What are the details of the FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) and CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Chronic Heart Failure) trials on intravenous iron supplementation with ferric carboxymaltose in patients with heart failure and iron deficiency?

FAIR-HF and CONFIRM-HF Trials on Intravenous Ferric Carboxymaltose in Heart Failure with Iron Deficiency

The FAIR-HF and CONFIRM-HF trials demonstrated significant improvements in functional capacity, symptoms, and quality of life in heart failure patients with iron deficiency treated with intravenous ferric carboxymaltose, with CONFIRM-HF also showing reduction in heart failure hospitalizations. 1

FAIR-HF Trial Details

Study Design

• Multicenter, randomized, double-blind, placebo-controlled phase III trial 1
• Enrolled 459 ambulatory patients with chronic heart failure and iron deficiency, with or without anemia 2

Inclusion Criteria

• NYHA functional class II or III heart failure 2
• Left ventricular ejection fraction (LVEF) ≤40% (for NYHA class II) or ≤45% (for NYHA class III) 2
• Iron deficiency defined as ferritin <100 μg/L or ferritin 100-299 μg/L with transferrin saturation <20% 2
• Hemoglobin level of 95-135 g/L 2

Treatment Protocol

• Randomized 2:1 to receive intravenous ferric carboxymaltose (FCM) or placebo (saline) 2
• FCM group received 200 mg weekly until iron repletion, followed by 200 mg monthly maintenance 1

Primary Endpoints

• Patient Global Assessment (PGA) at week 24 1
• NYHA functional class at week 24 1

Results

• 50% of FCM patients reported being much or moderately improved vs. 28% in placebo group (odds ratio 2.51) 2
• 47% of FCM patients achieved NYHA class I or II at week 24 vs. 30% in placebo group (odds ratio 2.40) 2
• Significant improvements in 6-minute walk test distance 1
• Improved quality of life measures 1
• Benefits observed in both anemic and non-anemic patients 2
• No significant differences in death rates or adverse events between groups 2

CONFIRM-HF Trial Details

Study Design

• Multicenter, double-blind, placebo-controlled trial designed to confirm long-term safety and efficacy 1
• 52-week study duration 3
• Enrolled 304 ambulatory symptomatic heart failure patients 3

Inclusion Criteria

• Symptomatic heart failure with LVEF ≤45% 1
• Elevated natriuretic peptides 3
• Iron deficiency defined as ferritin <100 μg/L or ferritin 100-299 μg/L with transferrin saturation <20% 3

Treatment Protocol

• Randomized 1:1 to receive FCM or placebo (saline) for 52 weeks 3
• Initial iron need calculated based on body weight and hemoglobin levels 1
• Maximum recommended cumulative dose of 1000 mg iron/week 1

Primary Endpoint

• Change in 6-minute walk test (6MWT) distance from baseline to week 24 3

Secondary Endpoints

• Changes in NYHA class, PGA, quality of life, fatigue scores 3
• Hospitalization rate for worsening heart failure 3

Results

• Significant improvement in 6MWT distance at week 24 (difference FCM vs. placebo: 33±11 m, p=0.002) 3
• Treatment effect sustained to week 52 (difference FCM vs. placebo: 36±11 m, p<0.001) 3
• Significant improvements in NYHA class, PGA, quality of life, and fatigue scores 3
• 61% reduction in risk of hospitalization for worsening heart failure (hazard ratio 0.39) 3
• Comparable death rates (FCM: 12, placebo: 14) and adverse event incidence between groups 3

Key Similarities and Differences Between Trials

Similarities

• Both targeted heart failure patients with reduced ejection fraction and iron deficiency 1
• Both demonstrated improvements in functional capacity, symptoms, and quality of life 1
• Neither was powered to evaluate effects on mortality 1

Differences

• FAIR-HF had a larger sample size (459 vs. 304 patients) 2, 3
• CONFIRM-HF had longer follow-up (52 weeks vs. 24 weeks) 1, 3
• CONFIRM-HF showed significant reduction in heart failure hospitalizations, which was not a primary endpoint in FAIR-HF 3
• Different primary endpoints: FAIR-HF focused on PGA and NYHA class, while CONFIRM-HF focused on 6MWT distance 2, 3

Clinical Impact and Guidelines

• Based on these trials, the 2016 ESC Heart Failure Guidelines recommend intravenous FCM for symptomatic patients with HFrEF and iron deficiency (Class IIa, Level of Evidence A) 1
• The 2022 AHA/ACC/HFSA guideline acknowledges that intravenous iron repletion improves exercise capacity and quality of life 1
• The 2017 ACC/AHA/HFSA focused update states that intravenous iron replacement might be reasonable to improve functional status and quality of life in NYHA class II and III HF patients with iron deficiency (Class IIb, Level of Evidence B-R) 1
• Oral iron therapy has not been shown to be effective for iron deficiency in heart failure patients 1

Safety Considerations

• Hypersensitivity reactions are a potential concern with intravenous iron products 4
• Caution is advised in patients with acute or chronic infection 1
• Increased risk of hypersensitivity in patients with immune or inflammatory conditions 1
• Limited evidence in patients with HFpEF (LVEF ≥50%) or HFmrEF (LVEF 40-49%) 1
• Safety not evaluated in patients with hemoglobin >15 g/dL 1

Subsequent Research

• The AFFIRM-AHF trial later showed that intravenous FCM in patients hospitalized for acute heart failure with iron deficiency reduced the risk of heart failure hospitalizations (RR 0.74) but had no significant effect on cardiovascular death 5
• Meta-analyses have confirmed that FCM reduces heart failure hospitalizations and cardiovascular hospitalizations but has no significant effect on mortality 6