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Original Article
A BS T R AC T
BACKGROUND
From the Department of Otorhinolaryn- Angioedema induced by treatment with angiotensin-convertingenzyme (ACE) in-
gology (M.B., U.S.), Mnchner Studien- hibitors accounts for one third of angioedema cases in the emergency room; it is
zentrum (B.S.), and Institut fr Med-
izinische Statistik und Epidemiologie usually manifested in the upper airway and the head and neck region. There is no
(A.H., V.K.), Klinikum rechts der Isar, approved treatment for this potentially life-threatening condition.
Technische Universitt Mnchen, and
the Department of Otorhinolaryngology,
Grosshadern Medical Center of the Uni-
METHODS
versity of Munich (K.S., M.H.), Munich, In this multicenter, double-blind, double-dummy, randomized phase 2 study, we
the Department of Otorhinolaryngology, assigned patients who had ACE-inhibitorinduced angioedema of the upper aerodi-
Head and Neck Surgery, Ulm University
Medical Center, Ulm (J.G., N.R., J.V.,
gestive tract to treatment with 30 mg of subcutaneous icatibant, a selective brady-
T.K.H.), and the Institute of Pharmacolo- kinin B2 receptor antagonist, or to the current off-label standard therapy consisting
gy and Clinical Pharmacology, University of intravenous prednisolone (500 mg) plus clemastine (2 mg). The primary efficacy
Hospital Dsseldorf, Dsseldorf (G.K.)
all in Germany. Address reprint re-
end point was the median time to complete resolution of edema.
quests to Dr. Ba at the Department of
Otorhinolaryngology, Klinikum rechts der RESULTS
Isar, Technische Universitt Mnchen,
All 27 patients in the per-protocol population had complete resolution of edema.
Ismaninger Str. 22, 81675 Munich, Ger-
many, or at m.bas.hno@gmail.com The median time to complete resolution was 8.0 hours (interquartile range, 3.0 to 16.0)
with icatibant as compared with 27.1 hours (interquartile range, 20.3 to 48.0) with
N Engl J Med 2015;372:418-25.
DOI: 10.1056/NEJMoa1312524 standard therapy (P=0.002). Three patients receiving standard therapy required
Copyright 2015 Massachusetts Medical Society. rescue intervention with icatibant and prednisolone; 1 patient required tracheotomy.
Significantly more patients in the icatibant group than in the standard-therapy
group had complete resolution of edema within 4 hours after treatment (5 of 13
vs. 0 of 14, P=0.02). The median time to the onset of symptom relief (according
to a composite investigator-assessed symptom score) was significantly shorter with
icatibant than with standard therapy (2.0 hours vs. 11.7 hours, P=0.03). The results
were similar when patient-assessed symptom scores were used.
CONCLUSIONS
Among patients with ACE-inhibitorinduced angioedema, the time to complete
resolution of edema was significantly shorter with icatibant than with combina-
tion therapy with a glucocorticoid and an antihistamine. (Funded by Shire and the
Federal Ministry of Education and Research of Germany; ClinicalTrials.gov num-
ber, NCT01154361.)
A
ngioedema induced by treatment in accordance with the provisions of the Decla-
with angiotensin-convertingenzyme (ACE) ration of Helsinki, the International Conference
inhibitors is estimated to occur in up to on Harmonisation Good Clinical Practice guide-
0.68% of patients who receive ACE inhibitors,1-5 lines, and current regulatory requirements.
although the true incidence is difficult to estimate The trial was designed by Klinikum rechts der
because symptoms can take years to appear.6 Isar at Technische Universitt Mnchen, Germany,
Although the risk of ACE-inhibitorinduced an- and was supported by an educational grant from
gioedema is low, the increasing use of ACE inhibi- Shire. The project management, monitoring, data
tors is resulting in a comparatively large number of management, and statistical analysis were super-
patients at risk for this condition,7 which ac- vised by Mnchner Studienzentrum (Technische
counts for one third of all cases of angioedema Universitt Mnchen). The statistical analysis was
treated in the emergency room.8 ACE-inhibitor performed by Metronomia Clinical Research.
induced angioedema affects almost exclusively the Shire had the opportunity to review and provide
upper aerodigestive tract but can, in rare cases, comments on the manuscript before submission
affect the gut. Obstruction of the upper airway but had no role in the design of the trial, the
occurs in 10% of cases and may proceed to acute collection or analysis of the data, or the decision
laryngeal obstruction and death.8,9 to submit the manuscript for publication. A medi-
Standard emergency room treatment of ACE- cal writer at Prime Healthcare, funded by Tech-
inhibitorinduced angioedema consists of symp- nische Universitt Mnchen, assisted with the
tomatic treatment with glucocorticoids and an- writing of the manuscript. The authors vouch for
tihistamines. However, because this form of the accuracy and completeness of the data and all
angioedema is not a histamine-mediated reaction, the analyses and for the fidelity of this report to
patients generally do not have a response to this the trial protocol, which is available with the full
therapy.10 Whether this off-label standard therapy text of this article at NEJM.org.
offers any clinical benefit remains subject to debate.
ACE inhibitors exert their therapeutic effects Patients
by blocking the conversion of angiotensin I to Patients 18 to 95 years of age who were receiving
angiotensin II; they also inhibit the breakdown ACE inhibitors and who presented to the emer-
of bradykinin, thereby increasing its activity. gency department with ACE-inhibitorinduced an-
Bradykinin-mediated hereditary angioedema is gioedema affecting the upper aerodigestive tract
usually treated with C1 inhibitor concentrates, (which includes the face, lips, cheeks, tongue, soft
which inhibit the formation of bradykinin, and palate or uvula, pharynx, and larynx) were eligi-
with the selective bradykinin B2 receptor antag- ble for inclusion. Patients with angioedema that
onist icatibant.11 In case reports of patients with was considered, on medical review, to be due to
ACE-inhibitorinduced angioedema who received causes other than ACE inhibitors were excluded.
treatment with icatibant (which is currently not Other exclusion criteria were a history of angio-
licensed for this indication), the time to a reduc- edema before the initiation of ACE-inhibitor thera-
tion of symptoms was similar to that seen with py, acute urticaria, unstable angina, acute myo-
icatibant in cases of hereditary angioedema.10,12-16 cardial ischemia, acute heart failure with a New
Here we report the results of a phase 2 study of York Heart Association class of III or IV, preg-
icatibant, as compared with standard combination nancy, and lactation. All patients provided writ-
therapy consisting of a glucocorticoid and an anti- ten informed consent.
histamine, in patients with ACE-inhibitorinduced
angioedema of the upper aerodigestive tract. Study Design
The study design is shown in Figure S1 in the
Supplementary Appendix, available at NEJM.org.
Me thods
Eligible patients were randomly assigned, in a
Study Oversight 1:1 ratio, to receive, within 10 hours after symptom
We performed this multicenter, double-blind, dou- onset, subcutaneous icatibant, at a dose of 30 mg
ble-dummy, randomized phase 2 study at four sites injected into the abdominal wall, or standard
in Germany. The study was approved by local in- therapy consisting of intravenous prednisolone
dependent ethics committees and was conducted (Solu-Decortin H, Merck) at a dose of 500 mg
* Plusminus values are means SD. The baseline characteristics are shown for the per-protocol population, which in-
cluded all patients who underwent randomization and received the study medication. There were no significant differ-
ences between the groups in any of the characteristics listed here. ACE denotes angiotensin-converting enzyme.
Investigators who were unaware of the treatment assignments assessed the intensity of six symptoms (pain, shortness
of breath, dysphagia, change in voice, sensation of a foreign body, and feeling of pressure) before treatment and 1, 2, 3,
4, 6, 8, 12, 24, and 48 hours after treatment, using a scale from 0 (no symptoms) to 3 (severe symptoms); a composite
symptom score was calculated from the average of the six symptom scores.
Investigators assessed the severity of angioedema at four locations (lips and cheeks, tongue, oropharynx, and hypo-
pharynx or larynx), using a scale from 0 (no angioedema) to 4 (very severe angioedema). Angioedema of the orophar-
ynx and hypopharynx was assessed by an ear, nose, and throat specialist, who performed endoscopy when necessary. A
composite angioedema score was calculated as the average of the four symptom scores.
Patients assessed the intensity of six symptoms (pain, shortness of breath, dysphagia, change in voice, sensation of a
foreign body, and feeling of pressure) before treatment and 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after treatment, with
the use of a visual-analogue scale (VAS) that ranged from 0 to 10, with higher scores indicating more severe symp-
toms. A composite score on the VAS was calculated as the average of the measurements for the six symptoms.
Disorders are included if they were noted in the medical history of more than three patients in either treatment group.
* Clinical outcomes were assessed in the per-protocol population. CI denotes confidence interval, IQR interquartile
range, and NE not estimable.
The P value was calculated with the use of the Wilcoxon rank-sum test.
The P value was calculated with the use of Fishers exact test.
The time to the onset of symptom relief was defined as the time to the first improvement (i.e., decrease) of at least 1
point in the composite score.
The P value was calculated with the use of the PetoPetoPrentice test.
tients who did not have a response to treatment with a significance level of 5% and were not ad-
(i.e., patients who required administration of res- justed for multiple testing.
cue intervention), the time to the complete reso-
lution of edema was set to the longest observed R e sult s
resolution time in the per-protocol study popula-
tion. The superiority of icatibant over standard Patients
therapy was assessed by a between-group com- Of the 32 patients screened, 30 were enrolled in
parison of the median time to the complete reso- the study during the period from July 2010 through
lution of edema, with the use of the Wilcoxon December 2011 15 patients in each group.
rank-sum test at a two-sided significance level of The median time from the onset of angioedema
5%. Various sensitivity analyses were performed to treatment was 6.1 hours (range, 3.0 to 10.0) in
to assess the robustness of the primary efficacy the icatibant group and 5.1 hours (range, 2.0 to
analysis (see the Supplementary Appendix). 9.3) in the standard-therapy group.
Secondary efficacy analyses were performed in In the case of 3 patients, the decision to ad-
the per-protocol population, whereas secondary minister treatment was made by the investigator
safety analyses were performed in the as-treated before randomization (icatibant therapy in the case
population, which included all patients who of 2 patients and standard therapy in the case of
received at least one dose of either study medica- 1 patient). These patients were excluded from the
tion, with results attributed to the treatment they per-protocol analyses, leaving 27 patients in the
actually received. (Patients in the standard-ther- per-protocol population. No patients discontin-
apy group who had no reduction in symptoms by ued the study owing to adverse events; however,
6 hours after treatment and were administered 4 patients were lost to follow-up (Fig. S2 in the
icatibant and prednisolone as rescue medication Supplementary Appendix).
were included in the standard-therapy group.) The The baseline characteristics of the per-proto-
number and percentage of patients who required col population are shown in Table1. Data on all
rescue intervention and the number and extent of 30 patients according to the treatment they re-
adverse events were compared between the groups ceived are provided in Table S1 in the Supplemen-
with the use of Fishers exact test. All statistical tary Appendix. All the patients were white. Five
tests of the secondary end points were two-sided patients in each group had had a previous episode
and second-line use of C1-inhibitor concentrates icatibant than with standard therapy consisting
in patients with ACE-inhibitorinduced angio- of glucocorticoids and antihistamines.
edema.21 However, icatibant is not currently li- Supported by an educational grant from Shire and by a grant
(01KN1104) from the Federal Ministry of Education and Re-
censed for this indication. search of Germany.
In conclusion, in this randomized trial involv- Disclosure forms provided by the authors are available with
ing patients with ACE-inhibitorinduced angio- the full text of this article at NEJM.org.
We thank the staff and coinvestigators at the participating
edema, complete resolution of edema was achieved centers, and Melanie Jones (Prime Healthcare, Knutsford, Unit-
significantly more quickly with subcutaneous ed Kingdom) for assistance with medical writing.
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