FAIR-HF Trial Overview
The FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) trial was a landmark multicenter, randomized, double-blind, placebo-controlled phase III study that demonstrated intravenous ferric carboxymaltose significantly improves symptoms, functional capacity, and quality of life in iron-deficient heart failure patients, regardless of anemia status. 1, 2
Study Design and Population
Patient Enrollment Criteria:
- 459 ambulatory patients with chronic heart failure enrolled 2, 3
- NYHA functional class II or III at baseline 2
- Left ventricular ejection fraction ≤40% (NYHA class II) or ≤45% (NYHA class III) 2, 3
- Iron deficiency defined as ferritin <100 μg/L, or ferritin 100-299 μg/L with transferrin saturation <20% 2, 3
- Hemoglobin levels between 9.5-13.5 g/dL (95-135 g/L), including both anemic and non-anemic patients 2, 3
Treatment Protocol:
- Patients randomized 2:1 to receive intravenous ferric carboxymaltose (FCM) versus placebo 1, 2
- FCM administered as 200 mg weekly until iron repletion (correction phase), followed by 200 mg monthly maintenance through week 24 1
- Study duration of 24 weeks 1, 2
Primary Endpoints and Results
The trial utilized dual primary endpoints assessed at week 24: 1
Patient Global Assessment (PGA):
- 50% of FCM-treated patients reported being much or moderately improved versus 28% receiving placebo 1, 2
- Odds ratio for improvement: 2.51 (95% CI 1.75-3.61) 2
NYHA Functional Class:
- 47% of FCM patients achieved NYHA class I or II at week 24 compared to 30% in placebo group 1, 2
- Odds ratio for improvement by one class: 2.40 (95% CI 1.55-3.71) 2
Secondary Outcomes
Exercise Capacity:
- Significant improvement in 6-minute walk test distance in FCM group versus placebo 1, 2
- Patients with decreased calculated plasma volume status from baseline to week 24 had greater increments in 6-minute walking distance (61.4 m vs 43.5 m, p=0.02) 4
Quality of Life Measures:
- Significant improvements in health-related quality of life assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) and EQ-5D instrument 1
- Significant improvements in fatigue scores 1
Consistency Across Subgroups:
- Results were similar in patients with anemia and those without anemia, demonstrating that iron deficiency itself—not just anemia—drives symptoms 2
Safety Profile
The trial demonstrated an acceptable safety profile: 2
- No differences in death rates between FCM and placebo groups 1
- No differences in adverse events or serious adverse events between groups 1, 2
- Side-effect profile deemed acceptable 2
Clinical Implications and Subsequent Validation
The FAIR-HF findings were subsequently confirmed in the CONFIRM-HF trial, which extended follow-up to 52 weeks and demonstrated sustained benefits with FCM treatment 1. The treatment effect remained consistent across all subgroups and was maintained through week 52 1.
Guideline Recognition:
- The 2022 AHA/ACC/HFSA guidelines cite FAIR-HF as key evidence showing significant improvement in NYHA classification, 6-minute walk test, and quality of life 1
- The European Society of Cardiology Heart Failure Management guidelines granted a Class IIa recommendation (Level of Evidence A) for treatment of iron deficiency with IV iron therapy in patients with heart failure and reduced ejection fraction based on FAIR-HF and subsequent trials 1
Mechanistic Insights
A substudy analysis revealed that FCM treatment was associated with:
- Early reductions in calculated plasma volume status (PVS) at 4 weeks (p<0.0001) 4
- Greater reductions in weight (p=0.02) 4
- Trend toward improved peripheral edema at 24 weeks (p=0.07) 4
- These findings suggest decongestion may be one mechanism by which iron repletion benefits heart failure patients 4
Key Limitations
Important caveats to consider: