Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department.
ABSTRACT Recent data are lacking about the number of patients with angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema who present to the emergency department (ED). Current management of the condition and clinical outcomes also are not known.
To describe the clinical epidemiology of ACEI-induced angioedema in patients who present to the ED.
We performed a medical record review of ACEI-induced angioedema in patients who presented to 5 EDs in the Emergency Medicine Network. A structured data abstraction form was used to collect each patient's demographic factors, medical history, and details about the angioedema that prompted the ED visit. The medical record review also focused on treatment provided in the ED and subsequent need for hospitalization.
We identified a total of 220 patients with ACEI-induced angioedema. The frequency of ACEI-induced angioedema among all patients with angioedema who presented to the ED was 30% (95% confidence interval, 26%-34%). The annual rate of visits for ACEI-induced angioedema was 0.7 per 10,000 ED visits. The most frequent presenting signs were shortness of breath, lip and tongue swelling, and laryngeal edema. Most patients (58%) were sent home directly from the ED, whereas 12% were regular inpatient admissions, 11% were admitted to the intensive care unit, and 18% were admitted under observation status (<24 hours). Pharyngeal swelling and respiratory distress were independent predictors of hospital admission and longer length of stay.
ACEI-induced angioedema accounted for almost one-third of angioedema treated in the ED, although it remains a rare ED presentation. A subgroup of these patients still needs inpatient hospitalization for management of upper airway angioedema.
- SourceAvailable from: Christian Drouet
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ABSTRACT: New concepts of idiopathic and iatrogenic angioedema underline the role of bradykinin, and the importance of catabolizing enzymes. A case is described of Angiotensin converting enzyme inhibitor (ACEi) and sitagliptin induced angioedema, where AO attacks decreased after the withdrawal of lisinopril but resolved only after the withdrawal of sitagliptin, an inhibitor of dipeptylpeptidase IV. ACE, aminopeptidase P and carboxypeptidase N were decreased down to 17%, 42%, 64% of median references values, and remained low one year after the interruption of these drugs: 56%, 28% and 50%, respectively. The combined deficiency of APP and CPN might enhance the inhibiting effect of the DPP IV inhibitor. The fact that this triple deficiency remained latent before and after the treatment indicates that searching for latent enzyme deficiencies should be carried out when there is intention to treat with a combination of drugs interfering with the bradykinin metabolism.European annals of allergy and clinical immunology 05/2014; 46(3):119-22.
Multicenter study of patients with angiotensin-
converting enzyme inhibitor–induced
angioedema who present to the emergency
Aleena Banerji, MD*; Sunday Clark, MPH, ScD†; Michelle Blanda, MD‡; Frank LoVecchio, DO§;
Brian Snyder, MD?; and Carlos A. Camargo Jr, MD, DrPH¶
Background: Recent data are lacking about the number of patients with angiotensin-converting enzyme inhibitor (ACEI)–
induced angioedema who present to the emergency department (ED). Current management of the condition and clinical outcomes
also are not known.
Objective: To describe the clinical epidemiology of ACEI-induced angioedema in patients who present to the ED.
Methods: We performed a medical record review of ACEI-induced angioedema in patients who presented to 5 EDs in the
Emergency Medicine Network. A structured data abstraction form was used to collect each patient’s demographic factors,
medical history, and details about the angioedema that prompted the ED visit. The medical record review also focused on
treatment provided in the ED and subsequent need for hospitalization.
Results: We identified a total of 220 patients with ACEI-induced angioedema. The frequency of ACEI-induced angioedema
among all patients with angioedema who presented to the ED was 30% (95% confidence interval, 26%–34%). The annual rate
of visits for ACEI-induced angioedema was 0.7 per 10,000 ED visits. The most frequent presenting signs were shortness of
breath, lip and tongue swelling, and laryngeal edema. Most patients (58%) were sent home directly from the ED, whereas 12%
were regular inpatient admissions, 11% were admitted to the intensive care unit, and 18% were admitted under observation status
(?24 hours). Pharyngeal swelling and respiratory distress were independent predictors of hospital admission and longer length
Conclusion: ACEI-induced angioedema accounted for almost one-third of angioedema treated in the ED, although it remains
a rare ED presentation. A subgroup of these patients still needs inpatient hospitalization for management of upper airway
Ann Allergy Asthma Immunol. 2008;100:327–332.
Angioedema is a life-threatening adverse event associated
with angiotensin-converting enzyme inhibitor (ACEI) ther-
apy. The number of patients taking ACEIs continues to rise,
leading to increasing rates of angioedema.1In 2001, there
were 35 million to 40 million prescriptions written for ACEIs
worldwide,2and in 2007, ACEIs remain the most frequent
class of medications prescribed for the treatment of hyper-
tension.3Angioedema occurs in approximately 0.1% to 2.2%
of patients treated with ACEIs,4–7with a higher incidence in
women and African Americans.8,9
Because of the large number of patients treated with this
class of medication, ACEIs became the most common
cause of angioedema in patients who presented to the
hospital and the ED in the early 1990s.10–13Unfortunately,
these data regarding the frequency of ACEI-induced an-
gioedema in patients who presented to the ED are at least
10 years old and more recent data are not available. Three
retrospective studies from that period found that among
patients who presented to the ED with angioedema (iden-
tified using the International Classification of Diseases,
Ninth Revision [ICD-9] code 995.1 for angioedema), 30%
to 40% of cases were associated with ACEIs.10,13,14Also,
despite the relatively high incidence of angioedema, few
data exist regarding current management and short-term
outcomes of patients who develop angioedema from
ACEIs. The aim of the current study is to address the lack
of recent data regarding the frequency, current treatment
practices, and outcomes of ACEI-induced angioedema in
patients who present to the ED.
Affiliations: * Division of Rheumatology, Allergy and Immunology,
Massachusetts General Hospital, Boston, Massachusetts; † Department of
Emergency Medicine, New York-Presbyterian Hospital, New York, New
York; ‡ Department of Emergency Medicine, Summa Health System, Akron,
Ohio; § Department of Emergency Medicine, Maricopa Medical Center,
Phoenix, Arizona; ? Department of Emergency Medicine, University of
California–San Diego Medical Center, San Diego, California; ¶ Department
of Emergency Medicine, Massachusetts General Hospital, Boston, Massa-
Disclosures: Authors have nothing to disclose.
Funding: This study was supported by Jerini AG (Berlin, Germany).
Received for publication July 24, 2007; Received in revised form Sep-
tember 13, 2007; Accepted for publication October 4, 2007.
VOLUME 100, APRIL, 2008327
MATERIALS AND METHODS
This study is a retrospective medical record review of angio-
edema in patients who presented to 5 EDs in the Emergency
Medicine Network (www.emnet-usa.org). Each site obtained
approval from their institutional review board and was asked
to review all cases of angioedema in patients who presented
to the ED between 2003 and 2005. The target sample size was
1,000 patients across the 5 sites. Prior studies from a decade
ago suggested that approximately 30%10,13,14of these 1,000
patients will have ACEI-induced angioedema, yielding 300
cases. Therefore, each of the 5 sites needed to abstract data on
a minimum of 60 patients with angioedema whose condition
was caused by an ACEI. If the number of patients with
ACEI-induced angioedema did not reach this predetermined
threshold of 60 patients, study sites were asked to review
medical records before 2003 or after 2005 to try to reach this
All patients with a primary ICD-9 code of 995.1 (angio-
edema) who presented to the ED during the study period were
eligible for medical record review. All medical records iden-
tified for review were reviewed to determine whether the
allergic reaction was associated with an ACEI. The medical
records were abstracted by physicians, researchers with PhD
degrees, or college graduates under the supervision of phy-
sician site principle investigators. Each site data abstractor
received a detailed training document to review before be-
ginning data abstraction. The 19-page training document in-
cluded detailed information about how to answer each of the
questions included in the data abstraction form. A standard
form was used to collect detailed information on patients with
ACEI-induced angioedema, including demographic factors,
history of asthma and/or allergies, prior episodes of angio-
edema, length of treatment with ACEIs, and details about the
current episode of angioedema that prompted the ED visit.
Specifics about the treatment provided in the ED, response to
treatment, and need for further hospitalization were also
recorded. Patients with a diagnosis of ACEI-induced angio-
edema were included for statistical analysis.
All analyses were performed using STATA statistical soft-
ware, version 9.0 (StataCorp, College Station, Texas). Data
were presented as proportions (with 95% confidence intervals
[CIs]), means (with SDs), or medians (with interquartile
ranges). Associations are examined using ?2test, t test, and
Wilcoxon rank sum test, as appropriate. Associations were
further evaluated using multivariate logistic regression. All P
values are 2-tailed, with P ? .05 considered statistically
Frequency of ACEI-Induced Angioedema
Among the 5 participating sites, we identified a total of 586
patients who presented to the ED with angioedema between
2003 and 2005. Among these 586 patients with angioedema,
175 patients (30% [95% CI, 26%–34%]) were found to have
ACEI-induced angioedema. The percentage of angioedema
cases associated with ACEIs was consistent across years
Three sites did not reach the predetermined goal of 60
ACEI-induced angioedema cases per site and therefore gath-
ered data from other years (ie, 1998 to 2002 and 2006). This
approach led to a final collection of detailed information from
220 patients with ACEI-induced angioedema (including 2
patients with angioedema from angiotensin receptor block-
Annual Rate of ED Visits
To determine the annual rate of ACEI-induced angioedema
ED visits, we focused on cases during 2003 to 2005. Using
these data, in addition to the number of angioedema visits to
each ED site during the same period, we calculated the annual
rate of visits (per 10,000 ED visits) for both angioedema and
ACEI-induced angioedema. The annual rate of visits for
angioedema and ACEI-induced angioedema varied across
sites, but we found an average of 2.2 visits for angioedema
and 0.7 visit for ACEI-induced angioedema per 10,000 ED
visits (Table 1).
Demographics and Medical History
The mean (SD) age of the 220 ED patients with ACEI-
induced angioedema was 60 (14) years. There was a slight
female predominance (62%). Most of the population was
either white (46%) or African American (42%), with the
remainder of Hispanic (9%) or Asian (1%) descent.
Although most patients had a history of hypertension
(98%), prompting treatment with an ACEI, the prevalence of
atopy (including asthma, 11%; food allergy, 6%; allergic
rhinitis, 4%; and atopic dermatitis, 1%) was much lower than
in the general population. Diabetes mellitus was recorded in
24%, coronary artery disease in 22%, congestive heart failure
in 7%, and chronic idiopathic urticaria in 1%.
The onset of ACEI-induced angioedema in patients before
they presented to the ED was variable, from less than 1 hour
Figure 1. Proportion of all patients with angioedema who had angiotensin-
converting enzyme inhibitor (ACEI)–induced angioedema by year.
328 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
to more than 12 hours, but the median duration was 4 to 6
hours. Most patients came from home (82%) and did not
arrive by ambulance (73%). Arrival by ambulance was asso-
ciated with a significant increase in pre-ED treatment (P ?
.001), including H1-blockers, H2-blockers, epinephrine, ste-
roids, and inhaled ?-agonists or oxygen and intravenous
Lisinopril was implicated in 60% of cases of ACEI-in-
duced angioedema. Enalapril was the next most frequent
cause (12%), followed by benazepril (6%). In most patients,
this was their first episode of angioedema. Patients were
taking an ACEI for an average of 6 months (interquartile
range, 1–18 months) before the development of the angio-
edema that prompted the ED visit.
Initial vital signs on presentation to the ED showed a mean
(SD) respiratory rate of 19/min (7/min), heart rate of 84/min
(17/min), a systolic blood pressure of 151 (26) mm Hg,
diastolic blood pressure of 82 (16) mm Hg, temperature of
97.6°F (1.3°F), and oxygen saturation of 97% (2%). Restrict-
ing the oxygen saturation to those breathing room air (n ?
139) yielded an average of 98% (2%).
The most prominent presenting signs documented in the
ED were shortness of breath, lip swelling, laryngeal edema,
and tongue swelling (Fig 2). Most patients were treated with
corticosteroids (75%) and diphenhydramine (73%). Rela-
tively few patients were treated with epinephrine (10%).
Intravenous fluids were used in 42%, oxygen in 9%, and
inhaled ?-agonists in only 4% of patients with ACEI-induced
Most patients were sent home directly from the ED (58%),
with a smaller number requiring regular inpatient admission
(12%) or admission to the intensive care unit (ICU) (11%).
The other 18% were admitted and discharged under observa-
tion status (ie, planned stay of ?24 hours). Overall, 14
patients (7%) required ventilatory support in the ED. The
type of ventilatory support was determined for 13 patients:
noninvasive ventilation (n ? 1), intubation (n ? 10), and
surgical airway (n ? 2). All 14 patients who received venti-
latory support in the ED were admitted to the hospital.
Patients who received ventilatory support had a longer hos-
pital length of stay in days (3 [95% CI, 2–6] days vs 1 [95%
CI, 1–2] days; P ? .001). Although statistical power was
limited, no statistically significant difference was found in the
number of hours spent in the ICU (48 [95% CI, 17–60] hours
vs 22 [95% CI, 17–24] hours; P ? .10). No deaths occurred
from ACEI-induced angioedema among the 5 sites during the
Admitted patients (observation, regular floor, or ICU ad-
mission) were similar to patients who were discharged to
home with respect to mean (SD) age (60  years vs 61 
years; P ? .94), sex (female, 63% vs 60%; P ? .72), and
race/ethnicity (race other than white, 60% vs 50%; P ? .17)
on univariate analysis. The time of symptom onset before ED
presentation, arrival by ambulance, any pre-ED treatment,
and the initial vital signs in the ED did not predict the need
for subsequent hospital admission. Patients were more likely
to be admitted to the hospital if they presented to the ED with
pharyngeal swelling (P ? .001) and respiratory distress (P ?
.001) but not if they presented with oral or facial swelling
(Table 2). This finding was confirmed by a multivariate
analysis of which factors at ED presentation predicted hos-
pital admission (Table 3). Our multivariate analysis further
Figure 2. Symptoms of angiotensin-converting enzyme inhibitor–induced
angioedema at initial presentation to the emergency department.
Table 1. Annual Rates of ED Visits for Angioedema and ACEI-Induced Angioedema
ED visits from
2003 to 2005
to EDs with
2003 to 2005
to EDs with
annually (per 10,000)
to EDs with ACEI
2003 to 2005
to EDs with ACEI
annually (per 10,000)
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ED, emergency department.
VOLUME 100, APRIL, 2008 329
suggests that race/ethnicity other than white also predicts the
need for subsequent hospital admission (P ? .049). Patients
who received ventilatory support had a longer hospital length
of stay in days (3 [95% CI, 2–6] days vs 1 [95% CI, 1–2]
days; P ? .001). Although statistical power was limited, no
statistically significant difference was found in the number of
hours spent in the ICU (48 [95% CI, 17–60] hours vs 22
[95% CI, 17–24] hours; P ? .10).
Our study found an overall frequency of 30% of ACEI-
induced angioedema among all patients with angioedema
who presented to the ED. ACEI-induced angioedema ac-
counts for almost one-third of angioedema treated in the ED.
This percentage is similar to data from studies completed
more than a decade ago, which reported values of approxi-
mately 30% to 38%.10,13,14Although there was slight variabil-
ity among the 5 different sites in this study, ACEI-induced
angioedema is a rare ED presentation (0.7 case per 10,000 ED
visits). Thus, the typical academic ED, with approximately
50,000 annual visits,15might expect to see 11 patients with
angioedema during a year, of which 3 to 4 cases would have
been associated with ACEI. The most frequent presenting
signs at the time of initial ED presentation were shortness of
breath, lip and tongue swelling, and laryngeal edema. How-
ever, pharyngeal swelling and respiratory distress were inde-
Table 2. ED Presentation and Clinical Course of ACEI-Induced Angioedema Patients Treated in the ED According to Disposition
VariableSent home (n ? 129) Admitted (n ? 91)P value
Time of onset, %
Arrived by ambulance, %
Pre-ED treatment, %
Initial respiratory rate, median (IQR)
Initial pulse rate, median (IQR)
Initial systolic blood pressure, median (IQR)
Initial diastolic blood pressure, median (IQR)
Initial temperature, median (IQR)
Initial oxygen saturation, median (IQR)
Pharyngeal swelling, %
Oral or facial swelling, %
Respiratory distress, %
Other pain, itching, or swelling, %
Received oxygen, %
IV line established, %
Epinephrine given in ED, %
Diphenhydramine given in ED, %
H1-blocker given in ED, %
H2-blocker given in ED, %
Steroids given in ED, %
Inhaled ?-agonists given in ED, %
Any ventilatory support given in ED, %
Additional medications given in ED, %
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ED, emergency department; IQR, interquartile range; IV, intravenous.
Table 3. Multivariate Predictors of Hospital Admission Among ACEI-Induced Angioedema Patients Treated in the Emergency Department
(95% confidence interval)
Age (per increasing 10-year increments)
Race/ethnicity other than white
Arrived by ambulance
Abbreviation: ACEI, angiotensin-converting enzyme inhibitor.
330ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
pendent predictors of hospital admission and longer length of
Our data are consistent with prior studies suggesting a
higher incidence of ACEI-induced angioedema among
women and African Americans.1,16,17Our results further sug-
gest that patients of races other than white were more likely
to need hospital admission (Table 3). The reason for a higher
incidence of ACEI-induced angioedema among African
Americans remains unclear but may be due to differences in
sensitivity to bradykinin.18–20
Interestingly, we found atopy, including asthma, food al-
lergy, allergic rhinitis, and atopic dermatitis, to be low com-
pared with the general population among all patients who
developed ACEI-induced angioedema. This finding is con-
sistent with the findings of the study by Pigman et al13;
however, Kostis et al7report seasonal allergies as a potential
risk factor (odds ratio, 1.65). Our data did not specifically
differentiate between seasonal and perennial allergic rhinitis.
Initial vital signs suggest that many of the patients were
relatively stable without significant tachycardia, hypotension,
fever, or hypoxia at initial presentation to the ED. An under-
lying diagnosis of hypertension in almost all of the patients
helps to explain why the average initial blood pressure was
elevated. Angioedema of the tongue and lips with no urticaria
and pruritus is the classic presentation of ACEI-induced
angioedema.2,16Our data show that, despite a normal pulse
oximetry, shortness of breath was the most commonly doc-
umented presenting sign of ACEI-induced angioedema, fol-
lowed by lip or tongue swelling and laryngeal edema. Our
review did not find patients who presented with significant
urticaria or pruritus in the ED. Previous studies report
odynophagia and tongue swelling at the time of presentation
as risk factors for further intervention and hospitalization.10
We found that pharyngeal swelling and respiratory distress in
the ED were independent predictors of subsequent hospital
admission (Table 2) and longer length of stay.
The 5 sites that were part of this study were all academic
centers with high-volume EDs. In general, the approach to the
treatment of a patient with angioedema was similar at each
site. A patient with severe angioedema (pharyngeal swelling,
respiratory distress) was observed more cautiously, received
more aggressive treatment, and was more likely to be admit-
ted to the hospital. Patients with mild angioedema were
simply observed in the ED and often discharged home with-
out subsequent hospital admission. This finding is consistent
with the approach one would expect in the treatment of a
patient who presents to the ED with mild vs severe symp-
We do not report any deaths among all patients who
presented to the ED with ACEI-induced angioedema similar
to other large studies.16Indeed, fatalities from ACEI-induced
angioedema are extremely rare, with only isolated case re-
ports in the literature.21–23Our study is novel in showing that
although most patients appear to have angioedema not requir-
ing intensive treatment in the ED, a subgroup (n ? 51 of 220
patients with ACEI-induced angioedema [23%]) was admit-
ted to either the inpatient ward or the ICU. This information
is important to our understanding of the ongoing management
of ACEI-induced angioedema to improve current and future
therapies for these patients.
Similar to recent single-center studies,16,24our multicenter
study confirmed that lisinopril was the most frequent ACEI to
cause ACEI-induced angioedema. This finding may be re-
flective of data showing that lisinopril has been the most
frequently prescribed ACEI.16,25Although our patients were
taking ACEIs for an average of 6 months before developing
angioedema, the literature suggests that 25% to 60% of
patients present within the first month of beginning to take an
ACEI.5,10,16,26However, patients can present with angioedema
anywhere from a few days to several years after starting to
take an ACEI.14,27
The mechanism of ACEI-induced angioedema remains
unclear but may be related to increases in bradykinin lev-
els.28,29Bradykinin would normally be degraded by ACE but
is inhibited in the presence of ACEI. Other enzymes such as
aminopeptidase P could degrade bradykinin but have also
been reported to be deficient in patients with ACEI-induced
angioedema.30If elevated bradykinin levels or an altered
sensitivity to bradykinin are the main culprits, then current
treatments (including antihistamines, corticosteroids, and epi-
nephrine) will presumably not be helpful.31Rather, newer
agents such as bradykinin receptor antagonists or kallikrein
inhibitors may provide novel alternatives for the treatment of
ACEI-induced angioedema; such medications are currently
under development for hereditary angioedema.32,33Lefebvre
et al34further suggest a role for substance P accumulation as
a result of low levels of dipeptidyl peptidase IV levels,
leading to an alternative explanation for ACEI-induced an-
gioedema. Clinical research on these new medications re-
quires a basic understanding of the clinical epidemiology of
ACEI-induced angioedema, which our study provides.
Nevertheless, our study has several potential limitations.
The first is the retrospective design. Using this study design
allowed us to quickly gather data for a median 3-year period
at 5 different sites. The frequency of ACEI-induced angio-
edema determined by this study suggests that prospective
studies would need to be run for several years and/or across
many sites to reach comparable numbers. Second, we were
limited by evaluating data that were documented in the ED
record. Although there undoubtedly is some variability from
record to record, as well as from site to site, we used standard
forms and were reassured by the relative similarity of data
across the years from 2003 to 2005 and among the 5 sites
involved in this study. Also, we did not sample any other
ICD-9 codes for the possibility of ACEI angioedema. We
believed that code 995.1 represented the best ICD-9 code for
our objective, and this was similar to how prior studies from
a decade ago were conducted, therefore allowing our recent
data to be compared with data previously published. This
approach could have led to an underestimation of the actual
number of cases of ACEI-associated angioedema. Addition-
ally, one could sample patients with diagnoses other than
VOLUME 100, APRIL, 2008 331
angioedema who presented to the ED to gather additional
data on the frequency of ACEI use. Lastly, our data are only
from the ED setting, so extrapolation to other clinical settings
In summary, ACEI-induced angioedema accounts for one-
third of angioedema treated in the ED. Although fatalities are
exceedingly rare, patients still need inpatient hospitalization
and intensive care treatment for management of respiratory
compromise and upper airway angioedema. Further research
into the exact mechanism of ACEI-induced angioedema and
development of novel treatment options is still needed. Re-
sults from our study provide a foundation to assist with study
planning and to help determine the potential benefit of future
novel treatments in either reducing the frequency of ACEI-
induced angioedema or improving outcomes of patients who
present to the ED with ACEI-induced angioedema.
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