Which medications are used in the treatment of acquired angioedema (AAE) due to C1 inhibitor (C1-INH) deficiency (C1-INH-AAE)?

Updated: May 20, 2020
  • Author: Amanda T Moon, MD; Chief Editor: William D James, MD  more...
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The goals of pharmacotherapy for acquired angioedema are to reduce morbidity and to prevent complications. Medication may be used for acute or preventive treatment.

In Europe, purified C1 inhibitor (C1-INH) has been available for the treatment of acute attacks of angioedema in hereditary angioedema (HAE) patients for decades, and it is now available in the United States. In October 2008, the US Food and Drug Administration (FDA) approved the use of C1-INH (Cinryze) at a dose of 1000 units IV 2-3 times/wk for prophylaxis to prevent HAE attacks. In October 2009, the FDA approved C1-INH (Berinert) at a dose of 20 units/kg IV for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE. Berinert was also approved for acute treatment of laryngeal attacks in January 2012.

In acquired angioedema, therapy for acute attacks may also be aborted with C1-INH concentrates. [15, 16] In one study of 44 patients with C1-INH–deficient AAE, treatment with plasma-derived C1-INH concentrate consistently decreased the duration of attacks compared with nontreatment. [15] Although there is wide variability in the degree of responsiveness, the findings are true even when a patient has autoantibodies against C1-INH. Rapid catabolism of C1-INH occurs in acquired angioedema and may require higher doses of C1-INH plasma concentrate compared with HAE. If C1-INH concentrate is unavailable, fresh-frozen plasma can be used.

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 greater than 99% versus placebo. [17]

In December 2009, ecallantide (Kalbitor), a kallikrein inhibitor, at a dose of 30 mg SC was approved for the treatment of acute attacks.

In August 2011, icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved for treatment of acute attacks of HAE in adults at a dose of 30 mg SC in the abdominal area. It is highly effective in decreasing the duration of attacks of acquired angioedema and was reported to successfully treat 26 of 26 patients. [16]

Androgens, such as danazol, may be beneficial in acquired angioedema type I, with one study reporting effective treatment of 23 (75%) of 31 patients. [16] Androgens are of no value in acquired angioedema type II. Prostate cancer and pregnancy preclude the use of androgens.

Antifibrinolytics, such as epsilon-aminocaproic acid and tranexamic acid, have been found to be more effective for long-term prophylaxis in those with acquired angioedema, although tranexamic acid has moderate efficacy as an abortive as well. [16]

Immunosuppressive therapy directed toward decreasing autoantibody production may be of value in patients with acquired angioedema type II, which may be accomplished by the use of plasmapheresis with cyclophosphamide.

In 2004 and 2006, two papers reported effective treatment of acquired angioedema cases with a series of 4 weekly injections with rituximab (a chimeric monoclonal antibody to CD20). In one study, rituximab treatment resulted in normalization of C1-INH and C4 levels and long-term remission of angioedema attacks in 3 patients with severe acquired angioedema. [18] In the second study, a patient with acquired angioedema type II refractory to standard treatment experienced a 6-month attack-free interval after treatment with rituximab. [19] Several other reports have supported the efficacy of rituximab in achieving remission of acquired angioedema in patients with either an underlying B-cell lymphoproliferative disorder or autoimmune disease. [20, 21, 22, 23] A long-term study of 10 patients over 10 years showed that rituximab decreased the number of attacks and increased the amount of C1-INH in patients with C1-INH–deficient acquired angioedema. [24]

Another immunosuppressant drug, etanercept, was reported to control angioedema in a 57-year old man with psoriatic arthritis. This man was treated with 25 mg of etanercept administered subcutaneously twice per week for recalcitrant psoriatic arthritis. The treatment also resulted in improvement of the patient's angioedema. The authors hypothesized that etanercept may have improved the angioedema by decreasing inflammation and vascular permeability. [25]

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