What is the role of iron supplementation in managing heart failure, particularly in patients with reduced ejection fraction?

Role of Iron Supplementation in Heart Failure

Intravenous iron supplementation is recommended for patients with NYHA class II and III heart failure with reduced ejection fraction (HFrEF) who have iron deficiency (defined as ferritin <100 ng/mL or ferritin 100-300 ng/mL with transferrin saturation <20%) to improve functional status, quality of life, and reduce hospitalizations. 1

Prevalence and Impact of Iron Deficiency in Heart Failure

• Iron deficiency is common in heart failure, affecting approximately 40-70% of patients, and can occur with or without anemia 1, 2
• Iron deficiency is independently associated with heart failure disease severity, reduced exercise capacity, worse symptoms, and poorer prognosis 1
• Iron plays vital roles in oxygen transportation (hemoglobin), storage (myoglobin), and is crucial for mitochondrial function and energy generation in cardiac and skeletal muscle 3

Diagnosis of Iron Deficiency in Heart Failure

• Iron deficiency in heart failure is defined as:

  • Serum ferritin <100 ng/mL (absolute iron deficiency) OR
  • Serum ferritin 100-300 ng/mL with transferrin saturation <20% (functional iron deficiency) 1

• Both ferritin and transferrin saturation should be measured simultaneously and evaluated together 1

• Mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration are unreliable markers of iron deficiency in heart failure 1

• Routine evaluation of iron status is recommended in:

  • All newly diagnosed heart failure patients
  • Existing heart failure patients who remain symptomatic despite optimal medical therapy
  • 1-2 times per year as part of routine follow-up
  • After hospitalization for heart failure 1

Treatment Recommendations

Intravenous Iron Therapy

• Intravenous iron (particularly ferric carboxymaltose) is recommended for patients with NYHA class II-III heart failure with reduced ejection fraction and iron deficiency 1

• Benefits of IV iron therapy in HFrEF include:

  • Improved functional capacity and NYHA class 1
  • Enhanced quality of life 1
  • Increased exercise capacity (6-minute walk test) 1
  • Reduced risk of heart failure hospitalizations 1
  • Limited but statistically significant improvements in left ventricular ejection fraction 1

• FDA-approved indication: Injectafer (ferric carboxymaltose) is indicated for iron deficiency in adult patients with heart failure and NYHA class II/III to improve exercise capacity 4

• Dosing for patients with iron deficiency and heart failure:

  • For patients weighing <70 kg with Hb 10-14 g/dL: 1,000 mg on day 1, no dose at week 6
  • For patients weighing ≥70 kg with Hb 10-14 g/dL: 1,000 mg on day 1,500 mg at week 6
  • Maintenance dose of 500 mg at weeks 12,24, and 36 if serum ferritin <100 ng/mL or serum ferritin 100-300 ng/mL with transferrin saturation <20% 4

Oral Iron Therapy

• There is an uncertain evidence base for oral iron repletion in heart failure 1
• Oral iron products have shown little efficacy in heart failure patients, with intravenous iron being preferred 2
• This may be due to impaired gastrointestinal absorption related to elevated hepcidin levels in heart failure patients 1

Key Clinical Trials

• FAIR-HF trial: Demonstrated improvements in NYHA class and functional capacity with ferric carboxymaltose in iron-deficient heart failure patients 1
• CONFIRM-HF trial: Showed improvements in 6-minute walk test in a larger cohort (n=304) of patients with iron deficiency and heart failure 1
• A meta-analysis of 5 prospective controlled studies (631 patients) showed that IV iron therapy in iron-deficient HFrEF patients resulted in:
  • Improved functional capacity and LVEF
  • No significant reduction in mortality 1

Important Considerations and Caveats

• Before initiating iron therapy, patients should be screened for potentially treatable causes of iron deficiency (e.g., gastrointestinal bleeding) 1
• The safety of IV iron is unknown in patients with heart failure and hemoglobin >15 g/dL 1
• The effect of treating iron deficiency in heart failure with preserved ejection fraction (HFpEF) remains unknown 1
• The long-term safety of iron therapy in HFrEF, HFmrEF, or HFpEF is not well established 1
• Current trials have been underpowered to detect reductions in hard clinical endpoints like mortality 1
• When administering IV iron, monitor for extravasation which may cause long-lasting brown discoloration at the site 4
• Check serum phosphate levels in patients at risk for low serum phosphate who require repeat treatment 4