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Supplements Hereditary Angioedema: Facilitating Diagnosis and Optimizing Clinical and Economic Outcomes [CPE/CME

Management and Prevention of Hereditary Angioedema Attacks

William R. Lumry, MD
Hereditary angioedema (HAE) is a rare genetic syndrome caused by a deficiency in functional C1 inhibitor that results in recurrent episodes of nonpruritic swelling of the hands, feet, arms, legs, trunk, face, genitalia, bowels, and larynx beginning in childhood or adolescence and continuing throughout the patient’s lifetime. Treatment for acute HAE attacks in the United States has been transformed by new therapies that inhibit the underlying mechanisms of angioedema—notably ecallantide, a potent and specific inhibitor of plasma kallikrein, and icatibant, a selective bradykinin receptor antagonist. These treatments, combined with safer formulations of plasma-derived C1 esterase inhibitor concentrate for HAE prophylaxis and acute treatment, have greatly improved the quality of life for people with HAE, many of whom can now lead fairly normal lives. This article reviews the current therapeutic landscape for HAE, including treatment for acute angioedema attacks, short- and long-term HAE prophylaxis, and home-based therapy.

(Am J Manag Care. 2013;19:S111-S118)
Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder caused by a deficiency of C1 inhibitor that results in recurrent episodes of nonpruritic subcutaneous and mucosal swellings usually localized to the extremities, face, bowels, genitalia, or upper respiratory tract.1,2 Attacks follow a fairly predictable clinical course—symptoms gradually worsen over the first 24 hours, then subside—but may vary considerably in frequency and severity.1,2 Abdominal attacks may be accompanied by severe pain, nausea, and vomiting.1,2 Laryngeal edema, though relatively rare compared with abdominal and skin swellings, is the most clinically significant manifestation of HAE; death may result from airway obstruction and asphyxiation.3,4 The rarity of HAE—an estimated 1 in 50,000 individuals are affected (range: 1 in 10,000–1 in 150,000)5—and the fact that symptoms can mimic a variety of other conditions means that diagnosis often lags behind the first appearance of symptoms by a few years to a decade or more.6,7 The differential diagnosis of HAE is particularly challenging for physicians in the primary care setting who may have limited awareness of the disease and minimal exposure to patients with HAE. Further, the pattern of HAE management in the United States differs from that in several European countries and Canada, where patients are generally referred to specialized treatment centers; in the United States, by contrast, people with HAE receive treatment in more diverse settings, including group and solo physician practices.8

Once an HAE diagnosis is confirmed, the patient should be referred to a specialist experienced in the management of the disorder, and a treatment plan should be created and individualized for the patient’s medical situation and preferences.4 The goal of effective HAE management is to restore a normal quality of life for the patient.4 While this would have been largely unthinkable (and unattainable) just a decade ago, there has been tremendous progress in the treatment and prevention of HAE attacks in recent years, with several effective HAE therapies now available.9 The following sections review the current treatment options for HAE, side effects of therapy, and issues related to the treatment of special patient populations.

Treatment of HAE

Contemporary medical management of HAE is divided between treatment of swelling attacks, short-term prophylaxis to avoid attacks during times of increased risk (eg, after medical or dental procedures), and long-term prophylaxis to reduce both the frequency and severity of attacks.1,7

Management of Acute Attacks.

Purified C1 Esterase Inhibitor. Purified, plasma-derived C1 inhibitor (C1INH) has been the standard of care for management of acute HAE attacks in Europe for several decades.2,10 In the United States, concerns about the potential for virus transmission and a lack of prospective, randomized clinical studies meant that C1INH replacement therapy was unavailable until quite recently.2,9 In October 2009, the US Food and Drug Administration (FDA) approved a purified, pasteurized esterase C1INH concentrate (Berinert) for the treatment of adults and adolescents experiencing acute episodes of abdominal, facial, or laryngeal edema associated with HAE.10,11 The efficacy of Berinert was established in the randomized, double-blind, placebo-controlled clinical study, IMPACT (International Multicenter Prospective Angioedema C1-INH Trial) 1, conducted in 125 patients with type I or II HAE.12 Study participants were randomly assigned to receive Berinert (10 or 20 U/kg) or placebo for single attacks of acute abdominal or facial edema.12 Patients who received Berinert at the 20-U/kg dose had a significantly shorter time to onset of symptom relief compared with placebo (0.5 vs 1.5 hours; P = .0025); those who received the 10 U/kg dose had only slight improvement that did not reach statistical significance.12 The FDA-approved dose of Berinert is therefore 20 U/kg of body weight.11

Subsequently, a prospective, nonrandomized, open-label extension study (IMPACT-2) evaluated Berinert for treating HAE attacks affecting any body site.13 During a median follow-up of 24 months, 57 patients experiencing a total of 1085 attacks were treated with single infusions of Berinert 20 U/kg.13 The median time to onset of symptom relief was 0.46 hours, while the median time to complete resolution of HAE symptoms was 15.5 hours.13 Sixteen patients (28.1%) experienced 48 episodes of laryngeal edema, with a median time to onset of symptom relief of 0.25 hours (0.10-1.25 hours).13 No patients treated with Berinert for laryngeal attacks required intubation, emergency procedures, or additional medication. Adverse events, reported in 25 patients (43.9%), were generally mild or moderate; 1 patient dropped out of the study due to an infusion-related reaction.13 In January 2012, the FDA granted a label expansion for Berinert to include treatment of laryngeal attacks and intravenous self-administration by properly trained patients.14

Cinryze, a pasteurized, nanofiltered C1INH formulation, has been approved for HAE prophylaxis since 2008.15 A randomized, double-blind, placebo-controlled trial demonstrated efficacy of this agent for treatment of attacks, although it is approved for this indication only in Europe.16 A total of 68 patients (35 in the C1INH group and 33 in the placebo group) were given 1 or 2 intravenous injections (1000 units each) of Cinryze or placebo within 4 hours of onset of an attack (laryngeal attacks were excluded).16 The median time to onset of unequivocal symptom relief, the study’s primary end point, was more than halved in the Cinryze arm compared with placebo (2 hours vs more than 4 hours; P = .02).16 In an open-label extension part of the trial, the median time to response was 30 minutes among 82 patients who experienced 447 separate attacks.16

Ecallantide (Kalbitor). Ecallantide is a potent and specific inhibitor of plasma kallikrein, a contact system protease that cleaves kininogen, a high–molecular-weight protein, to release bradykinin (see Figure 1).1 Bradykinin is the primary mediator of angioedema in HAE through its binding to the bradykinin B2 receptor on the surface of vascular endothelial cells.17,18 In December 2009, the FDA approved ecallantide for the treatment of HAE attacks in patients 16 years or older based on results from 2 randomized, double-blind, placebo-controlled phase 3 trials (EDEMA3 and EDEMA4) conducted in 168 patients with HAE.19,20

In EDEMA3, 72 individuals with HAE who presented with an acute swelling attack were randomized to receive ecallantide 30 mg administered subcutaneously or placebo.21 Patients in the ecallantide group had significantly greater improvements versus placebo in 2 patient-reported symptom severity and outcome measurements—the treatment outcome score (P = .004) and the mean symptom complex severity score (P = .01)—at 4 hours posttreatment.21 The estimated time to significant improvement was 165 minutes versus 240 minutes in the ecallantide and placebo groups, respectively (P = .14).21 In EDEMA4, 96 patients with acute HAE attacks were randomized to treatment with ecallantide (30 mg) or placebo.22 As in EDEMA3, ecallantide-treated patients in EDEMA4 had significant improvement in both treatment outcome (P =.003) and symptom severity scores (P = .01) versus placebo at 4 hours after dosing.22

The most common adverse events associated with ecallantide therapy were headache, nausea, diarrhea, pyrexia, injection-site reactions, and nasopharyngitis.19,23 In the EDEMA trials, 3 patients in the ecallantide group experienced injection-site reactions versus 1 patient in the placebo group.23 The rate of seroconversion to both anti-ecallantide antibodies and to neutralizing antibodies was 1.6%; while seroconversion did not appear to affect the efficacy or safety of ecallantide, the sample size was too small to be conclusive.23 Additionally, the ecallantide package insert contains a boxed warning for the potential for anaphylaxis. Among 255 patients treated in the ecallantide clinical studies, 10 (3.9%) experienced anaphylaxis; for the 187-patient subgroup that received subcutaneous ecallantide, anaphylaxis was reported in 5 patients (2.7%).19 For this reason, ecallantide should be administered by a healthcare professional trained in recognition and treatment of hypersensitivity reactions, and is not recommended for self-administration.

Icatibant (Firazyr). Icatibant, a selective bradykinin B2 receptor antagonist, is indicated for the treatment of HAE attacks in patients at least 18 years of age.24 Three randomized, controlled clinical trials (For Angioedema Subcutaneous Treatment [FAST]-1-3) involving a total of 223 patients with HAE evaluated icatibant (30-mg subcutaneous injection) for the treatment of cutaneous, abdominal, or mild-to-moderate laryngeal attacks (patients with severe laryngeal attacks received open-label icatibant).24,25 Icatibant was compared with placebo in FAST-1 and FAST-3, and with tranexamic acid, an oral antifibrinolytic agent, in FAST-2.25,26

In FAST-3, icatibant-treated patients (n = 43) had significant improvement in 3 main outcome measures compared with placebo (n = 45): time to at least a 50% reduction in symptom severity (2.0 vs 19.8 hours; P <.001, primary end point); onset of symptom relief (1.5 versus 18.5 hours; P <.001); and time to almost complete symptom relief (8.0 versus 36 hours; P = .012).26 Median time to onset of symptom relief was 2.5 hours for icatibant versus 4.6 hours for placebo (P = .14) in FAST-1, and 2 hours for icatibant versus 12 hours for tranexamic acid (P <.001) in FAST-2.25 The median time to nearly total symptom relief was 8.5 hours for icatibant and 19.4 hours for placebo (P = .08), and 10 hours for icatibant versus 51 hours for tranexamic acid (P <.001) in FAST-1 and FAST-2, respectively.25 No icatibant-treated patients in the FAST1-3 trials with nonlaryngeal symptoms required rescue medication.25,26

Ten patients in the intent-to-treat population in FAST- 3 received icatibant for laryngeal attacks: 5 patients with mild-to-moderate attacks (3 icatibant, 2 placebo) and 5 with severe attacks (open-label icatibant).26 The median time to onset of symptom relief was 2.5 hours in patients treated with double-blind icatibant, and 2.3 hours for those treated with open-label icatibant.26 Of the 2 patients in the laryngeal attack group randomized to placebo, 1 received icatibant as rescue medication 3.4 hours after receiving placebo, while the other patient had severe laryngeal symptoms and received open-label icatibant before placebo was administered.26 In a post hoc analysis of 21 icatibant-treated patients in FAST-3 who experienced laryngeal edema as their first attack, the median time to at least 50% symptom relief was 2 hours.26

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