Iron supplementation in heart failure and iron deficiency: does it help?

Iron deficiency (ID) is present in 30-80% of patients with heart failure (HF) and is associated with poor prognosis. Intravenous (IV) iron therapy has been evaluated in several randomized controlled trials and consistently shown to improve functional outcomes. In FAIR-HF, 50% of patients receiving FCM achieved NYHA class improvement to I or II by 24 weeks vs 30% with placebo. CONFIRM-HF showed a significant 33-meter increase in 6-minute walk distance (6MWD) at 24 weeks (p=0.002), alongside improvements in NYHA class. The recent trial FAIR-HF2 demonstrated smaller but significant gains in 6MWD (+10.7 m) and global well-being at 12 months. Cardiovascular outcomes have been more variable. AFFIRM-AHF showed a 26% reduction in total HF hospitalizations (HR 0.74; 95% CI, 0.58-0.94) with IV iron vs placebo. Although the composite of cardiovascular death or first HF hospitalization was narrowly non-significant (HR 0.79; 95% CI, 0.62-1.01), the effect may still be clinically meaningful. IRONMAN, using ferric derisomaltose vs placebo, was neutral for the primary endpoint of HF hospitalization and cardiovascular death (RR 0.82; 95% CI, 0.66-1.02) but showed benefit in a COVID-censored sensitivity analysis (RR 0.76; 95% CI, 0.58-1.00). In HEART-FID, involving over 3,000 patients, no benefit was also seen with IV iron for the composite of death, HF hospitalization, and 6MWD at 99% CI, however was significant at 95% CI. FAIR-HF2 showed a 21% reduction in the primary endpoint (HR 0.79; 95% CI 0.61-1.02) with IV iron, which did not meet statistical significance, but a prespecified 12-month sensitivity analysis demonstrated a 29% reduction in first cardiovascular death or HF hospitalization (0.71 (95% CI, 0.53-0.94) and a 35% reduction in total HF hospitalizations (RR 0.65; 95% CI, 0.47-0.90). The most recent meta-analysis (n>7,000) showed a 28% reduction of composite of cardiovascular death and HF hospitalizations at 1 year (RR 0.72; 95% CI, 0.55-0.89) with IV iron. Benefits were sustained at longer term follow up and were consistent across most subgroups. The totality of evidence supports IV iron in HFrEF with ID to improve symptoms and reduce HF hospitalizations, especially in the first year. Future research should explore optimal long-term dosing, sex-specific responses, and the role of IV iron in HF with preserved ejection fraction.