Key Points:
- Iron deficiency is common in patients with heart failure with reduced ejection fraction (HFrEF) and is associated with worse outcomes.
- The FAIR-HF2 trial assessed the impact of intravenous iron supplementation on cardiovascular outcomes and quality of life in iron-deficient HFrEF patients.
- Intravenous iron failed to meet its primary endpoints of cardiovascular death or heart failure hospitalization, but it significantly improved quality of life, particularly in the first year of treatment.
- A meta-analysis incorporating over 7,000 patients confirmed a benefit of intravenous iron supplementation in HFrEF, supporting current guideline recommendations.
Iron deficiency is common among patients with heart failure with reduced ejection fraction (HFrEF) and is associated with worse outcomes, including fatigue, weakness, and shortness of breath. As a result, current guidelines recommend routine screening for iron deficiency. However, previous outcome trials of intravenous (IV) iron therapy in heart failure—AFFIRM-AHF, IRONMAN, and HEART-FID—failed to demonstrate a statistically significant benefit for their respective primary endpoints. These trials may have narrowly missed their efficacy goals due to slow enrollment, challenges with follow-up and dosing adherence during the COVID-19 pandemic, and, more importantly, relatively low maintenance-phase therapy rates after initial iron repletion.
FAIR-HF2 (Ferric Carboxymaltose Assessment of Morbidity and Mortality in Patients with Iron Deficiency and Chronic Heart Failure) was the final ongoing outcomes trial evaluating IV iron therapy, specifically ferric carboxymaltose (FCM), versus placebo. The primary objective of FAIR-HF2 was to assess whether a higher maintenance dose of IV iron (>1,000 mg per year) could improve outcomes in ambulatory HFrEF patients.
Dr. Stefan D. Anker, MD, a heart failure cardiologist at Charité–Universitätsmedizin Berlin and the study’s lead author, presented the results at the American College of Cardiology’s Annual Scientific Session (ACC.25).
FAIR-HF2 enrolled 1,105 patients with HFrEF across 70 centers in six countries (Germany, Italy, Portugal, Slovenia, Hungary, and Poland). Eligible participants had iron deficiency at baseline, defined as a serum ferritin level below 100 ng/mL or a ferritin level of 100-299 ng/mL with transferrin saturation (TSAT) below 20%. Patients (median age 70 years, two-thirds male) were randomized to receive either IV ferric carboxymaltose or placebo (intravenous saline) in a blinded manner. The iron supplementation group received an initial dose of 1,000-2,000 mg, followed by maintenance doses of 500 mg every four months, with a median follow-up of 21 months.
The second primary outcome (total heart failure hospitalizations) occurred 264 times in the ferric carboxymaltose group vs 320 times in the placebo group (rate ratio, 0.80 [95% CI, 0.60-1.06]; P = .12). The third primary outcome (cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation <20%) occurred in 103 patients in the ferric carboxymaltose group vs 128 patients in the placebo group (hazard ratio, 0.79 [95% CI, 0.61-1.02], P = .07). A similar amount of patients had at least 1 serious adverse event in the ferric carboxymaltose group (269; 48.2%) vs in the placebo group (273; 49.9%) (P = .61).
Researchers observed that treatment effects were most pronounced in the first year, when cumulative iron dosing was highest (average total iron received: 2,040 mg in year one vs. 925 mg and 750 mg in years two and three, respectively).
Patients receiving iron supplementation also reported significant improvements in quality of life compared to placebo, as measured by standardized health-related questionnaires. Safety outcomes, including all-cause mortality, cardiovascular mortality, and infection rates, were comparable between groups, confirming the safety of IV iron therapy in this population. A meta-analysis incorporating over 7,000 patients from multiple clinical trials further reinforced the benefit of IV iron therapy in HFrEF.
“Intravenous iron was particularly beneficial in the first year, suggesting a dose-dependent effect on outcomes,” said Dr. Anker. “These findings reinforce guideline recommendations for IV iron in HFrEF patients with iron deficiency.”
Despite these findings, the trial faced several challenges, including disruptions due to the COVID-19 pandemic, funding constraints, and evolving heart failure treatment guidelines, which led to early discontinuation of therapy in some patients. These factors may have contributed to the lack of statistical significance in the primary endpoints, despite numerical reductions in cardiovascular events.
Because FAIR-HF2 focused solely on HFrEF, further research is needed to determine whether IV iron therapy also benefits patients with heart failure with preserved ejection fraction (HFpEF). Additionally, future studies will explore potential sex-based differences in treatment response, as suggested by findings from the meta-analysis.
FAIR-HF2 was funded by DZHK Germany and CSL Vifor. The trial results were simultaneously published in The Journal of the American Medical Association.