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.