Hereditary Angioedema Treatment & Management

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 ^[14] or kallikrein inhibitor or, if those are unavailable, fresh-frozen plasma. In HAE with normal C1 inhibitor levels, infusion of C1-INH has proven to be ineffective. ^{[24, 25]}

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. ^[26] 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) ^[27] :

• 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. ^[28] 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. ^[11]

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. ^[5] 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. ^[8] Two randomized, double-blind, placebo-controlled trails, EDEMA4 and EDEMA3, established the safety and efficacy of ecallantide. ^[29] 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. ^[8]

A more recent study demonstrated that ecallantide can be safely used to treat multiple episodes of HAE. ^[30] 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. ^[30]

In 2010, Cicardi et al reported significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide compared with placebo. ^[31] 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. ^[10]

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. ^[32]

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.

C1-INH products that are approved for prophylaxis include Cinryze (IV administration) and Haegarda (SC administration). In June 2017, the FDA approved the first subcutaneous C1 esterase inhibitor (Haegarda) for prevention of HAE attacks in patients aged 12-72 years. Approval was based on the phase 3 COMPACT trial (n=90), which showed C1-INH 60 IU twice weekly SC reduced the median number of HAE attacks by 90% compared with placebo. The study also showed use of rescue medication was reduced by >99% versus placebo. ^[12]

In August 2018, the FDA approved lanadelumab, a monoclonal antibody that targets kallikrein, for prophylaxis of HAE. Approval was based on the HELP clinical trial, which investigated the efficacy and safety of lanadelumab for long-term prophylaxis against angioedema attacks in HAE. Of 125 patients, 113 completed the trial. All lanadelumab dosing regimens significantly reduced the mean monthly attack rates of HAE compared to placebo (P < 0.001) over the 26-week duration of the study. The 300 mg SC every 2 week regimen reduced attacks by 92.8% from baseline in patient with < 2 attacks per month and by 88.2% in patients whose baseline was 2 to < 3 attacks per month. ^[13]  Lanadelumab has since been approved for children aged 2 years and older with lower doses. ^[33]  

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. ^{[15, 21]}

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. ^{[21, 34, 35, 36]}

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. ^[37]

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.