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^[1] or kallikrein inhibitor or, if those are unavailable, fresh-frozen plasma. In HAE type III, infusion of C1-INH has proven to be ineffective.^{[16, 17]}

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.^[18] 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.

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.^[19] 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.^[20] 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.^[20]

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.^[21] In January 2012, an additional indication for laryngeal angioedema was approved by the FDA. 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.^[22] Two randomized, double-blind, placebo-controlled trails, EDEMA4 and EDEMA3, established the safety and efficacy of ecallantide.^[23] 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.^[22]

In 2010, Cicardi et al reported significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide compared with placebo.^[24] 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.^{[25, 26]}

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.^[26]

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.^[27]

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.^{[2, 12]}

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.

Rhucin, a recombinant human C1-INH produced by Pharming (Leiden, The Netherlands), is available in Europe but not approved by FDA.^[28] Icatibant (Firazyr), a bradykinin B2 receptor antagonist produced by Jerini (Berlin, Germany), blocks the effects of bradykinin. This drug received a nonapprovable letter from the FDA in April 2008.

Two phase III clinical trials, EASSI and FAST-3, are enrolling patients in the United States to determine the efficacy, safety, and tolerability of icatibant.^{[29, 30]} The drug is currently available in Europe only and case reports of icatibant use have recently been published.^[10]

In Germany, 5 patients with HAE were treated with a single dose of icatibant, 30 mg, administered subcutaneously during acute attacks; significant improvement was seen and only minor adverse effects were reported. Two of these patients were experiencing abdominal attacks, and 3 were experiencing angioedema of the extremities and/or face.^[31]

In France, 3 patients were similarly treated with a subcutaneous dose of icatibant, 30 mg, with resolution of symptoms. One patient required a second dose 6 hours later. The major adverse effect reported was reaction at the injection site.^[32]

A study by Cicardi et al reported a significant benefit of icatibant when used for acute HAE attacks compared with tranexamic acid in one trial. A second trial comparing icatibant with placebo did not show a significant difference, although the early use of rescue medication may have obscured the benefit of icatibant.^[33]

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.^{[34, 12, 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.