Background
Phase 3, double-blind, placebo-controlled RCT (FAIR-HF). 459 patients with symptomatic systolic heart failure (NYHA class II–III, LVEF ≤40%), iron deficiency (serum ferritin <100 ng/mL or ferritin 100–299 ng/mL with TSAT <20%), and hemoglobin 9.5–13.5 g/dL. Iron deficiency is common in HF (~50%), independent of anemia, and is associated with reduced exercise capacity, poor QoL, and worse outcomes. Ferric carboxymaltose (FCM, Ferinject/Injectafer) is an IV iron formulation that can be administered in large single doses without a test dose or extended infusion time. Anemia was present in ~50% — the trial enrolled both anemic and non-anemic iron-deficient HF patients to test the effect of iron repletion specifically.
Interventions and follow up
Arm A: IV ferric carboxymaltose (FCM) 200 mg weekly until iron repletion (target ferritin 100–500 ng/mL with TSAT ≥20%), then monthly maintenance doses for 24 week
Arm B: IV normal saline (placebo)
Primary endpoint: Patient Global Assessment (PGA) and NYHA class at week 24
mFollow up: 24 week
Arm B: IV normal saline (placebo)
Primary endpoint: Patient Global Assessment (PGA) and NYHA class at week 24
mFollow up: 24 week
Results
PGA improvement (much/moderately improved): 50% (FCM) vs 28% (placebo); OR 2.51, 95% CI 1.75–3.61 — P<.001
NYHA class improvement (≥1 class): 47% vs 30%; OR 2.40, 95% CI 1.55–3.71 — P<.001
6-minute walk test improvement: +35 m (FCM) vs +5 m (placebo); P<.001
Benefit in anemic and non-anemic patients: Similar benefit regardless of baseline Hgb
NYHA class improvement (≥1 class): 47% vs 30%; OR 2.40, 95% CI 1.55–3.71 — P<.001
6-minute walk test improvement: +35 m (FCM) vs +5 m (placebo); P<.001
Benefit in anemic and non-anemic patients: Similar benefit regardless of baseline Hgb
Adverse events
Main adverse events: Hypersensitivity reactions rare (<1%). Injection-site reactions uncommon. No serious cardiovascular safety signals. Mild transient hypophosphatemia with high-dose FCM in some patients. No significant difference in serious AEs or death between arms. FCM administration well-tolerated as IV push over 15 minutes.
Conclusions
IV ferric carboxymaltose significantly improved patient global assessment, NYHA class, and exercise capacity in iron-deficient HF patients, with benefit in both anemic and non-anemic patients, establishing IV iron as a disease- modifying therapy for iron deficiency in HF.
Key Limitations
Key Limitations: 24-week primary analysis — limited long-term outcomes data. No cardiovascular mortality or hospitalization benefit demonstrated (underpowered). Anemia correction contributed to benefit in some — isolating pure iron effect from hemoglobin effect is not possible. Placebo was saline injection, so complete blinding uncertain (though raters were blinded). Selection criteria (LVEF ≤40%) limited to HFrEF — HFpEF not studied in this trial.
Clinical Context
FAIR-HF established IV iron as standard therapy for iron-deficient HF. Subsequent trials (CONFIRM-HF, AFFIRM-AHF) confirmed benefit including reduction in HF hospitalizations. The IRONOUT-HF trial (oral iron) was negative — oral iron is not effective for iron-deficient HF due to poor absorption. AFFIRM-AHF (ferric carboxymaltose post-hospitalization for acute decompensated HF) showed significant reduction in HF hospitalizations. Current ESC/ACC/AHA HF guidelines recommend IV iron (ferric carboxymaltose or ferric derisomaltose) for iron-deficient HFrEF to improve symptoms and QoL.
References