Many new therapeutic options have been developed in recent years for hereditary angioedema (HAE) types I and II. Strategies for treating HAE include medications that fall into three broad categories: medications taken regularly with the goal of preventing HAE attacks from occurring (long-term prophylactic treatments), medications taken briefly before an event likely to cause an HAE attack (short-term prophylaxis) and medications to treat HAE attacks (abortive treatments; also called on-demand treatment).
Long-term prophylactic treatments
Typically, prophylactic treatments are medications taken regularly to prevent HAE attacks from occurring. As patients vary greatly in the frequency they have HAE attacks, long-term prophylaxis is not recommended for all patients. Published guidelines vary in their recommendations. The WAO/EAACI guideline recommends: “Long-term prophylaxis should be individualized and considered in all severely symptomatic HAE-1/2 patients taking into consideration the activity of the disease, frequency of attacks, patient’s quality of life, availability of healthcare resources, and failure to achieve adequate control by appropriate on-demand therapy” 
Historically, orally administered attenuated androgens (versions of male sex hormones such as danazol (Cyclomen®) were amongst the first prophylactic treatments used for HAE . The use of danazol is limited by the undesirable androgen side effects. Therefore, the lowest dose needed to mostly prevent HAE attacks is desired trying to keep the overall dose to less than 200 mg daily. Androgens are not recommended in pregnant women, women trying to get pregnant, nor in children .
Another therapy used for many years to prevent HAE attacks has been oral antifibrinolytics such as tranexamic acid (Cyclokapron®). This medication interferes with fibrin formation and action. Recent studies have shown that it is effective in only a small proportion of patients in preventing HAE attacks. Furthermore, it can increase the risk of blood clots. Therefore, it is only recommended for the prophylaxis of HAE attacks should other therapies not be available or not be tolerable .
Plasma-derived C1-inhibitor (C1-INH) is currently the preferred long-term prophylaxis for HAE attacks. Cinryze ® is administered intravenously (into a vein) and Haegarda ® is administered subcutaneously (under the skin) every 3 to 4 days. These replacement therapies have been shown to significantly decrease the frequency of HAE attacks [2-5].
Replacement therapy with recombinant C1-INH subcutaneously has been under investigation for prophylaxis but is not currently licensed for this indication . The human monoclonal antibody targeting plasma kallikrein (lanadelumab; administered subcutaneously every two weeks) has been used for long-term prophylaxis but is not yet licensed in Canada (application pending) .
Certain procedures may increase the risk that HAE patients develop an HAE attack (e.g. dental work or airway intubation may trigger life-threatening throat or airway swellings; surgical or instrument interventions may trigger local swellings; stressful situations may trigger an HAE event). Therefore, it is generally recommended that HAE patients be given medications prior to such procedures or for short periods of time around stressful events known to trigger swellings in that patient. C1-INH is the most commonly used short-term prophylaxis. If the risk of the procedure seems low or uncertain and C1-INH or icatibant intervention is immediately available if swelling occurs, then having abortive (on-demand) intervention may be chosen rather than short-term prophylaxis. If abortive therapies such as C1-INH are not immediately available, then danazol may be used starting days before an elective procedure or upcoming stressful event that cannot be avoided. If danazol is contraindicated and C1-INH or icatibant abortive on-demand therapy not immediately available, then solvent-detergent treated fresh frozen plasma may be considered. [2,3].
Abortive (on-demand) therapy
Whereas long-term prophylactic therapy is only recommended in patients with more frequent attacks, all HAE patients should have access to abortive therapies. These are medications to be taken when patients are having a significant attack in order to reverse this attack. Most believe that early abortive therapy is more successful than later intervention. As airway events may be life threatening, immediate abortive therapy should be used and immediate medical attention should be sought [2,3]. Abortive therapies around the world include plasma-derived (pd) and recombinant (rh) C1-INH (pd-C1-INH Berinert ®, pd-C1-INH Cinryze ®; rh-C1-INH Ruconest ®); bradykinin receptor antagonist icatibant (Firazyr ®); kallikrein inhibitors (ecallantide, Kalbitor ®). In Canada, only Berinert ® and Firazyr are licensed for treatment of an acute HAE attack.
C1-INH formulations are usually given intravenously either by medical personnel or self-administered or administered by a trained care-giver. Icatibant may be self-administered subcutaneously or administered by medical personnel or by trained care-givers.
(See the What Causes HAE section for bradykinin and kallikrein targeting)
Should no other therapies be available, fresh frozen plasma (a component of donated blood; preferably solvent-detergent treated) may be used to treat HAE attacks .
In addition to specific HAE medications used to treat acute attacks, patients may also require more general medical interventions. For instance, severe abdominal attacks may require supportive treatments such as intravenous fluids (rehydration) or medications to control pain. For attacks affecting airways, patients may require emergency medical care to maintain their ability to breath.
Medication currently being developed
More recently, a monoclonal antibody medication called Lanadelumab that targets kallikrein has been investigated as a long-term prophylactic agent but no data are available as yet as an abortive therapy. [8, 9]. Other new molecules are currently being developed such as oral kallikrein antagonist.
Treatment guidelines for HAE with normal C1 esterase inhibitor / HAE type III (HAE nC1INH)
There are fewer patients diagnosed with HAE with normal C1 esterase inhibitor (HAEnC1INH) and there are many diagnostic groupings . There are therefore few clinical trials to interpret the best prophylactic or abortive interventions for such patients.
Long-term prophylaxis for HAE nC1INH
Danazol, tranexamic acid, and C1-INH have been used for long-term prophylaxis but it is difficult to predict outcome in any given patient until clinical intervention has been tried. The best intervention is yet to be determined for each of the clinical groupings in HAE nC1INH patients. The side-effect profile in a given patient for a given intervention is also difficult to predict (such as blood clot risk with C1-INH or anti-fibrinolytics). Anecdotally, the progesterone-only birth control pill may decrease attack frequency .
Short-Term Prophylaxis for HAE nC1INH
There are no clinical trials as yet investigating short-term prophylaxis in patients with HAE nC1INH. The same short-term prophylaxis used for HAE type I and II patients may be tried .
Abortive therapy for HAE nC1INH
As there are few clinical trials in abortive therapy HAE nC1INH, one usually tries the same approach as in HAE type I and II patients. However, giving additional C1INH to patients with normal C1INH increases the risk of blood clots .
Triggers / Medications to avoid
Avoiding (or limiting exposure to) certain triggers can decrease attack frequency in some patients. Common triggers that can bring on HAE attacks may include physical pressure or injury to part of the body (for example, gripping a lawn mower for a long period of time can trigger attacks affecting the hands in some patients) and emotional stressors. Dental work is a common trigger for HAE attacks. Certain medications can exacerbate HAE including estrogens (such as estrogen in the birth control pill or estrogen supplementation given for symptoms of menopause) as well as some blood pressure medications including angiotensin converting enzyme inhibitors (ACE inhibitors) and perhaps angiotensin receptor blockers. HAE patients taking these classes of medications should discuss with their physicians whether these medications could be contributing to their symptoms and whether other classes of medications could be used.
1. Gelfand, J.A., et al., Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med, 1976. 295(26): p. 1444-8.
2. Betschel, S., et al., Canadian hereditary angioedema guideline. Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology, 2014. 10(1): p. 50.
3. Maurer, M., et al., The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy, 2018.
4. Henry Li, H., M. Riedl, and J. Kashkin, Update on the Use of C1-Esterase Inhibitor Replacement Therapy in the Acute and Prophylactic Treatment of Hereditary Angioedema. Clin Rev Allergy Immunol, 2018.
5. Longhurst, H., et al., Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor. N Engl J Med, 2017. 376(12): p. 1131-1140.
6. Farkas, H., Pharmacological Management of Hereditary Angioedema with C1-Inhibitor Deficiency in Pediatric Patients. Paediatr Drugs, 2018. 20(2): p. 135-151.
7. Farkas, H. and K.V. Kohalmi, Icatibant for the treatment of hereditary angioedema with C1-inhibitor deficiency in adolescents and in children aged over 2 years. Expert Rev Clin Immunol, 2018.
8. Riedl, M.A., et al., An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Clin Transl Allergy, 2017. 7: p. 36.
9. Banerji, A., et al., Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med, 2017. 376(8): p. 717-728.
10. Magerl, M., et al., Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment. Immunol Allergy Clin North Am, 2017. 37(3): p. 571-584.
11. Zuraw BL. Hereditary angioedema with normal C1 inhibitor: Four types and counting. J Allergy Clin Immunol. 2018 Mar;141(3):884-885. doi: 10.1016/j.jaci.2018.01.015. Epub 2018 Feb 2.
For more information:
- Betschel, S., et al., Canadian hereditary angioedema guideline. Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology, 2014. 10(1): p. 50. (https://aacijournal.biomedcentral.com/articles/10.1186/1710-1492-10-50)
- Maurer, M., et al., The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy, 2018.
- www.uptodate.com: Cicardi, M. and Zuraw, B, Hereditary angioedema: General care and long-term prophylaxis. May 2018.
- www.uptodate.com: Cicardi, M. and Zuraw, B, Hereditary angioedema: Treatment of acute attacks. May 2018.