Download Treatment of angiotensin receptor blocker‐induced Angioedema: A

The Laryngoscope
C 2015 The American Laryngological,
V
Rhinological and Otological Society, Inc.
Treatment of Angiotensin Receptor Blocker-Induced
Angioedema: A Case Series
Ulrich Strassen, MD; Murat Bas, MD; Thomas K. Hoffmann, MD; Andreas Knopf, MD; Jens Greve, MD
Background: Angiotensin II receptor antagonists have been proposed as a replacement therapy after the occurrence of
either an angiotensin converting enzyme (ACE) inhibitor-induced angioedema or cough. However, recent studies indicate that
angioedema is associated with elevated bradykinin levels in a small fraction of patients treated with angiotensin-II-receptor
blockers, suggesting a common pathophysiological mechanism. To date, a standard treatment for angiotensin II receptor
blocker-induced angioedema does not exist.
Methods: We present a case series of patients admitted to our hospital due to angioedema induced by an angiotensin II
receptor blocker. The patients were either treated with either icatibant (n 5 3) or prednisolone-21-hydrogen succinate/clemastine (n 5 5). Both patient groups were compared with an untreated patient cohort (n 5 3). All patients were previously
diagnosed with essential hypertonia.
Results: Icatibant was an effective therapy for angiotensin II receptor blocker-induced angioedema. Full symptom recovery was achieved after 5 to 7 hours, whereas symptom remission occurred within 27 to 52 and 24 to 54 hours in patients
treated with Solu-Decortin prednisolone/clemastine and untreated patients, respectively. The recovery time for icatibant was
similar to that described in previous studies regarding the therapeutic efficacy of icatibant for the treatment of hereditary
angioedema and patients suffering from angiotensin converting enzyme inhibitor-induced angioedema.
Conclusions: Icatibant is a safe and effective substance for the treatment of angiotensin II receptor blocker–induced
angioedema. Although the pathophysiology of angiotensin II receptor blocker-induced angioedema remains unclear, it appears
to be associated with the bradykinin pathway.
Key Words: Angioedema, icatibant, B2 receptor antagonist, angiotensin receptor blocker , Quincke edema.
Level of Evidence: 4.
Laryngoscope, 125:1619–1623, 2015
INTRODUCTION
Up to 18% of patients treated with angiotensin converting enzyme inhibitors (ACEi) suffer from ACEiinduced cough,1,2 and approximately 0.1% to 0.7%3–5 of
patients present with angioedema of the head and neck
region. These so-called ACEi-induced angioedema (AE)
episodes account for approximately 25% to 38%6–8 of all
AE patients admitted to emergency departments.
From the Department of Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich (U.S., M.B., A.K), Munich; and the
Department of Oto–Rhino–Laryngology, Head and Neck Surgery, Ulm
University Medical Center (T.K.H., J.G.), Ulm, Germany.
Editor’s Note: This Manuscript was accepted for publication
December 19, 2014.
Ulrich Strassen, M.D., was an investigator in company-sponsored
scientific studies for CSL Behring, Shire, and ViroPharma GmbH; and
he received a travel grant from Shire and ViroPharma to present at a
scientific congress.
Jens Greve, M.D., and Murat Bas, M.D., were investigators in
company-sponsored scientific studies for Jerini AG, ViroPharma GmbH,
and BioAlliance Pharma SA; and they received a travel grant from Shire
and CSL Behring to present at a scientific congress. Both investigators
have presented at company-sponsored meetings for Shire and received
honoraria from CLS Behring, Shire, and ViroPharma GmbH.
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Send correspondence to Dr. Med, Ulrich Strassen, Department of
Otorhinolaryngology, Head and Neck Surgery, Technical University of
Munich, Ismaningerstr 22, 81675 Munich, Germany.
E-mail: [email protected]
DOI: 10.1002/lary.25163
Laryngoscope 125: July 2015
Reduced metabolism of bradykinin via ACE has been
suggested as the underlying cause of these side
effects.9,10 First-line therapy consists of replacing the
antihypertensive medication. The B2 receptor antagonist
icatibant (Firazyr, Shire, Lexington, MA) could be effective for the treatment of those attacks.11,12 Angiotensin
receptor blockers (ARB) are recommended as a secondline treatment in these cases13 because of their similar
ability to improve the long-term prognosis of patients
suffering from arterial hypertension and congestive
heart failure.
Although ACEi treatment is the most common
cause of angioedema, there are other important factors.
Recent case reports and reviews indicate that patients
receiving ARB therapy can also develop similar angioedema. Such AE cases have been reported after therapy
with candesartan,14 losartan,15,16 olmesartan17 and valsartan,18 and the patients were treated with different
dosages of corticosteroids, H1 and H2 antihistamines,
and epinephrine. These patients remitted between 24
hours19 and a few days16 after treatment. The localization of these AE cases is similar to that of ACEi-induced
AE. The cumulative incidence of ARB-induced AE per
1,000 persons is approximately 0.44 to 0.81 and appears
to be most prevalent in patients treated with valsartan.20 The incidence of ARB-induced AE in patients who
suffered from ACEi-induced AE is estimated to be
approximately 10%.13
Strassen et al.: Treatment of ARB-Induced Angioedema
1619
Although ACEi-induced AE is caused by the
decreased degradation of bradykinin via ACE and the
subsequent elevation of bradykinin levels, leading to AE
via the B2 receptor,21,22 other mechanisms have been
postulated to cause ARB-induced AE.10,23 Angiotensin II
(AT-II) receptor blockage causes a compensatory increase
in angiotensin II levels24 and binding to the AT-II receptor. Stimulation of endothelial AT-II receptors elevates
the concentration of bradykinin.25,26 Furthermore, the
fraction of angiotensin II binding to AT-II-receptors
increases when the AT-I receptor is blocked.27 Recent
publications demonstrate that bradykinin concentrations
are increased in patients treated with losartan.28 Therefore, the formation of bradykinin-induced AE is likely in
this patient group.
Direct binding of ARB to AT-II receptors might also
explain the existence of ARB-induced AE. Interestingly,
losartan can bind the B2-receptor and act as a partial
agonist.29
ACE- and ARB-induced AE are usually localized in
the upper aerodigestive tract, and they can lead to
severe upper airway obstruction, with the need for
either intubation or a tracheotomy; therefore, these conditions should be handled with extreme care despite
their rarity. The current treatment strategy of ARBinduced AE consists of glucocorticoids and antihistamines, although these drugs are largely ineffective.30
To date, causal therapeutic schemes have not been
developed.
The present study aimed to determine the therapeutic efficacy of different treatment strategies for ARBinduced angioedema.
AE symptomatology, after which they were admitted to our hospital until complete symptom remission.
The following data were recorded from patient files: time
between the onset of swelling; time to initial symptom relief;
and time between clinical onset and complete symptom relief,
as assessed by direct fiberoptic nasopharyngolaryngoscopy that
was performed until the complete remission of symptoms.
Complete symptom relief was defined as complete recovery
from all visual symptoms, as documented in the patient file,
and was associated with discharge of the patient from the hospital with no further drug treatment related to angioedema.
Patients were also questioned regarding side effects,
including the relapse and recurrence of swelling in either the
same or a different location at the time of discharge and 3
months thereafter.
RESULTS
The clinical data for all patients are listed in Table
I. Photo documentation of one patient upon presentation
in the emergency department (a) and after complete
symptom remission (b) is provided in Figure 1.
Untreated Patients
All three patients experienced angioedema of the
tongue. Of these, one patient presented an additional
AE of the ary region, one presented an additional AE of
the mouth floor, and one experienced an AE of the
supraglottic endolarynx. Patients were taking irbesartan, candesartan, and losartan at 30, 8, and 50 mg,
respectively. The mean time interval to complete symptom relief was 38 hours (range 24–54 hours) (Fig. 2).
During the follow-up period, neither side effects nor AE
reoccurrences were reported.
MATERIALS AND METHODS
Study Design
This retrospective analysis was based on cases treated in
the two German clinics (Technical University of Munich and
Ulm University Medical Center). Patients aged 18 years were
treated and monitored at the Department of Otorhinolaryngology, Head and Neck Surgery at the Technical University of
Munich, Germany, and the Department of Oto–Rhino–Laryngology, Head and Neck Surgery at the Ulm University Medical
Center, Ulm, Germany.
The diagnosis of an ARB-induced AE was based on the
patients’ medical history and accurate examination. AEs of
unknown origin, those occurring in the absence of ARB treatment, and those with a known etiology other than ARB treatment (e.g., C1-esterase inhibitor deficiency, ACEi treatment, or
allergic urticaria) were excluded.
ARB medication was discontinued in all patients, and
replacement antihypertensive drugs were prescribed after a cardiology consultation.
Data Collection
At first patient contact in our outpatient clinic, the cutaneous and subcutaneous swellings were recorded with respect to
clinical symptoms, severity, and course of the attacks.
A mirror exam and direct fiberoptic nasopharyngolaryngoscopy were carried out in all subjects. Patients were then personally interviewed and examined by physicians experienced in
Laryngoscope 125: July 2015
1620
Patients Treated With Icatibant
Three patients were treated with 30 mg of icatibant. Of these, one patient presented with AE of the
endolarynx, aryepiglottic folds, and inter-ary region; one
presented with AE of the lower lip, cheek and tongue;
and one had an angioedema of the tongue and the aryepiglottic fold. All patients received an ARB regimen,
which consisted of daily doses of candesartan, valsartan,
and olmesartan (32, 160, and 10 mg, respectively), to
treat arterial hypertension.
The mean time to complete symptom relief was 6
hours (range 5–7 hours) (Fig. 2).
All of the patients treated with icatibant experienced local skin irritation with erythema and cutaneous
burning. In all cases, these local reactions resolved spontaneously within approximately 2 hours. Neither side
effects nor AE reoccurrences were reported during the
follow-up period.
Patients Treated With Prednisolone-21-Hydrogen
Succinate/Clemastine
Five patients were treated with 250 mg of
prednisolone-21-hydrogen succinate and 2.68 mg of clemastine intravenously. Three patients suffered from AE of
the tongue, two showed edema of the epiglottis, two
Strassen et al.: Treatment of ARB-Induced Angioedema
Laryngoscope 125: July 2015
Strassen et al.: Treatment of ARB-Induced Angioedema
1621
arterial hypertension
arterial hypertension,
diabetes mellitus,
hypothyreosis
arterial hypertension,
diabetes mellitus 2
arterial hypertension,
coronary heart disease
arterial hypertension,
bronchial asthma
Uvula, upper lip
Tongue, uvula
Epiglottis, aryepiglottic
fold
Epiglottis, tongue
arterial hypertension,
coronary heart disease
arterial hypertension
Tongue, aryepiglottic fold
Lip, tongue, endolarynx
Tongue, mouth floor
Tongue
none
none
Icatibant
none
Icatibant
Corticosteroid/H1
antihistamine
Corticosteroid/H1
antihistamine
Icatibant
Corticosteroid/H1
antihistamine
Corticosteroid/H1
antihistamine
Corticosteroid/H1
antihistamine
Therapy
108
not done
112
117
not done
9.1
8
5.4
5.53
4.56
6
107
not done
8.8
8.1
12.08
8.8
Leukocytes
115
103
not done
110
fC1-INH
15.1
0.9
3.4
0.8
not done
0.8
0.3
0.7
0.15
1.2
2.3
CRP
ACE 5 angiotensin converting enzyme; ARB 5 angiotensin receptor blockers; C1-INH 5 C1 esterase inhibitor; CRP 5 C-reactive protein.
arterial hypertension
arterial hypertension
arterial hypertension
Lip, tongue, cheek
Epiglottis, aryepliglott fold
arterial hypertension,
hypothyreosis
Medical Conditions
Tongue, aryepiglottic fold
Localization
not done
not done
5
not done
23
46
22
not done
not done
44
not done
ACE
not done
0.7
0.9
not done
1.1
1.1
1.2
0.9
1.2
0.8
0.5
Creatinine
730
183
365
200
unknown
1825
365
730
274
unknown
> 730
Time of
ARB intake
TABLE I.
Characteristics of All Patients Included in the Study (ACE Levels in U/L; Creatinine and CRP in Mg/Dl; Leukocytes in G/L; C1-INH Activity In %).
24
54
6
36
7
5
36
48
52
36
27
Time to
Remission
male
male
female
female
male
female
female
male
male
male
female
Sex
Fig. 2. Time (hours) to complete remission of symptoms for all
patients and mean time (hours) to complete symptom remission
(hours) for the three patient groups.
Fig. 1. Patient suffering from angiotensin receptor blockersinduced angioedema upon presentation in the emergency department (a) and after complete symptom remission (b). [Color
figure can be viewed in the online issue, which is available at www.
laryngoscope.com.]
presented with edema of the aryepiglottic folds, one had
an edema of the upper lip and one presented AE of the
uvula.
All of the patients received an ARB regimen, which
consisted of daily doses of losartan, candesartan and valsartan (50, 8 and 160 mg, respectively), to treat arterial
hypertension. The mean time to complete relief of symptoms was 39.8 hours (range 27–52 hours) (Fig. 2). Neither side effects nor AE reoccurrences were reported
during the follow-up period.
option for hereditary and ACEi-induced AE11,12 and
could have a beneficial effect on ARB-induced AE if the
edema was induced by bradykinin.
In the icatibant group, the time to symptom
improvement and remission were satisfactory compared
with the untreated patients and patients treated with
prednisolone-21-hydrogen succinate and clemastine in
our clinic, as well as cases reported in the literature.
Symptom remission was observed after 5 to 7 hours for
patients in the icatibant group, whereas remission
times of 24 to 54 hours and 27 to 52 hours were
observed for untreated and combined corticosteroid and
antihistamine-treated patients, respectively. These data
correspond to the mean time to symptom relief for icatibant in the treatment of hereditary and ACEi AE. The
mean time to complete symptom remission in these studies was between 4 an 10 hours for the icatibant group
and between 19 and 51 hours for the placebo group.11,34
No adverse effects except for a local skin irritation at
the injection site were observed after the administration
of icatibant.
DISCUSSION
Bradykinin effects vascular leakage primarily via
the bradykinin B2 receptor.31,32 As a result, kinininduced acute AE is not responsive to classic antiallergic
drugs.11 However, the current strategy to treat acute
ARB-induced AE consists of the application of corticosteroids and antihistamines.33 Remission times after this
therapy are similar to the values observed by placebo
treatment. Therefore, novel and efficient therapeutic
concepts are urgently needed.
Binding of the competitive antagonist icatibant to
the B2 bradykinin receptor reduces its activation. As a
result, this drug represents an effective therapeutic
Laryngoscope 125: July 2015
1622
CONCLUSION
One major weakness of this study is that the AE
severity was not graded in any of the patients. Nevertheless, the severity grade at admission is not correlated
with the clinical course of AE in the subsequent hours;
the time from the beginning of an attack of the upper
airway to life-threatening asphyxiation can vary from 10
minutes to 14.3 hours, and initial symptoms can be
minor.35
Despite the observed rapid symptom relief in ARBinduced AE after treatment with icatibant, our case
series can only provide proof of concept and does not
Strassen et al.: Treatment of ARB-Induced Angioedema
meet the level of high significance achieved in randomized, blinded, and prospective studies. The small sample
size of this study did not allow us to assess statistical
significance. Additional randomized, blinded prospective
studies with larger sample sizes are needed to determine
whether icatibant is an effective therapy for ARBinduced AE. Although the sample size is small due to
the low incidence of ARB-induced AE, this is the first
case series comparing different treatment schemes. In
summary, the administration of 30 mg of icatibant might
serve as an effective therapeutic option for the treatment of ARB-induced AE.
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