In the landmark FAIR-HF2 randomized clinical trial (NCT03036462)1, intravenous (IV) ferric carboxymaltose did not significantly reduce heart failure (HF) hospitalizations or cardiovascular deaths in patients with heart failure and iron deficiency, despite improving patient-reported quality of life outcomes. Results were presented at ACC.252 and concurrently published in JAMA3. 

The trial enrolled 1,105 patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency, defined by ferritin levels less than 100 ng/mL or between 100–299 ng/mL with transferrin saturation (TSAT) under 20%. Conducted across 70 centers in six European countries, participants received IV ferric carboxymaltose (initial dose up to 2 g followed by approximately 500 mg every four months) or placebo (saline). 

After a median follow-up of nearly 17 months, primary endpoints—including cardiovascular death or first heart failure hospitalization—showed no statistically significant improvement. Although the IV iron group demonstrated a 21% relative reduction in these events compared to placebo (16.7% vs. 21.9%; hazard ratio 0.79; p=0.04), this did not meet the trial's stringent significance thresholds. 

Similarly, total heart failure hospitalizations were not significantly different between groups (26.4% for iron therapy vs. 33.4% for placebo; p=0.12). In the subgroup of patients with TSAT under 20%, event rates remained statistically non-significant (18.9% with IV iron vs. 25.6% placebo; p=0.07). 

However, significant improvements were noted in patient quality of life, a key secondary outcome, highlighting symptomatic benefits of IV iron therapy. The safety profile was favorable, with similar rates of serious adverse events between treatment and placebo arms (~48% each). 

Heart failure expert Himabindu Vidula, MD, underscored the nuanced findings: "FAIR-HF2 validates transferrin saturation as an important marker of iron deficiency but challenges earlier assumptions of enhanced benefits at TSAT levels below 20%." 

Lead investigator Stefan D. Anker, MD, PhD, emphasized the value of IV iron for symptom management. "This trial confirms current guidelines: intravenous iron in HFrEF patients is beneficial for improving symptoms and quality of life, with potential added benefits in the initial treatment phases," Dr. Anker commented. 

References: 

• FAIR-HF2 Clinical Trial, NCT03036462, Link: https://clinicaltrials.gov/study/NCT03036462 (Access on April 14, 2025) 
• ACC.25 Scientific Session, 2025 FAIR-HF2: Ferric Carboxymaltose Safe With Some Benefits For Heart Failure, Link: https://www.acc.org/Latest-in-Cardiology/Journal-Scans/2025/03/24/16/30/sun-8am-fair-hf2-acc-2025, (Accessed on April 14, 2025) 
• Anker SD, Friede T, Butler J, et al. Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency: The FAIR-HF2 DZHK05 Randomized Clinical Trial. JAMA. 2025 Mar 30:e253833. doi: 10.1001/jama.2025.3833. Epub ahead of print. PMID: 40159390