Iron deficiency and anaemia are common phenomena in patients with heart failure. Various studies, including FAIR-HF2, coordinated in Hamburg (Prof. Karakas) and Berlin (Prof. Dr. Stefan D. Anker, Charité – Universitätsmedizin Berlin), have shown that people with left ventricular heart failure and a reduced systolic ejection fraction (45 per cent or lower) benefit from treating their iron deficiency with intravenous (i.v.) iron administration. Both their quality of life and their prognosis improve.
However, there are gender-specific differences, as Prof. Karakas and his co-authors have now been able to show in a pre-specified, i.e. pre-planned, separate analysis of the data from men and women in the study: Of the 1,105 participants (737 men and 368 women) who had been randomly assigned to receive either intravenous iron carboxymaltose or placebo, only the men benefited prognostically. In these men, the combined primary endpoint of the study, consisting of cardiovascular death and hospitalisation for heart failure, was significantly reduced by 26 per cent. In contrast, among women who received iron supplementation, this primary endpoint was actually slightly more frequent (non-significantly by 7 per cent) and there were also indications of an increased risk of mortality with iron supplementation (non-significantly by 46 per cent). This was despite the fact that the women reported symptomatic and functional improvements.
Clear prognostic advantages for men only
‘Iron therapy has many advantages in heart failure, but these results suggest that the prognostic effectiveness of intravenous iron supplementation in heart failure depends significantly on gender,’ says award winner and senior physician at the UKE, Prof. Karakas, assessing the results. ‘While men achieve clear prognostic advantages, women do not benefit in this regard. Our work thus provides new, clinically highly relevant evidence for personalised treatment of heart failure and iron deficiency and underlines the need to systematically include gender-specific aspects in future studies and guidelines.’
Cardiologist Prof. Dr. Thomas Voigtländer, Chairman of the German Heart Foundation, praises the results: "This pre-specified analysis of FAIR-HF2 is the most comprehensive to date on the gender-specific effects of intravenous iron in heart failure. This is a surprising result given that gender-based analyses in most large heart failure studies have shown similar efficacy of modern therapies in men and women." According to the cardiologist, this applies, for example, to the SGLT2 inhibitors dapagliflozin and empagliflozin, to vericiguat and to the so-called “ARNI” sacubitril/valsartan. ‘The fact that this does not appear to apply to intravenous iron administration highlights the importance of further follow-up studies to examine these gender-specific data in more detail. Gender-specific therapy is the most obvious form of personalised medicine,’ said the chairman of the Heart Foundation and medical director of the Diakonie Clinics in Frankfurt.
Preclinical data suggested gender differences
Prof. Karakas and his team at the UKE do not yet have an explanation for the gender-specific effectiveness of iron. The men and women in the FAIR-HF2 study were of similar age, averaging 70 and 69 years old, respectively, with most of the women being postmenopausal. On average, they were ‘healthier’ and had fewer comorbidities than the men, so even more beneficial results than for the male participants had been expected for them. ‘However,’ Prof. Karakas emphasises, ‘there is already preclinical data that points to gender-specific differences in iron homeostasis, i.e. the balance of iron levels, hormone regulation and inflammatory processes.’
For Martina Grote, founder and namesake of the science award, the results once again make it clear: ‘There are obviously significant differences between male and female hearts that are relevant for treatment. This shows how important research in this area is in order to achieve optimal treatment outcomes for men and women in the long term through personalised, gender-specific therapies.’
Women-specific heart problems and treatments are becoming more widely recognised
The Martina Grote Science Award ‘Frauenherzen’ (Women's Hearts) from the German Heart Foundation was announced for the first time in 2023 in collaboration with the project group ‘Women and Family in Cardiology’ and the ‘Working Group on Gender Medicine in Cardiology’ of the German Society for Cardiology – Heart and Circulatory Research (DGK). It is endowed with 10,000 euros and will be awarded annually. The selection from the scientific applications submitted will be made by an independent panel of experts.
This year's award was presented to Prof. Dr. Dr. Mahir Karakas in Frankfurt by the German Heart Foundation. The work of this dedicated cardiologist, who has already conducted extensive research into gender-specific aspects of disease and is currently coordinating the submission of a corresponding joint research programme, is particularly welcomed by the founder, Martina Grote. Heart problems specific to women are also becoming increasingly recognised in research. ‘The “Frauenherzen” science award aims to support precisely this research and further raise awareness of this topic.’
Original publication: Karakas, Mahir et al., Intravenous ferric carboxymaltose in heart failure with iron deficiency (FAIR-HF2 DZHK05 trial): Sex-specific outcomes,European Journal of Heart Failure, July 2025.
Source: Press release German Heart Foundation
