Hereditary Angioedema Treatment & Management
- Author: Michael M Frank, MD; Chief Editor: Michael A Kaliner, MD more...
Treatment of hereditary angioedema (HAE) consists of prophylaxis, management of acute attacks, and prophylactic therapy in situations where attacks may occur. Patients with hypotension due to sequestration of fluid in the extravascular space require intravascular fluid replacement may require large amounts of intravenous fluids to maintain hemodynamic stability. Abdominal pain is treated with narcotics. In cases of serious laryngeal edema causing respiratory obstruction, intubation or tracheostomy should be performed.
For information on treatment of acute angioedema episodes, see Emergent Treatment of Angioedema.
In HAE types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1 inhibitor (C1-INH) concentrates or kallikrein inhibitor or, if those are unavailable, fresh-frozen plasma. In HAE type III, infusion of C1-INH has proven to be ineffective.[22, 23]
For prophylaxis, attenuated androgens are currently the initial mode of treatment. Therapy should be minimized, balancing disease severity with minimizing adverse effects. The drug most commonly used is danazol, but all attenuated androgens are useful in treatment. C1-INH concentrates have become available for prophylaxis and treatment of acute attacks.
A discussion of future plans, such as pregnancy, should be routine. Guidelines on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency have been published based on roundtable discussions at the 6th C1 Inhibitor Deficiency Workshop. Briefly, estrogens and androgens should be mostly avoided while planning and throughout pregnancy. Plasma-derived human C1 inhibitor concentrate is the preferred treatment for these patients. See the International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency.
World Allergy Organization guidelines
The World Allergy Organization (WAO) issued the following 2013 recommendations for the management of hereditary angioedema types I and II (HAE-I/II) :
Assess all patients suspected of having HAE-I/II for blood levels of C4, C1 esterase inhibitor (C-INH) protein, and C1-INH function
Consider on-demand treatment for all HAE attacks that (1) result in debilitation/dysfunction and/or (2) involve the face, neck, or abdomen; attacks affecting the upper airways must be treated
Treat all HAE attacks as early as possible with C1-INH, ecallantide, or icatibant; do not use oral antifibrinolytics as on-demand treatment
Consider intubation or tracheotomy early in progressive upper airway edema
Administer adjuvant therapy in HAE attacks when indicated, but use specific therapies without delay when indicated
All HAE-I/II patients should (1) have on-demand treatment for 2 attacks and (2) carry their on-demand treatment at all times
Plasma-derived (pd)C1-INH is the preferred on-demand therapy for HAE-I/II attacks in children and for pregnant or breastfeeding women
All patients should have an action plan, product available to treat HAE attacks, and an HAE identification card
Self-administration of treatment should be taught to all patients given on-demand treatment that is licensed for self-administration
All patients should have at least 1 annual assessment by an HAE specialist
The WAO’s 2013 recommendations regarding prophylaxis and screening in HAE are as follows:
Consider administering short-term preprocedural prophylaxis, particularly in cases involving dental/intraoral surgery, bronchoscopy or endoscopy, endotracheal intubation, or manipulation of the upper airway or pharynx
Before beginning long-term prophylaxis with androgens, assess the patient for cardiac risk factors and obtain a complete blood count (CBC), urine analysis, liver function test results, a lipid profile, and liver ultrasonography
During the use of androgens for long-term prophylaxis and for 6 months after cessation of therapy, monitor the patient’s CBC, urine analysis, lipid profile, liver function test results, and blood pressure every 6 months; perform annual ultrasonography of the liver
Defer screening children for HAE-I/II until the age of 12 months; test all offspring of an affected parent
Family members of HAE-I/II patients should be screened so that appropriate therapy can be available for treatment
Administer hepatitis A and B vaccinations to HAE-I/II patients receiving blood products, including pdC1-INH; administer influenza vaccine to all HAE-I/II patients
Until recently, no effective agent for acute attacks of HAE existed in the United States. Now, several agents have been approved, and others are in the midst of the US Food and Drug Administration (FDA) approval process. The new therapeutic agents are leading to a reevaluation of the best approaches to therapy. These new agents are all much more expensive than attenuated androgens.
The nano filtered C1 inhibitor concentrate Cinryze was approved by the FDA in 2008 for prophylaxis of HAE attacks and is reported to be effective in acute attacks as well. In 2 randomized trials by Zuraw et al, use of the nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks in patients with HAE and, when used for prophylaxis, reduced the frequency of acute attacks.
The C1 esterase inhibitor Berinert was approved in September 2009 by the FDA for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE. In January 2012, an additional indication for laryngeal angioedema was approved by the FDA. Use was expanded to include children younger than 12 years in July 2016. Berinert is also approved for patient self-administration after proper training by a healthcare professional.
During HAE attacks, unregulated plasma kallikrein activity results in excessive bradykinin generation, resulting in swelling. Ecallantide (Kalbitor) is a recombinant agent that is a potent, selective, reversible kallikrein inhibitor. This drug decreases the rate of C1-INH catabolism, allowing for C1-INH concentrate to be more effective.
The FDA approved ecallantide in December 2009 for treating acute HAE attacks in patients aged 16 years and older. Two randomized, double-blind, placebo-controlled trails, EDEMA4 and EDEMA3, established the safety and efficacy of ecallantide. After multiple drug administrations, some patients developed antidrug antibodies and experienced allergic or anaphylactic-like reactions. Thus, the FDA issued a black box warning and recommends that the drug only be administered by a healthcare professional who can treat anaphylaxis.
A more recent study demonstrated that ecallantide can be safely used to treat multiple episodes of HAE. The trial involved 147 patients who received treatment for 625 HAE episodes. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on the number of episodes treated. The primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Results showed no reduction of efficacy with repeated use of ecallantide. In addition, no new safety signals were detected.
In 2010, Cicardi et al reported significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide compared with placebo. This was a double-blind, placebo-controlled trial in 71 patients.
Icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved by the US Food and Drug Administration for treatment of acute attacks HAE in adults. Approval was based on 3 double-blind, randomized, controlled clinical trials known as For Angioedema Subcutaneous Treatment (FAST) 1, 2, and 3.[9, 10]
FAST 3 was a placebo-controlled study of 98 adult patients with a median age of 36 years. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), composed of averaged assessments of skin swelling, skin pain, and abdominal pain. The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with icatibant (n=43) compared with placebo (n=45) was 2 hours (95% confidence interval [CI], 1.5, 3.0) versus 19.8 hours (95% CI, 6.1, 26.3), respectively (P < .001). The median times to almost complete symptom relief were 8 versus 36 hours for icatibant and placebo, respectively. Additional rescue medications were used by 3 patients (7%) treated with icatibant and 18 patients (40%) treated with placebo.
With all of these agents, the time to response is in part determined by the duration of the attack. The response is more rapid early in an attack. Response is also determined by attack severity and location, in that peripheral edema responds more slowly to treatment. The time to onset of response appears roughly similar with all of the agents and the average response is often noted in about an hour.
Prophylactic treatment is instituted if patients are afflicted with frequent and/or severe episodes.
Danazol may be used at doses that prevent attacks; normalizing the levels of C1-INH is not necessary. The most significant complication of long-term use may be arterial hypertension.
The 17-alpha-alkylated androgens rarely cause hepatotoxicity and liver tumors, but they should be used at the lowest effective dosage. Regular monitoring of liver function test results, lipid levels, and liver ultrasonography findings is recommended. Although virilization may be an issue with women, keeping to the lowest possible dose usually obviates this concern. Contraindications to the use of androgens include prostate cancer, pregnancy, childhood, and breastfeeding.
Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid can also be used for prophylaxis, although they have not been found to be as effective as the androgenic agents. These agents are the option for pregnant women.
Short-term prophylaxis for surgical procedures, especially dental work, is necessary. C1-INH infusions can be given 24 hours before the procedure or just prior to it. Alternatives, such as antifibrinolytics or androgens, can be used, and they should be started 5 days before the procedure and continued for 2 days afterwards. More reliably fresh frozen plasma (FFP) infusions can be given the day of surgery or the day before.[13, 19]
Treatment of Underlying Causes
Eradication of the underlying cause of the attack, such as Helicobacter pylori or another infectious agent, may lead to resolution of symptoms. Careful attention should be given to medications being taken by the patient that may have contributed to an attack, such as contraceptives, hormone replacement therapy, or angiotensin-converting enzyme (ACE) inhibitors.
Several protease inhibitors have been found to have functional overlap with C1-INH (eg, antithrombin III, beta-macroglobulin, alpha1-antitrypsin) and may be therapeutic options in the future.[19, 34, 35, 36]
Diet and Activity
No particular dietary restrictions are necessary. Activity is not limited with HAE, but it is prudent for patients to try to avoid activities such as camping that take them many hours away from possible emergency treatment.
Primary care physicians who are unfamiliar with HAE may want to consult an allergist/immunologist to aid with the diagnosis and management of these patients. Once the diagnosis of HAE is made, patients and their families may benefit from discussions with a genetic counselor.
A clinical guideline summary from the American Academy of Allergy, Asthma & Immunology, Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help, may be helpful.
Once recovery is achieved, proper referral for education and long-term management should be arranged. Anticipatory guidance with respect to oral surgery or any major procedure that will involve airway instrumentation should be stressed during follow-up care.
Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al. When is prophylaxis for hereditary angioedema necessary?. Ann Allergy Asthma Immunol. 2009 May. 102(5):366-72. [Medline].
Bankhead C. Another Drug for HAE Wins FDA Approval. MedPage Today. Jul 17 2014. [Full Text].
Riedl MA, Bernstein JA, Li H, Reshef A, Lumry W, Moldovan D, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014 Feb. 112(2):163-169.e1. [Medline].
Starr JC, Brasher GW, Rao A, Posey D. Erythema marginatum and hereditary angioedema. South Med J. 2004 Oct. 97(10):948-50. [Medline].
Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol. 2009 Jul. 124(1):129-34. [Medline].
Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. 2006 Jul. 81(7):958-72. [Medline].
US Food and Drug Administration (FDA). FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema. [Full Text].
Zuraw B, Yasothan U, Kirkpatrick P. Ecallantide. Nat Rev Drug Discov. 2010 Mar. 9(3):189-90. [Medline].
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):532-41. [Medline]. [Full Text].
Lumry WR, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. American Academy of Allergy, Asthma, & Immunology Meeting. March 22, 2011; Abstract L2.
Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):513-22. [Medline]. [Full Text].
Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996 Jun 20. 334(25):1630-4. [Medline].
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4. 359(10):1027-36. [Medline].
Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009 Feb. 15(2):69-78. [Medline].
Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006 Nov. 26(4):709-24. [Medline].
Davis AE 3rd. Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am. 2006 Nov. 26(4):633-51. [Medline].
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005 Mar. 139(3):379-94. [Medline]. [Full Text].
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006 Mar. 119(3):267-74. [Medline].
Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976 May. 84(5):580-93. [Medline].
Nielsen EW, Gran JT, Straume B, Mellbye OJ, Johansen HT, Mollnes TE. Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses. J Intern Med. 1996 Feb. 239(2):119-30. [Medline].
Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH. Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest. 1971 Oct. 50(10):2143-9. [Medline]. [Full Text].
Kreuz W, Martinez-Saguer I, Aygören-Pürsün E, Rusicke E, Heller C, Klingebiel T. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion. 2009 Sep. 49(9):1987-95. [Medline].
Sachse MM, Khachemoune A, Guldbakke KK, Kirschfink M. Hereditary angioedema. J Drugs Dermatol. 2006 Oct. 5(9):848-52. [Medline].
Caballero T, Farkas H, Bouillet L, Bowen T, Gompel A, Fagerberg C, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012 Feb. 129(2):308-20. [Medline].
Craig T et al. WAO Guideline for the Management of Hereditary Angioedema. Available at http://ainotes.wikispaces.com/file/view/WAO+Guideline+for+the+Management+of+HAE+-+2012.pdf. Accessed: February 8, 2013.
Morgan BP. Hereditary angioedema--therapies old and new. N Engl J Med. 2010 Aug 5. 363(6):581-3. [Medline].
US Food and Drug Administration. Advisory Committee Briefing Document:Kalbitor (ecallantide)For Acute Attacks of Hereditary Angioedema. [Full Text].
Lumry WR, Bernstein JA, Li HH, Macginnitie AJ, Riedl M, Soteres DF, et al. Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: Open-label continuation study. Allergy Asthma Proc. 2013 Mar. 34(2):155-61. [Medline].
Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):523-31. [Medline].
Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol. 1997 Feb. 99(2):194-6. [Medline].
Krause K, Metz M, Zuberbier T, Maurer M, Magerl M. Successful treatment of hereditary angioedema with bradykinin B2-receptor antagonist icatibant. J Dtsch Dermatol Ges. 2010 Apr. 8(4):272-4. [Medline].
Bouillet L, Boccon-Gibod I, Ponard D, Drouet C, Cesbron JY, Dumestre-Perard C, et al. Bradykinin receptor 2 antagonist (icatibant) for hereditary angioedema type III attacks. Ann Allergy Asthma Immunol. 2009 Nov. 103(5):448. [Medline].
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):532-41. [Medline].
Bracho FA. Hereditary angioedema. Curr Opin Hematol. 2005 Nov. 12(6):493-8. [Medline].
Zuraw BL. Current and future therapy for hereditary angioedema. Clin Immunol. 2005 Jan. 114(1):10-6. [Medline].
Zuraw BL. Novel therapies for hereditary angioedema. Immunol Allergy Clin North Am. 2006 Nov. 26(4):691-708. [Medline].
American Academy of Allergy, Asthma & Immunology. Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help. J Allergy Clin Immunol. 2006 Feb. 117(2 Suppl Consultation):S495-523. [Medline].
Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004 Sep. 114(3 Suppl):S51-131. [Medline].
Bork K, Witzke G. Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol. 1989 Mar. 83(3):677-82. [Medline].
Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol. 1991 Apr. 87(4):768-73. [Medline].
Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med. 1976 Dec 23. 295(26):1444-8. [Medline].
Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol. 1981 Sep. 68(3):181-7. [Medline].
A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3). [Full Text].
Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000 Jul 15. 356(9225):213-7. [Medline].
EASSI - Evaluation of the Safety of Self-Administration With Icatibant. [Full Text].
Johnson K. Real-world use of icatibant improves angioedema. Medscape Medical News. November 12, 2013. [Full Text].
Leiden, The Netherlands. Biotech company Pharming Group NV ("Pharming" or "the Company") (NYSE Euronext: PHARM) today announces that, in agreement with the European Medicines Agency (EMEA), the dossier for the European Marketing Authorisation Application (MAA) of Rhucin(R) will be submitted in September 2009. [Full Text].
Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011 Dec. 107(6):529-37. [Medline].
Maurer M, Aberer W, Bouillet L, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One. 2013. 8(2):e53773. [Medline]. [Full Text].
Riedl M, Longhurst H, Fabien V, Lumry WR, Maurer M. Icatibant for the treatment of non-laryngeal hereditary angioedema attacks: comparison of outcomes from a controlled phase III trial and a real-world setting (abstract P85). Presented at: The American College of Allergy, Asthma & Immunology (ACAAI) 2013 Annual Scientific Meeting; November 9, 2013; Baltimore, Maryland.