What are the treatment options for hereditary angioedema (HAE)?

Treatment Options for Hereditary Angioedema (HAE)

First-line treatments for HAE include C1 inhibitor concentrates, bradykinin receptor antagonists, and plasma kallikrein inhibitors, with the choice depending on HAE subtype, attack severity, and medication availability. 1

HAE Subtypes and Diagnosis

HAE is classified into different subtypes based on C1 inhibitor (C1INH) levels and function:

• Type I HAE: Low C1INH antigenic and functional levels (most common)
• Type II HAE: Normal C1INH antigenic levels but decreased C1INH functional levels
• HAE with normal C1INH: Normal C1INH levels and function, may be associated with increased bradykinin signaling 1, 2

Diagnosis requires:

• Low C1INH antigenic or functional level
• Decreased C4 levels
• Generally normal C1q levels 1

Treatment Strategies for HAE

1. On-Demand Treatment (Acute Attacks)

FDA-approved medications for acute HAE attacks include:

• Plasma-derived C1INH (pdC1INH) - IV administration

  • Indicated for treatment of acute abdominal, facial, or laryngeal attacks in adults and children 3
  • Mechanism: Directly replaces the deficient protein

• Icatibant - Subcutaneous administration

  • Indicated for treatment of acute attacks in adults ≥18 years 4
  • Mechanism: Bradykinin B2 receptor antagonist

• Ecallantide - Subcutaneous administration

  • Indicated for treatment of attacks in patients ≥12 years
  • Mechanism: Plasma kallikrein inhibitor 1

• Recombinant human C1INH (rhC1INH) - IV administration

  • Indicated for treatment of attacks in adult and adolescent patients
  • Mechanism: C1INH replacement 1

Important note: Epinephrine, corticosteroids, and antihistamines are NOT effective for HAE attacks and should not be relied upon 1.

2. Short-Term Prophylaxis

Used before procedures or anticipated triggers:

• C1INH concentrate: 1000-2000 U or 20 U/kg for children (first-line) 1
• Fresh frozen plasma: 2 units (10 mL/kg for children) administered several hours before procedure (alternative when C1INH unavailable) 1
• High-dose attenuated androgens: 6-10 mg/kg/day in divided doses (maximum 200 mg danazol 3 times daily) for 5-10 days before and 2 days after procedure (alternative option) 1

3. Long-Term Prophylaxis

Options include:

• Plasma-derived C1INH: IV or subcutaneous administration

  • Starting dose: 1000 U every 3-4 days, adjustable based on response
  • First-line prophylactic option 1

• Lanadelumab: Subcutaneous administration

  • Highly effective prophylactic option 1

• Attenuated androgens (e.g., danazol, stanozolol):

  • Effective but considered second-line due to side effects
  • Low-to-moderate doses can provide effective prophylaxis 1

• Antifibrinolytic agents (e.g., tranexamic acid):

  • Less effective than androgens but relatively safe
  • Option when other treatments unavailable or contraindicated 1

Treatment Algorithm Based on Clinical Scenario

For Acute Attacks:

1. Mild to moderate peripheral attacks:

   • C1INH concentrate, icatibant, or ecallantide (if available)
   • If first-line agents unavailable, fresh frozen plasma may be used with caution 1

2. Severe attacks or laryngeal involvement:

   • Immediate C1INH concentrate (preferred) or icatibant
   • Ensure airway management capabilities are available 1

For Long-Term Prophylaxis:

Consider the following factors when deciding on prophylaxis:

• Attack frequency and severity
• Impact on quality of life
• Access to acute care
• Comorbid conditions

Decision pathway:

1. First-line: C1INH concentrate (IV or subcutaneous) or lanadelumab
2. Second-line: Attenuated androgens (contraindicated in pregnancy)
3. Third-line: Antifibrinolytic agents 1

Special Considerations

Pregnancy

• Androgens are contraindicated
• Plasma-derived C1INH is the preferred treatment
• Attacks may increase during pregnancy but typically decrease during delivery
• Risk increases during postpartum period 1

Resource-Limited Settings

In countries with limited access to first-line therapies:

• Attenuated androgens or tranexamic acid may be used for prophylaxis
• Fresh frozen plasma (with caution) for acute attacks
• Efforts should be made to improve access to modern HAE treatments 1

Common Pitfalls to Avoid

1. Misdiagnosis: HAE symptoms can be mistaken for allergic reactions, leading to inappropriate treatment with antihistamines and corticosteroids

2. Delayed treatment: Prompt treatment of acute attacks is essential, especially for laryngeal attacks which can be life-threatening

3. Inappropriate medication use: Avoid using medications that may exacerbate HAE:

   • ACE inhibitors (can increase bradykinin levels)
   • Estrogen-containing medications (can worsen symptoms in women) 1

4. Inadequate patient education: All patients should be educated about:

   • Trigger avoidance
   • Early recognition of attacks
   • Self-administration of acute medications when appropriate 1

5. Failure to adjust prophylaxis: Base prophylaxis dosing on clinical response rather than laboratory parameters 1