Prophylactic Therapies for Reducing Laryngeal Attacks in Hereditary Angioedema
Plasma-derived C1 inhibitor (pdC1-INH) replacement therapy is the most effective prophylactic treatment for preventing laryngeal attacks in HAE, with evidence demonstrating complete abolition of laryngeal edema episodes when used for long-term prophylaxis. 1
Evidence for Laryngeal Attack Prevention
Plasma-Derived C1-INH: Superior Efficacy
In patients with severe HAE receiving regular pdC1-INH for individual replacement therapy, 24 laryngeal edema episodes per year were completely eliminated, compared to continued laryngeal attacks during danazol prophylaxis. 1
This represents the strongest evidence available for preventing the most life-threatening manifestation of HAE, as laryngeal attacks historically carry approximately 30% mortality rates when untreated. 2
The complete cessation of laryngeal attacks occurred alongside significant reduction in overall attack frequency (p < 0.001) compared to danazol. 1
Lanadelumab: Effective but Less Specific Data
Lanadelumab 300 mg every two weeks demonstrated that the prophylactic treatment effect was less pronounced for laryngeal attacks compared to peripheral attacks, suggesting it may not provide the same level of laryngeal protection as pdC1-INH. 3
Despite this limitation, lanadelumab is FDA-approved for prophylaxis in patients aged 2 years and older and does reduce overall attack frequency. 4
Laryngeal attacks still accounted for 2-7% of all breakthrough attacks in patients receiving lanadelumab prophylaxis. 3
Berotralstat: Limited Laryngeal Protection
Berotralstat showed more pronounced prophylactic effect in peripheral attacks than in abdominal and laryngeal attacks, indicating inferior protection against life-threatening laryngeal episodes. 3
This differential efficacy makes berotralstat a less optimal choice when laryngeal attack prevention is the primary concern. 3
Androgens: Insufficient Evidence for Laryngeal Protection
While attenuated androgens (danazol) provide effective long-term prophylaxis for general HAE attacks, no specific data exist demonstrating their efficacy in preventing laryngeal attacks specifically. 5
The study showing complete elimination of laryngeal attacks with pdC1-INH specifically enrolled patients who had failed or were intolerant to danazol, suggesting danazol was insufficient for preventing these life-threatening episodes. 1
Androgens require several days to become optimally effective and are not reliably effective for acute attacks, raising concerns about their ability to prevent rapidly progressive laryngeal swelling. 5
Clinical Algorithm for Prophylaxis Selection
First-Line Choice for Laryngeal Attack Prevention
Plasma-derived C1-INH should be the first-line prophylactic agent when prevention of laryngeal attacks is the primary goal, given the only available evidence showing complete elimination of laryngeal episodes. 1
For long-term prophylaxis, pdC1-INH or lanadelumab are recommended as first-line options by guidelines, with pdC1-INH preferred when laryngeal attack history exists. 6, 2
Second-Line Options
Lanadelumab 300 mg subcutaneously every two weeks is an appropriate alternative, though with less robust evidence for laryngeal attack prevention specifically. 4, 3
Berotralstat should be considered third-line given its reduced efficacy for laryngeal attacks. 3
Androgens (danazol) may be used when first-line agents are unavailable or contraindicated, but lack specific evidence for laryngeal protection. 6, 2
Critical Clinical Considerations
Breakthrough Attacks Still Occur
Even with optimal prophylaxis, laryngeal attacks can still occur—they accounted for 2-7% of all breakthrough attacks across all prophylactic agents in observational and interventional studies. 3
This means all HAE patients must have immediate access to on-demand treatment regardless of prophylactic therapy, as 49-94% of breakthrough attacks required on-demand therapy. 3
Laryngeal attacks should be observed in a medical facility capable of performing intubation or tracheostomy, with close monitoring for change in voice, loss of ability to swallow, or difficulty breathing. 2
Special Populations
During pregnancy, pdC1-INH is the only recommended prophylactic agent, as androgens are contraindicated due to teratogenic effects and should be discontinued at least 2 months before attempting conception. 2, 7
For children aged 2-11 years, tranexamic acid is preferred over androgens for long-term prophylaxis due to concerns about growth and development, though pdC1-INH and lanadelumab are also approved options. 6, 4
Common Pitfalls to Avoid
Do not rely on standard angioedema treatments (epinephrine, corticosteroids, antihistamines) for HAE prophylaxis or acute management—these are completely ineffective. 5, 2, 7
Do not assume prophylaxis eliminates the need for on-demand therapy—breakthrough attacks occur with all prophylactic agents and require immediate treatment. 3
Do not use androgens as first-line prophylaxis in patients with history of laryngeal attacks when pdC1-INH is available, given the lack of specific evidence for laryngeal protection and the definitive evidence for pdC1-INH. 1
Do not delay observation or treatment of suspected laryngeal attacks—these are potentially life-threatening with historical mortality rates of 30%. 2, 8