Preventive Treatment of Hereditary Angioedema: A Review of Phase III Clinical Trial Data for Subcutaneous C1 Inhibitor and Relevance for Patient Management.

PURPOSE: Hereditary angioedema (HAE), most often caused by a genetically mediated deficiency in the activity of C1 inhibitor (C1INH) protein, is characterized clinically by recurrent episodes of localized swelling without wheals. HAE attacks can be painful, debilitating, and even fatal, resulting in physical discomfort, emotional stress, and interruptions of work, school, and/or social activities, all of which can affect health-related quality of life (HRQoL). Subcutaneous C1INH (C1INH[SC]) is recommended as a first-line option for long-term prophylaxis (LTP) in HAE. This narrative review provides a concise but comprehensive overview of all published data generated from the pivotal Phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) study program, which evaluated the use of C1INH(SC) as LTP. METHODS: A PubMed search was performed using the search terms subcutaneous C1 inhibitor plus COMPACT with no filters, and another search was performed using the term subcutaneous C1 inhibitor, with output limited to clinical trial data only. All publications that reported data generated during the Phase III COMPACT study were included. Data presentation focused on the US Food and Drug Administration-approved dose of 60 IU/kg. FINDINGS: The search strategy identified a total of 11 publications that reported data and analyses from the Phase III COMPACT study. Publications reported overall findings from the double-blind, placebo-controlled, crossover COMPACT study and a subsequent long-term open-label extension (OLE) study. Other published analyses included pharmacokinetic/pharmacodynamic data, HRQoL assessments, and findings in patient subgroups including women, pediatric patients, and patients ≥65 years of age. Subgroup analyses reported good safety and efficacy profiles among age-based subgroups from the COMPACT OLE, including pediatric patients, patients ≥65 years of age with comorbidities, and among female patients, despite a tendency for HAE to be more severe in women. A number of significant HRQoL improvements were noted with C1INH(SC) use, including better overall health status, less anxiety, and less work- and activity-related impairment versus placebo (double-blind study), and compared with baseline (OLE). IMPLICATIONS: This review provides a concise overview of all published COMPACT study data with C1INH(SC). The data reviewed here portray a high level of efficacy and tolerability with C1INH(SC), even during periods of treatment that exceed 2 years, which does not appear to vary based on patient age or sex. Clinically relevant improvements in multiple facets of HRQoL were also reported, including better overall HRQoL, less anxiety and depression, and less disruptions in work attendance and productivity. These data should be useful for assessing the appropriateness of C1INH(SC) therapy for individual patients.

Recognition and Differential Diagnosis of Hereditary Angioedema in the Emergency Department.

BACKGROUND: Angioedema (AE) is a clinical syndrome marked by localized swelling of the subcutaneous layer of the skin or the submucosal layer of the respiratory or gastrointestinal tracts. While AE is commonly mediated by histamine (allergic AE), some types result from excessive bradykinin activity, including hereditary AE (HAE), acquired AE, and angiotensin-converting enzyme inhibitor-induced AE. These are less common but important to consider given different treatment requirements and potentially serious outcomes, including death from laryngeal swelling. OBJECTIVE: This review describes the pathophysiology and clinical features of AE as well as the diagnosis and treatment of AE in the emergency department (ED). DISCUSSION: Bradykinin-mediated AE does not respond to antihistamines and corticosteroids. By contrast, several targeted, effective therapies are available, including C1-inhibitor (C1-INH) concentrates, which replace the missing protein activity underlying some bradykinin-mediated AE, and medications that directly lessen bradykinin activity (eg, ecallantide and icatibant). Urticaria is generally absent in bradykinin-mediated AE and serves as a primary differentiating factor in the clinical diagnosis. Relevant laboratory assessments may include C1-INH levels, C1-INH function, and C4 complement. Patients with HAE or a family member can communicate their known diagnosis when presenting to the ED, and some may even bring their own medication(s) with them. Patients newly diagnosed with HAE in the ED should be referred for specialized outpatient care upon ED discharge. CONCLUSIONS: There is a great need for ED clinicians to be aware of HAE, its differential diagnosis, and appropriate treatment to ensure that patients receive optimal and timely treatment.

Expert perspectives on hereditary angioedema: Key areas for advancements in care across the patient journey.

BACKGROUND: Published literature documents the substantial burden of hereditary angioedema (HAE) with C1 inhibitor deficiency on the quality of life and work productivity of patients. However, despite advances in the field and the availability of guidelines to advise health care providers (HCP) on the diagnosis and management of HAE, there are still many challenges to overcome. For example, delayed diagnosis and misdiagnosis are common, and treatment practices vary worldwide. OBJECTIVE: An international expert panel was convened to consider opportunities for improvements that would benefit patients with HAE. METHODS: Based on professional and personal experiences, the experts developed schematics to describe the journey of patients through the following stages: (1) onset of symptoms and initial evaluation; (2) referral/diagnosis; and (3) management of HAE. More importantly, the panel identified key areas in which it was possible to optimize the support provided to patients and HCPs along this journey. RESULTS: Overall, this approach highlighted the need for wider dissemination of algorithms and scientific data to more effectively educate HCPs from multiple disciplines and the need for more research to inform appropriate treatment decisions. Furthermore, HAE awareness campaigns, accurate online information, and referral to patient advocacy groups were all considered helpful approaches to support patients. CONCLUSION: More detailed and widespread information on the diagnosis and management of HAE is needed and may lead to advancements in care throughout the journey of the patient with HAE.