How is iron deficiency treated in patients with heart failure?

Iron Deficiency in Heart Failure: Diagnosis and Treatment

Overview and Clinical Significance

Iron deficiency is a critical comorbidity affecting up to 50% of heart failure patients and should be routinely screened and aggressively treated with intravenous ferric carboxymaltose in symptomatic patients with HFrEF, as this improves functional capacity, quality of life, and reduces heart failure hospitalizations. 1

Iron deficiency in heart failure is associated with:

• Reduced functional capacity and impaired exercise tolerance 1
• Worse quality of life 1
• Increased risk of hospitalizations and mortality, independent of anemia status 1, 2
• More severe heart failure symptoms 3

Diagnostic Criteria

Screen all heart failure patients for iron deficiency using the following thresholds: 1

• Serum ferritin <100 μg/L, OR
• Serum ferritin 100-299 μg/L with transferrin saturation (TSAT) <20%

Important diagnostic considerations:

• Iron deficiency should be diagnosed regardless of anemia status 1
• Patients with hemoglobin >15 g/dL have not been studied and should be excluded from treatment 1
• Always investigate for reversible causes of iron deficiency, particularly gastrointestinal bleeding, before initiating treatment 1

Treatment Recommendations

Intravenous Iron: First-Line Therapy

Intravenous ferric carboxymaltose (FCM) should be considered (Class IIa, Level A recommendation) in symptomatic patients with HFrEF (LVEF <40%) and iron deficiency to improve symptoms, exercise capacity, and quality of life. 1

Key evidence supporting IV iron:

• The FAIR-HF and CONFIRM-HF trials demonstrated significant improvements in patient global assessment, NYHA class, 6-minute walk distance, and quality of life over 6-24 weeks 1
• Secondary endpoint analysis showed reduced risk of heart failure hospitalizations 1
• Benefits were observed in both anemic and non-anemic patients 1
• Meta-analyses confirm sustained improvements in functional capacity, symptoms, quality of life, and reduced hospitalization rates over up to 52 weeks 1

Dosing Regimen for Heart Failure Patients

For patients ≥50 kg: 4, 5

• Standard regimen: 750 mg IV in two doses separated by at least 7 days (total 1,500 mg per course)
• Alternative single-dose regimen: 15 mg/kg body weight up to maximum 1,000 mg IV as a single dose

For patients <50 kg: 4, 5

• 15 mg/kg body weight IV in two doses separated by at least 7 days

Weight-based dosing for heart failure with specific hemoglobin levels: 4

• Patients <70 kg with Hb <10 g/dL: 1,000 mg on Day 1, then 500 mg at Week 6
• Patients ≥70 kg with Hb <10 g/dL: 1,000 mg on Day 1, then 1,000 mg at Week 6

Maximum weekly dose: 1,000 mg iron (20 mL FCM) per week 1, 4

Administration Technique

FCM can be administered via two methods: 1, 4

1. Undiluted slow IV push: 100 mg/min (15 minutes for 1,000 mg dose)
2. IV infusion: Requires dilution, but avoid over-dilution as this affects drug stability

Critical safety protocol:

• Observe patients for adverse effects for at least 30 minutes following each injection 1, 6, 4
• Ensure resuscitation facilities are immediately available due to potential anaphylaxis risk 4
• Staff must be trained and equipped to monitor for and manage hypersensitivity reactions 4

Monitoring Strategy

Initial reassessment: 1, 6, 4

• Re-evaluate iron status (ferritin and TSAT) at 3 months after the correction dose
• Early re-evaluation is critical to determine need for additional iron repletion

Ongoing monitoring: 4

• Re-evaluate iron parameters 1-2 times per year in patients with known heart failure
• If no response or hemoglobin decreases, investigate for occult blood loss and other underlying causes

Expected response: 6

• Reticulocytosis occurs at 3-5 days after administration
• Mean hemoglobin increase of 8 g/L over 8 days for a single 1,000 mg dose
• Mean ferritin increase of 264 ng/mL from baseline
• In the CONFIRM-HF trial, change from baseline to Week 24 showed ferritin increase of 269 ng/mL, TSAT increase of 9%, and hemoglobin increase of 0.6 g/dL 5

Oral Iron: Not Recommended

Oral iron therapy is NOT effective for iron deficiency in heart failure and should not be used. 1, 4

Reasons oral iron fails in heart failure: 1, 7

• Poor gastrointestinal absorption, further impaired in heart failure patients
• Slow and inefficient iron repletion (may require >6 months)
• Gastrointestinal side effects in up to 60% of patients
• No demonstrated improvement in exercise capacity or symptoms
• Poor compliance due to pill burden in heart failure patients

Contraindications

Absolute contraindications to IV FCM: 1, 4, 8

• Hypersensitivity to FCM or any excipients
• Known serious hypersensitivity to other parenteral iron products
• Anemia not attributed to iron deficiency (e.g., other microcytic anemias)
• Evidence of iron overload or disturbances in iron utilization
• Hemoglobin >15 g/dL

Cautions and Special Populations

Use with caution in: 1, 8

• Acute or chronic infection: Stop FCM in patients with ongoing bacteremia
• Known drug allergies: Patients with history of severe asthma, eczema, or atopic allergies have increased hypersensitivity risk
• Immune/inflammatory conditions: Increased risk in systemic lupus erythematosus and rheumatoid arthritis

Limited or no evidence in: 1

• HFpEF (LVEF ≥50%): No clinical evidence for IV FCM
• HFmrEF (LVEF 40-49%): Limited clinical evidence

Adverse Events

Common side effects (≥1% to <10%): 4

• Dizziness, headache
• Hypertension
• Hypophosphatemia
• Injection-site reactions
• Nausea

Serious adverse events: 4

• Anaphylactic/anaphylactoid reactions: 0.1% of patients
• Other serious hypersensitivity reactions: 1.5% of patients

Monitor closely for: 4

• Signs and symptoms of hypersensitivity during and after administration
• Hypertension following each administration
• Symptomatic hypophosphatemia in patients requiring repeat courses

Clinical Benefits: What to Expect

Proven improvements in HFrEF patients (LVEF ≤45%): 1, 4

• Improved functional capacity and exercise tolerance (6-minute walk distance increased by 25 meters at 24 weeks) 5
• Reduced heart failure symptoms and improved NYHA class
• Enhanced health-related quality of life
• Potential reduction in heart failure-related hospitalizations

Important limitation:

• Trials were not powered to evaluate mortality benefit 1
• The effect on major outcomes and long-term safety in HFrEF, HFmrEF, or HFpEF remains unknown 1

Practical Implementation

When to repeat treatment: 5

• FCM treatment may be repeated if iron deficiency or IDA reoccurs
• Monitor iron parameters regularly to identify need for repeat dosing

Setting for administration: 4

• Can be administered in hospital or community settings
• Requires trained staff and equipment for managing hypersensitivity reactions

Common Pitfalls to Avoid

1. Don't wait for anemia to develop - Iron deficiency causes harm independent of hemoglobin levels 1
2. Don't use oral iron - It is ineffective in heart failure patients 1, 4
3. Don't skip the 30-minute observation period - Hypersensitivity reactions can occur 1, 6, 4
4. Don't over-dilute FCM for infusion - This affects drug stability 1
5. Don't forget to investigate reversible causes - Always rule out GI bleeding and other sources 1
6. Don't use in patients with hemoglobin >15 g/dL - Safety not established 1