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% |