Importance: Uncertainty remains about the efficacy of intravenous iron in patients with heart failure and iron deficiency.

Objective: To assess the efficacy and safety of ferric carboxymaltose in patients with heart failure and iron deficiency.

Design, setting, and participants: This multicenter, randomized clinical trial enrolled 1105 patients with heart failure (defined as having a left ventricular ejection fraction of ≤45%) and iron deficiency (serum ferritin level <100 ng/mL; or if transferrin saturation was <20%, a serum ferritin level between 100 ng/mL and 299 ng/mL) at 70 clinic sites in 6 European countries from March 2017 to November 2023. The median follow-up was 16.6 months (IQR, 7.9-29.9 months).

Intervention: Administration of ferric carboxymaltose (n = 558) initially given at an intravenous dose of up to 2000 mg that was followed by 500 mg every 4 months (unless stopping criteria were met) vs a saline placebo (n = 547).

Main outcomes and measures: The primary end point events were (1) time to cardiovascular death or first heart failure hospitalization, (2) total heart failure hospitalizations, and (3) time to cardiovascular death or first heart failure hospitalization in patients with a transferrin saturation less than 20%. All end point events were measured through follow-up. The end points would be considered statistically significant if they fulfilled at least 1 of the following conditions: (1) P ≤ .05 for all 3 of the end point comparisons, (2) P ≤ .025 for 2 of the end point comparisons, or (3) P ≤ .0167 for any of the 3 end point comparisons (Hochberg procedure).

Results: Of the 1105 participants (mean age, 70 years [SD, 12 years]; 33% were women), cardiovascular death or first heart failure hospitalization (first primary outcome) occurred in 141 in the ferric carboxymaltose group vs 166 in the placebo group (hazard ratio, 0.79 [95% CI, 0.63-0.99]; P = .04). 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).

Conclusions and relevance: In patients with heart failure and iron deficiency, ferric carboxymaltose did not significantly reduce the time to first heart failure hospitalization or cardiovascular death in the overall cohort or in patients with a transferrin saturation less than 20%, or reduce the total number of heart failure hospitalizations vs placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT03036462