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Disease Hereditary Angioedema HAE with normal C1-INH Function Acquired Angioedema Angiotensin Converting Enzyme Inhibitor-Induced Angioedema Idiopathic Angioedema Plasma-derived Nanofiltered C1-INH concentrate (C1INH) (Berinert/Cinryze) Successful treatment of acute episodes of angioedema with partly purified C1 inhibitor –used successfully in 5 patients Gadek et al (31) Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. C1-INH infusions effective in 6 women. Progestins and tranexamic acid were also used. Bork et al. (63) Acquired angioedema. Review of literature recommending efficacy of C1-INH, Icatibant or Ecallantide in AAE. Cicardi et al. (98) Use of C1-Inhibitor for ACE-I AE Decreases Mechanical Ventilation Time. Case report of efficacy and resolution of airway edema. Urnoski, et al. (85) Prophylactic treatment with plasma-derived C1-inhibitor in idiopathic non-histaminergic angioedema. Report of three cases of idiopathic nonhistaminergic receiving C1-INH infusions in literature and one additional case of a 11 year old child receiving C1-INH infusion. Gravante et al (21) A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. 22 patients treated with C1-INH improved twice as fast compared to 13 in placebo group. Kunschak et al. (32). Angioedema Related to AngiotensinConverting Enzyme inhibitor. Both Icatibant and C1-INH infusions decreased time to resolution. Javaud, et. Al. (86) Effect of C1-Esterase-inhibitor in angiotensinconverting enzyme inhibitor-induced angioedema. Less intubation and more rapid recovery in the C1-INH treated group (10 patients). Greve, et Al. (87) Treatment of hereditary angioedema with a vaporheated C1 inhibitor concentrate. 11 patients treated with more rapid resolution of angioedema. Waytes et al. (33) Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. More rapid relief of symptoms with C1-INH than with placebo in 125 patients. No seroconversion to HIV or hepatitis occurred with infusions. Craig et al. (34) ACE-I induced angioedema treated with complement C1-inhibitor concentrate. Case report of efficacy. Rasmussen et al. (88) Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema. 68 patients treated with C1-INH had resolution in 2 hours and placebo >4 hours. Zuraw et al. (35) Safety and efficacy of prophylactic nanofiltered C1inhibitor in hereditary angioedema. 146 subjects studied and 93% reduction in attacks with C1-INH. Zuraw et al. (36) Recombinant Human C1-INH (rC1INH) (Conestat alpha or Ruconest) 11 adult patients (with HAE or acquired AE) studied with rapid resolution but with quicker relapse of symptoms in some patients. Manson et al (9) Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency. Review of 10 clinical studies demonstrating drug efficacy. Moldovan et al. (39) Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency. Review of 10 clinical studies demonstrating drug efficacy. Moldovan et al. (39) 11 adult patients (with HAE or acquired AE) studied with rapid resolution but with quicker relapse of symptoms in some patients. Manson et al (9) NONE NONE Treatment of an acute attack of type III hereditary angioedema with ecallantide. Case report demonstrating efficacy. Cronin et al. (68) Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency. 12 episodes in 3 patients effectively treated. Patel et al. (10) Effectiveness of ecallantide in treating ACE-I induced angioedema in the emergency department. Triple-blind (patient, physician, and statistician), randomized, placebocontrolled, phase 2 study. 10% more patients on Ecallantide had early discharge from emergency room compared to placebo. Bernstein et al. (89) Idiopathic nonhistaminergic angioedema successfully treated with ecallantide, icatibant, and C1 esterase inhibitor replacement. Case report. Stahl et al. (22) Summary of 2 randomized trials comparing recombinant and purified C1-INH versus placebo showed active drug greatly decreased time to resolution of angioedema. Kawalec et al (41) Kallikrein inhibitor Ecallantide (Kalbitor) Management of acute attacks of hereditary angioedema: Review of two trials revealed safety and efficacy of ecallantide. Duffey et al. (91)A clinical trial of ecallantide, a novel kallikrein inhibitor. 49 participated in a dose escalation study. All doses tolerated, and symptoms greatly improved with ecallantide over placebo. Schneider et al. (25) EDEMA4 double blinded plaebo controlled study of 96 HAE patients. Symptom severity score improved with ecallantide. Levy et al. (43) Ecallantide for the Treatment of Acute Attacks in Hereditary Angioedema. (EDEMA3 trial). 71 patients treated and treatment group experienced greatly improved symptoms and outcomes compared to placebo. Cicardi, et. al. (44) Ecallantide for the Acute Treatment of Angiotensin-Converting Enzyme InhibitorInduced Angioedema: A Multicenter, Randomized, Controlled Trial. Multicenter, phase 2, double-blind study with subjects randomized to receive a single subcutaneous dose of ecallantide (10, 30, or 60 mg) or placebo plus physician-directed conventional therapy. Not much improvement with Ecallantide over placebo. Lewis et al. (90) Successful treatment of idiopathic angioedema with ecallantide. Case report. Berry et al. (23) Resolution of an acute attack of idiopathic angioedema with ecallantide. Case report. Dy et al. (24) Icatibant Bradykinin B2 receptor antagonist Icatibant (Firazyr) Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema. FAST-1 (56 patientsversus placebo) and FAST-2 (74 patients-versus tranexamic acid). Relief of angioedema symptoms faster with Icatibant. Cicardi et al. (25) Prophylactic use of icatibant before tracheal intubation of a patient with hereditary angioedema type III. Iturri et al. (62) Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3. Well-tolerated and effective in 88 episodes of laryngeal or cutaneous angioedema. Lumry et al. (26) Bradykinin receptor 2 antagonist for hereditary angioedema type III attacks. Case report showing efficacy. Bouillet et al. (63) Randomized placebo-controlled trial of the bradykinin B(2) receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Rapid and near complete resolution seen with Icatibant in 43 patients. Lumry et al. (27) Icatibant for HAE type III. Canadian Agency for Drugs and Technologies in Health. Summary document of published efficacy studies. (64) Rapid resolution of erythema marginatum after icatibant in acquired angioedema. Bygum et al. (11) Treatment of acquired angioedema with icatibant: Case report of efficacy Zanichelli et al. (12) Successful treatment of an acute attack of acquired angioedema with the bradykinin-B2-receptor antagonist icatibant. Case report of efficacy. Weller et al. (13) A randomized trial of Icatibant…Multicenter, double-blind, double-dummy, randomized phase 2 study. The time to complete resolution of edema was significantly shorter with icatibant than with combination therapy with a glucocorticoid and an antihistamine Bas, et. al. (91) Therapeutic efficacy of Icatibant in Angioedema Induced by ACEI: A Case Series. 8 patients with ACEI-induced angioedema treated with single dose of Icatibant. First symptom improvement after Icatibant injection occurred at a mean time of 50.6 minutes and complete relief of symptoms at 4.4 hours. Bas, et. al. (92) Treatment of ACE-I related angioedema with icatibant: a case series. 13 patients treated. Symptom relief was reported at 30 min. A complete resolution of symptoms was observed at 5 hours. Bova, et. Al. (93) Idiopathic nonhistaminergic angioedema successfully treated with ecallantide, icatibant, and C1 esterase inhibitor replacement. Case report. Stahl et al. (22) Successful treatment of a facial attack of angioedema with icatibant in a patient with idiopathic angioedema. Case report. Montinaro et al. (26) Nonhistaminergic idiopathic angioedema: clinical response to icatibant. Case report. Colas et al. (27) Treatment of idiopathic nonhistaminergic angioedema with bradykinin B2 receptor antagonist icatibant. Case report. Del et (28) Supplemental Table 1: Evidence supporting the use of specific therapies in non-histaminergic (bradykinin-mediated) forms of angioedema.