Present work Weisman, 2020 Pfaue, 2019 Sinert, 2017 Sinert, 2017 Straka, 2016 Straka, 2016 Javaud, 2015 Bova, 2015 Bas, 2015 Bas, 2015 Roberts, 2012 Sanchez Borges, 2010 Bas, 2010 Bas, 2010 Banerji, 2008 Grant, 2007 Malde, 2007 Bas, 2005 Circadi, 2004 Chiu, 2001 Agostoni, 1999
Sample size 30 297 84 60 (placebo) 61 (icatibant) 18 (placebo) 12 (icatibant) 62 13 14 (placebo group) 13 (icatibant group) 91 9 47 (historical cohort) 8 (icatibant) 220 228 64 25 64 74 39
Study design retrospective retrospective retrospective prospective prospective prospective prospective prospective retrospective prospective prospective retrospective retrospective retrospective retrospective retrospective retrospective retrospective retrospective retrospective retrospective retrospective
case control case control descriptive randomized controlled trial (icatibant vs placebo in ACEi-AE) randomized controlled trial (icatibant vs placebo in ACEi-AE) randomized controlled trial (icatibant vs placebo in ACEi-AE) randomized controlled trial (icatibant vs placebo in ACEi-AE) observational case control randomized controlled trial (icatibant vs placebo in ACEi-AE) randomized controlled trial (icatibant vs placebo in ACEi-AE) descriptive descriptive case control case control descriptive descriptive descriptive case control descriptive case control case control
monocenter multicenter monocenter multicenter multicenter multicenter multicenter multicenter monocenter multicenter multicenter multicenter monocenter monocenter monocenter multicenter monocenter monocenter monocenter monocenter multicenter monocenter
Study period 6 years 4 years 6 years 2 years 2 years 8 years 8 years 2,5 years not mentioned 18 months 18 months 1 year 5 years 7 years not mentioned 2 years 4,5 years 13,5 years 16 years 10,5 years 7 years 6,5 years
2014-2019 2013-2017 2010-2016 2013-2015 2013-2015 2007-2015 2007-2015 2012-2014 2010-2011 2010-2011 2010-2011 2005-2009 2003-2005 1999-2004 1991-2004 1997-2003 1993-2002 1993-1999 1992-1998
ACEi-AE definition no urticaria no C1-INH deficiency no attacks before introduction no recurrence after discontinuation not mentioned no urticaria or pruritus no evidence of allergy no family history of AE no other cause of AE (hereditary, acquired, allergic) no family history of AE no attacks before ACEi introduction no urticaria inefficacy of standard therapy no other cause of AE (hereditary, acquired, allergic) no family history of AE no attacks before ACEi introduction no urticaria inefficacy of standard therapy no urticaria or pruritus no attacks before ACEi introduction no urticaria or pruritus no attacks before ACEi introduction no other cause according to AE expert (no rash, no family history of AE, no C1-INH deficiency, inefficacy of standard therapy) no other cause (food allergy, insect bite, drugs, infectious disease, C1-INH deficiency, inefficacy of standard therapy) based on expert opinion (exclusion of patients with urticaria or with attacks before ACEi introduction) based on expert opinion (exclusion of patients with urticaria or with attacks before ACEi introduction) not mentioned not mentioned no other cause (C1-INH deficiency, allergy, urticaria) no recurrence after discontinuation no other cause (C1-INH deficiency, allergy, urticaria) no recurrence after discontinuation based on investigators’ opinion ICD-10 code of AE exclusion of AE from ”unrelated causes” based on drug adverse reaction database not mentioned (exclusion of allergic reactions) no other cause according to AE expert (no personal or family history of allergy, no other causative agent, no C1-INH deficiency) 16% had attacks before ACEi introduction and 13% after ACEi discontinuation diagnosis code of AE no other likely cause (traumat, food allergy, medications) based on expert opinion
Inclusion criteria ACEi-AE referred to AE consult ACEI-AE admitted to ED first attack of RAA-AE referred to ORL departement ACEI-AE admitted to ED ACEI-AE admitted to ED ACEI-AE admitted to ED ACEI-AE admitted to ED ACEI-AE admitted to ED ACEi-AE admitted to ED and treated with icatibant ACEI-AE admitted to ED ACEI-AE admitted to ED ACEI-AE admitted to ED ACEi-AE referred to allergy department ACEI-AE admitted to ED ACEI-AE admitted to ED ACEI-AE admitted to ED ACEI-AE admitted to ED RAA-AE according to drug adverse reaction database ACEI-AE admitted to ED ACEi-AE referred to AE clinic ACEI-AE admitted to ED ACEi-AE referred to AE clinic
Patient characteristics
Male 63% 43% 52% 42% 56% 33% 42% 56% 77% 57% 69% 45% 78% 63% 38% 35%% 40% 32% 56% 26% 54%
Age at baseline visit median 64 yo (IQR 17) mean 62,8 yo (SD 13,2) median 71 yo (range 43-94) mean 61.8 yo (SD 13.4) mean 60.9 yo (SD 12.1) mean 60.7 yo (SD 10.8) mean 56.3 yo (SD 13.4) median 63 yo (IQR 54-74) median 74 yo (IQR 52-86) mean 69.4 yo (SD 16.6) mean 62.4 yo (SD 9.7) median 56 yo (range 26-93) mean 63,4 yo (range 51-77) mean 62 yo (SD 11) range 61-91 yo mean 60 yo (SD 14) mean 61.6 yo (range 22-101) median 59 yo (range 32-92) mean 69,3 yo (SD 2,3) median 63 yo (range 46-84) median 61 yo (range 40-82)
Follow-up median 21 mo (IQR 37) none none 3 day after discharge 3 day after discharge mean 4.36 (SD 2.19) y mean 4.36 (SD 2.19) y median 18 yo (IQR 11-30) 1 visit (exact delay not mentioned) 1 visit 14d after discharge 1 visit 14d after discharge none none mean 4.3 y 3 to 6 months none yes (exact duration not mentioned) yes (exact duration not mentioned) median 11 mo (range 1-80) none yes (minimum 6 mo)
Personal history of allergy or atopic conditions 20% seasonal allergy 44% seasonal allergy 50% asthma, 11%; food allergy, 6%; allergic rhinitis, 4%; atopic dermatitis, 1% drug allergy 14% 0%
ACEi exposure
Therapeutic class(es)
- ACEi alone 83% 96% 80% 95% 100% 95% 92% 100%
- ACEi + ARBs 3% 4% 5% 0% 0% 0% 0%
- ACEi + DPP-4i 13% 2% 5% 0% 5% 8%
Duration of exposure median 23 mo (IQR 103) 59% exposed for > 12 mo 25% started within 90d of the attack 27% started within 90d of the attack mean 63 mo (SD 64) mean 26 mo (SD 28) median 12 mo (IQR 1-49) median 48 mo (range 7-240) range 30min-2y mean 37 mo (SD 25) range 12-132 mo mean 6 mo (range 1–18) median 3 mo (range 0-120) mean 1.8 y (range 1d-10y) mean 35.8 mo (SD 5.3) median 12 mo (range 0-156) median 6 mo (range 1d-8y)
Characteristics of AE attack - onset
Previous attacks median 2 (IQR 2) 8% 0% 7% 0% 17% 34% (median 3 (IQR 1-3)) 77% (range 1-6) 36% 38% none for most patients 8% (1 or 2) 0% some patients
Preferential attack onsent in evenings and night 25% 60% outside regular working hours
Characteristics of AE attack - plateau
Affected sites
- Lips 50% 67% 83% 50% 38% 29% 23% 25% 44% 70% 54% 32%
- Tongue 47% 61% 45% 44% 85% 71% 62% 28% 55% 50% 52% anterior 40%; base 11% 20% 39% 46%
- Uvula 10% 5% 5% 8%
- Oral cavity (excluding lips, tongue and uvula) 23% 75% eyelids 17% eyelids 25% 42% 8% 64% 46% 22% 13% 13%
- Throat (pharynx, larynx) 30% 40% 24% 54% pharynx 36%; larynx 50% pharynx 31%; larynx 46% 22% 50% 59% pharynx 9%; larynx 4% 13%
- Face (excluding lips) 10% 27% 50% 58% 22% 23% cheeks 14%; face 21% cheeks 23%; face 23% 22% cheeks 20%; eyes 10% 19% 86% 85%
Urticaria 0% 4% 5% 3%
Dyspnea and/or dyspnhonia 33% 4% dyspnea 89%; dysphonia 29% dyspnea 9% 54%
Characteristics of AE attack - resolution
Duration of attacks without treatment median 24 (IQR 42) hr onset of attack to study drug : median 7.9 (IQR 5.5-9.7) hr study drug to onset of symptom relief: median 1.6 (IQR 0.5-3.9) hr study drug to discharge criteria: median 4.0 (IQR 1.0-6.0) hr onset of attack to study drug : median 7.8 (IQR 5.6-9.4) hr study drug to onset of symptom relief: median 2.0 (IQR 0.6-3.1) hr study drug to discharge criteria: median 4.0 (IQR 2.0-6.0) hr onset of attack-onset of relief: median 11 (IQR 7-40) hr onset of attack-complete resolution: median 54 (IQR 33-63) hr onset of attack-onset of relief: median 7.9 (95%CI 1.2-11.8) hr onset of attack-complete resolution: median 27.1 (IQR 20.3-48.0) hr onset of attack-onset of relief: median 2.0 (95%CI 2.0-6.3) hr onset of attack-complete resolution: median 8.0 (IQR 3.0-16.0) hr onset of attack-complete resolution: mean 33 (SD 19.4) hr onset of attack-complete resolution: mean 4,4 (SD 0.8) hr 39% improved in <4h from admission median 12 hr (range 2-146) (treatment not mentioned)
Treatments of attacks
Antihistamines 60% 93% 85% 88% 85% 89% 92% 70% 77% 100% 0% 100% 100% 73% 89% 98% 100% ?
Corticosteroids 60% 96% 85% 85% 80% 89% 92% 56% 100% 100% 0% 100% 100% 75% 89% 98% 100% ?
Adrenalin 10% 21% 85% 18% 26% 17% 0% 8% 54% 10% 14% 100% ?
Tranexamic acid 30%
Icatibant 63% 13% 66% 100% 21% (rescue therapy) 100% 0% 100%
C1-INH concentrate 13% 0% 100% 27%
Upper airway control procedures 0% 26% 11% 0% 2% 6% 17% 2% 0% 7% 0% 4% 11% 10% 0% 7% 10% 3% 4% 2% 15% 3%