , Adriane Stas  4   9 , Stefan Kluge  1 , Dominik Jarczak  1 , Geraldine DeHeer  1 , Meike Rybczynski  10   2 , Antoni Bayes-Genis  11 , Michael Böhm  12 , Andrew J S Coats  13 , Frank Edelmann  14   15 , Gerasimos Filippatos  16 , Gerd Hasenfuß  4   17 , Wilhelm Haverkamp  8 , Mitja Lainscak  18   19 , Ulf Landmesser  20   21   22 , Iain C Macdougall  23 , Bela Merkely  24 , Burkert M Pieske  25 , Fausto J Pinto  26 , Tienush Rassaf  27 , Jennifer K Visser-Rogers  28 , Giuseppe Rosano  29   30   31   32 , Maurizio Volterrani  33   34 , Stephan von Haehling  4   17 , Markus S Anker  20   21   22 , Wolfram Doehner  35 , Hüseyin Ince  25 , Friedrich Koehler  36   37   38 , Gianluigi Savarese  39 , Muhammad Shahzeb Khan  6   40 , Ursula Rauch Kröhnert  20   21   22 , Tommaso Gori  41   42 , Teresa Trenkwalder  43   44 , Ibrahim Akin  45   46 , Christina Paitazoglou  47 , Iwona Kobielusz-Gembala  48 , Luca Kuthi  24 , Norbert Frey  49 , Manuela Licka  49 , Stefan Kääb  50 , Karl-Ludwig Laugwitz  51   52 , Piotr Ponikowski  53 , Stefan D Anker  8
Affiliations

Intravenous ferric carboxymaltose in heart failure with iron deficiency (FAIR-HF2 DZHK05 trial): Sex-specific outcomes

Mahir Karakas et al. Eur J Heart Fail. .

Abstract

Aims: Intravenous iron has emerged as a guideline-recommended therapy in patients with heart failure and iron deficiency, but the potential sex-related differences in efficacy are unknown. We aimed to assess sex-specific outcomes in the Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality (FAIR-HF2-DZHK05) trial.

Methods and results: FAIR-HF2 included 1105 heart failure patients with a left ventricular ejection fraction ≤45% and iron deficiency. A total of 368 women (mean age 68.7 ± 13.0 years) and 737 men (mean age 70.5 ± 11.0 years) were randomized to intravenous ferric carboxymaltose or placebo. The three primary endpoints were (i) time to cardiovascular death or first heart failure hospitalization, (ii) total heart failure hospitalizations, and (iii) time-to-first event of cardiovascular death or heart failure hospitalization only in patients with transferrin saturation <20% at baseline. The hazard ratio (HR) for the first primary outcome was 1.07 (95% confidence interval [CI] 0.63-1.82, p = 0.80) in women and 0.74 (95% CI 0.57-0.95, p = 0.016) in men, while the rate ratios (RRs) for the second primary outcome were 1.06 (95% CI 0.55-2.05, p = 0.86) and 0.79 (95% CI 0.58-1.08, p = 0.136), respectively, and the HRs for the third primary outcome event were 1.21 (95% CI 0.62-2.36, p = 0.58) and 0.73 (95% CI 0.55-0.97, p = 0.028), respectively. Regarding safety outcomes, the HR for all-cause mortality was 1.46 (95% CI 0.78-2.76, p = 0.24) in women, suggesting increased mortality risk under iron supplementation, in contrast to 0.86 (95% CI 0.64-1.16, p = 0.33) in men (p for interaction = 0.13).

Conclusions: This analysis indicates relevant differential efficacy of intravenous iron in heart failure across both sexes. While men receiving ferric carboxymaltose experienced a clinically relevant reduction in cardiovascular death and heart failure hospitalizations, women did not derive similar benefits. The results are clinically relevant and prompt validation in other large outcome trials of intravenous iron supplementation in heart failure.

Clinical trial registration: ClinicalTrials.gov NCT03036462.

Keywords: Ferric carboxymaltose; Heart failure; Iron deficiency; Randomized controlled clinical trials; Sex‐specific outcomes.

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