American Journal of Therapeutics 19, 180–184 (2012)

Are Patients Aware of Angiotensin-Converting

Enzyme Inhibitor–Associated Adverse Effects?

Anastasia Khoubaeva, MD,1,2,3 Kate Murray, MSc,1,2 Patricia M. Mitchell, RN,1,2*

Hillary A. Zaniboni, BS,1,2 James A. Feldman, MD, MPH,1,2
and Mark B. Mycyk, MD1,2,4

It is important for patients to understand the potential adverse effects (AEs) of their daily medications.
Because associated adverse effects (ACEIs) may result in life-threatening angioedema, we sought to
assess patients’ level of awareness of ACEI AEs, determine if patients have an appropriate action plan
in the event of an ACEI AE, determine if a brief educational intervention in the emergency department
(ED) could improve knowledge about ACEI AEs. This was a prospective in-person survey conducted
between August and December 2008 in a large urban academic ED. The survey instrument was used to
collect data on demographics, recognition of ACEI AEs, and action plans. A follow-up survey to assess
recall of AEs was done 7 days after ED discharge. Of 208 eligible patients, 113 enrolled: sixty-five (58%)
were females, median age was 55 years [interquartile range (IQR) 47–64]. The majority of participants
(69%) had a high-school diploma or less. On a 5-point Likert scale (5 = ‘‘very important’’), the median
reported level of overall concern for ACEI AEs was 5 (IQR 4–5). Twenty-seven (25%) of the participants
reported being told that ACEIs have potential AEs at the time of the initial prescription. Correct
identification of potential ACEI-associated AEs in the ED was variable with a median of 8 of 16
correctly answered questions (IQR 6–10). At follow-up, the median score was 9 (IQR 6–10). There was
no association between educational level and number of correct AE responses (P = 0.10). Despite a high
level of expressed concern regarding ACEI AEs, patients’ knowledge of AEs was poor, and recall was
minimally improved at follow-up. Most patients have a plan in the event of an AE.

Keywords: adverse drug reaction, adverse drug effect, angiotensin-converting enzyme inhibitor,
medication knowledge

INTRODUCTION in the world. Over 40 million people worldwide have

All medications, even the ones considered most
beneficial, have adverse effects (AEs). It is important
for patients to understand the benefits of their daily
medications and recognize potential AEs that can be
immediately life threatening. Angiotensin-converting
enzyme inhibitors (ACEIs) have become one of the
most commonly prescribed classes of antihypertensives
1
Boston University School of Medicine, Boston, MA; 2Boston
Medical Center, Boston, MA; 3University of Chicago Medical
Center, Chicago, IL; and 4Cook County Hospital, Chicago, IL.
The authors have no conflicts of interest to declare.
*Address for correspondence: Department of Emergency Medicine,
Dowling 1-South, 1 BMC Place, Boston, MA 02118. E-mail:
patricia.mitchell@bmc.org
1075-2765 Ó 2012 Lippincott Williams & Wilkins
used ACEIs since 1980 when the first ACEI was
introduced.1 Despite well-recognized benefits of ACEIs
for patients with hypertension, congestive heart
failure, and renal disease, AEs such as angioedema
and upper-airway obstruction have been noted to occur
unexpectedly.2–4 One study reported that the rate of
angioedema was estimated as 1.6 per 1000 person-years
of ACEI use with African Americans having a .4-fold
risk as compared with the general population.5 Over
30% of all angioedema cases in the emergency de-
partment (ED) have been reported to be ACEI related.6
This adverse drug event is unpredictable and occurs
rapidly, so the patient’s knowledge about this compli-
cation and having an appropriate action plan are
important in preventing morbidity or death. Prescrib-
ers are expected to educate their patients taking ACEIs
about this potential complication.7
www.americantherapeutics.com
ACEI-Associated Adverse Effects
Although patients have indicated that they want to
be informed about side effects by their providers,
studies have reported a poor understanding about
adverse medication side effects.8,9 There are no studies
that have determined whether patients taking ACEIs
are aware of the risk of angioedema or have been
counseled on an appropriate action plan.
The goals of our study were to assess patients’ level
of awareness of ACEI AEs and to determine if patients
have an appropriate action plan in the event of an ACEI
AE. Because we hypothesized that patients would have
a poor understanding about ACEI AEs, we also wanted
to determine if a brief educational intervention in the
ED could improve knowledge about ACEI AEs 7 days
after discharge.
METHODS
Study design
This was a prospective study conducted from August
2008 through December 2008. We administered an
in-person survey to determine baseline knowledge
about ACEI AEs, performed a standardized educational
intervention, and measured the degree of knowledge of
ACEI AEs 7 days after discharge from the ED.
Study setting and population
This study took place at the Boston Medical Center, an
urban, academic level-I trauma center, which treats
a predominately underserved population with over
128,000 ED and urgent care visits yearly. This study
was approved by our Institutional Review Board.
Study participants were consecutive consenting
adults 22 years or older presenting to the Boston
Medical Center ED or urgent care between 8:00 AM and
11:30 PM, Monday through Friday. Screening for eligible
participants occurred in real time using an electronic
ED tracking system (ibex PulseCheck) that included
a list of patient medications entered at the time of ED
triage. Patients were deemed eligible for participation
in the study if they were taking an ACEI at the time
of ED presentation, were English speaking, and were
available 7 days later for a telephone follow-up survey.
Excluded from this study were patients presenting to
the ED with angioedema, nursing home residents,
prisoners, those receiving home nursing services, those
presenting for sexual assault or elder abuse issues, and
those with altered mental status, or those who were
otherwise medically unstable.
Survey instrument
The survey instrument was a 3-part tool developed and
piloted in ED patients currently taking ACEIs. The
www.americantherapeutics.com
181
instrument used closed-format multiple choice ques-
tions adapted from 2 previous study surveys used to
evaluate the degree of knowledge about the safety
profile of medications.7,10 The reading level of the final
survey instrument used in our study was at the sixth-
grade level. All survey instruments were administered
in-person by a trained research assistant (RA).
Part 1: participant angiotensin-converting enzyme inhibitor
history
Participants were asked closed-format multiple choice
questions (with the possibility of choosing all that apply
when applicable) to identify which ACEI they were
using, prescribing history with regard to the ACEI, and
whether they recalled being informed about potential
AEs at the time of the initial prescription and by whom.
Participants were also asked about past ACEI-associated
AEs they had experienced. The level of concern about
AEs was measured using a 5-point Likert scale, with
1 being ‘‘unimportant’’ and 5 being ‘‘very important.’’
Part 2: adverse effect recognition
Participants were asked to identify correctly ‘‘possible
ACEI-associated AEs’’ from a list of 16 (10 of which
were correct). As the list was read, participants were
asked to classify each item as a potential ACEI AE with
a yes or no response.
Part 3: action plan
Participants were asked to identify their action plan in
the event any ACEI-induced AEs were to occur.
Responses for each question included the following:
(1) wait and see what happens; (2) call my doctor/
nurse; (3) go to the emergency department; and (4)
other—specified. Appropriateness of the action plan
for each AE was determined according to committee
consensus of a reasonable response to each AE before
the study was initiated.
Survey conclusion
After the survey instrument was administered, partic-
ipants were read out a list of potential serious AEs of
ACEIs by the RA. Participants were informed that the
list was not all inclusive and were encouraged to speak
with their health care provider if they wanted to learn
more about ACEIs. The participants were then advised
that if one of these serious AEs were to occur at anytime
in the future they should seek immediate medical
attention.
Seven-day telephone follow-up
Each participant was contacted by an RA 7 days after
their initial visit to the ED. Knowledge about AEs was
reassessed using a structured survey instrument.
American Journal of Therapeutics (2012) 19(3)
182 Khoubaeva et al

Data analysis listed in Table 1. Action plan responses are listed in

Table 2. Twenty-three subjects were lost to follow-up.
The primary outcome of this study was change in ACEI
AE knowledge at 7 days from their initial knowledge
level at the time of their visit to the ED. Secondary
outcomes were patients’ education level associated LIMITATIONS
with baseline AE knowledge, patient ratings about the
importance of AE knowledge, and appropriateness of These data were acquired from a single, urban,
patient action plans. academic ED, which treats a predominantly under-
The sample size was calculated assuming that the served population, and therefore, its generalizability to
well-informed patient should get at least 12 of 16 (or other patient populations is uncertain. A future study
75%) AE recognition questions correct. The probability should include a setting with a more diverse patient
of achieving this by chance alone is 0.04. Using an exact population in terms of socio–economic status and
1-sample test of a proportion, a sample size of educational background. Some of the survey questions
113 participants would provide 80% power to detect were susceptible to recall bias, because independent
an increase of 6% above chance. This is equivalent to confirmation of historical data (e.g., patient discussions
10% of the patients being well-informed in AE with their prescriber) was beyond the scope of this
recognition of their ACEI. Descriptive statistics were study. When attempting to assess action plans in
calculated. A paired t-test was used to assess differ- response to AEs, hypothesis guessing may have
ences in AE recall at 7-day follow-up. We used SAS influenced participants’ responses to indicate a higher
version 9.1 for all analyses. likelihood of seeking help than they actually would if
an AE was experienced. Finally, our study included
only English speaking patients. Because patient aware-
RESULTS ness of their own medical problems and medication
risks depend on accurate communication with their
Of 208 patients eligible for the study, 113 consented and
providers, including nonEnglish speaking patients
agreed to be enrolled. Sixty-five patients (58%) were
could affect the results of a study of this nature.
females, and the median age was 55 years [interquartile
range (IQR) 47–64]. The self-assigned racial profile of
the participants was as follows: 70 (63%) were black,
22 (19%) were white, 9 (8%) were Hispanic/Latino, and DISCUSSION
12 (11%) were categorized as ‘‘other.’’ The majority of
participants, 78 (69%), had a high-school diploma or Our results demonstrate that despite a high level of
less. On a 5-point Likert scale (5 = ‘‘very important’’), expressed concern regarding ACEI AEs, patients’
the median reported level of overall concern for ACEI knowledge of these AEs was poor. This finding is
AEs was 5 (IQR 4–5). Of the 113 participants, only consistent with other studies on patient’s medication
23 (20%: 95%CI 13%–29%) reported hearing the word knowledge.10,11 The reason why knowledge and
‘‘angioedema’’ before they were approached for this awareness of ACEI AEs are so poor remains unknown.
study. Twenty-seven (25%) of the participants reported We were unable to determine any association between
being told that ACEIs have potential AEs at the time of the level of knowledge of AEs with several variables,
the initial prescription; 51% reported receiving this including gender, age, education level, or race/ethnic-
information some time later during their course of ity in an attempt to answer this question.
treatment; and 11% reported hearing about ACEI AEs
from a pharmacist. One hundred and one (89%)
participants did not know that their prescribed Table 1. AE questions answered correctly by race/
antihypertensive medication belonged to a class of ethnicity.
medications known as ACEIs. Median (IQR) n
The correct identification of potential ACEI-associated
AEs was variable with a median of 8 of 16 correctly Black/African American 8/16 (7–10) 70
answered questions and an IQR (6–10). At the 7-day Caribbean 6/16 (5–6) 3
follow-up, the median score was 9 with an IQR (6–10). Hispanic/Latino 7/16 (6–8) 9
There was no association between participant Native American 10/16 (10–10) 1
Other 5.5/16 (5–6) 2
educational level and the number of correct AE
White 8/16 (6–10) 22
responses (P = 0.10). Questions answered correctly
Unspecified 7/16 (6–9) 6 P = 0.08
by participants according to their race/ethnicity are
American Journal of Therapeutics (2012) 19(3) www.americantherapeutics.com
ACEI-Associated Adverse Effects 183

Table 2. Action plan in the event of AEs. At 7-day follow-up, there was minimal improvement
in the knowledge of ACEI AEs. This is surprising given
Difficulty in breathing
the high level of expressed concern regarding AEs in
Call Dr./Nurse 25/113 22.12%
our study and in previous studies.9 Although the Joint
Go to ED 71/113 62.83%
Wait and see 17/113 15.04% Commission has made medication reconciliation a na-
Swelling of the eyes tional safety priority,13 our results call into question the
Call Dr./Nurse 43/113 38.05% efficacy of medication reconciliation in the ED. After
Go to ED 49/113 43.36% administering the study survey instrument, our RAs
Wait and see 21/113 18.58% spent more time reviewing ACEI AEs with participants
Swelling of the tongue than most providers are able to spend talking with their
Call Dr./Nurse 29/113 25.66% patients, so the amount of time spent providing
Go to ED 72/113 63.72% patients with AE information is not likely a limiting
Wait and see 12/113 10.62% factor. Further studies exploring how best to convey
Swelling of the hands and feet*
medical information are warranted.
Call Dr./Nurse 41/113 36.28%
Regarding participants’ action plans in the event of
Go to ED 40/113 35.40%
Wait and see 31/113 27.43% AEs, it appears that most patients would have taken
Diarrhea action if they were to experience any of the symptoms
Call Dr./Nurse 27/113 23.89% read to them. However, the indicated course of action
Go to ED 13/113 11.50% chosen by participants was not always appropriate for
Wait and see 73/113 64.60% the severity of an AE. Our study suggests that at least
Cough for potentially life-threatening symptoms such as ACEI
Call Dr./Nurse 30/113 26.55% angioedema, providers should ensure that patients
Go to ED 11/113 9.73% have an appropriate understanding of that side effect
Wait and see 72/113 63.72% and an appropriate action plan.
Rash
Call Dr./Nurse 51/113 45.13%
Go to ED 21/113 18.58%
Swelling of the lips*
Call Dr./Nurse 45/113 39.82% CONCLUSIONS
Go to ED 42/113 37.17%
Wait and see 25/113 22.12% Despite a high level of expressed interest in medication
Abdominal Pain AEs, most patients do not have an adequate knowledge
Call Dr./Nurse 38/113 33.63% of these AEs or an appropriate action plan. Patients’
Go to ED 44/113 38.94% recognition of ACEI-associated AEs was minimally
Wait and see 31/113 27.43% improved at the 7-day follow up. Further research
Nausea and Vomiting needs to be done to determine whether lack of patient
Call Dr./Nurse 30/113 26.55%
knowledge about serious side effects of ACEIs
Go to ED 35/113 30.97%
contributes to preventable morbidity and mortality
Wait and see 48/113 42.48%
and whether education about an ‘‘ACEI Action Plan’’
*One response missing. can improve patient safety.

We found that only 25% of the participants recalled

being told about ACEI-associated AEs at the time of the
original prescription, and only half reported that they
were given this information later during their treat-
ment. These data suggest a major missed opportunity
to educate patients and therefore a potential risk to
patient safety. There has been some discussion in the
literature indicating that patients’ lack of awareness of
AEs is largely a failure of primary care providers to
inform their patients.8,12 Whether or not primary
prescribers discussed ACEI AEs with patients could
not be confirmed by our study, but it is important to
note that our study participants did not remember
discussing ACEI AEs in the majority of cases.
www.americantherapeutics.com
ACKNOWLEDGEMENTS
We are eternally grateful to Kathy Shea for the
enthusiasm exhibited every day and careful attention
to all details in our Research Section at the Boston
Medical Center. We thank Laura White, PhD, for her
statistical support and all members of the ED staff for
their cooperation throughout this study. Finally, we
would like to extend our heartfelt thanks to the
community of patients at the Boston Medical Center–
without them this and other studies could not have been
done.
American Journal of Therapeutics (2012) 19(3)
184
REFERENCES
1. Chobanian AV, Bakris GL, Black HR, et al. National Heart,
Lung, and Blood Institute Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: the JNC 7 report.
JAMA. 2003;289:2560–2572.
2. Agostoni A, Cicardi M, Massimo C, et al. Angioedema
due to angiotensin-converting enzyme inhibitors. Immu-
nopharmacology. 1999;44:21–25.
3. Agusti A, Bonet S, Arnau J, et al. Adverse effects of ACE
inhibitors in patients with chronic heart failure and/or
ventricular dysfunction. Drug Safety. 2003;26:895–908.
4. Byrd JB, Adam A, Brown NJ. Angiotensin-converting
enzyme inhibitor-associated angioedema. Immunol
Allergy Clin North Am. 2006;26:725–737.
5. Brown NJ, Ray WA, Snowden M, et al. Black Americans
have an increased rate of angiotensin converting enzyme
inhibitor-associated angioedema. Clin Pharmacol Ther.
1996;60:8–13.
6. Banerji A, Clark S, Blanda M, et al. Multi-center study of
patients with angiotensin-converting enzyme inhibitor
induced angioedema presenting to the emergency
American Journal of Therapeutics (2012) 19(3)
Khoubaeva et al
department. Ann Allergy Asthma Immunol. 2008;100:
327–332.
7. Lombardi C, Crivellaro M, Dama A, et al. Are physicians
aware of the side effects of angiotensin-converting
enzyme inhibitors? A questionnaire survey in different
medical categories. Chest. 2005;128:976–979.
8. Wynne HA, Long A. Patient awarness of the adverse
effects of non-steroidal anti-inflammatory drugs
(NSAIDS). Br J Clin Pharmacol. 1996;42:253–256.
9. Ziegler DK, Mosier MC, Buenaver M, et al. How much
information about adverse effects of medication do
patients want from physicians? Arch Intern Med. 2001;
161:706–713.
10. Kompoliti K, Goestz C, Morrissey M, et al. Gilles de la
tourette Syndrome: Patient’s knowledge and concern of
adverse effects. Mov Disord. 2006;21:248–252.
11. Hughes L, Whittlesea C, Luscombe D. Patients’ knowl-
edge and perceptions of the side-effects of OTC
medication. J Clin Pharm Ther. 2002;27:243–248.
12. Gibbs, S, Waters, WE, George, CF. Communicating
information to patients about medicine. Prescription
information leaflets: a national survey. J Roy Soc Med.
1990;83:292–297.
13. Joint Commission. Available at: http://www.
jointcommission.org/AccreditationPrograms/Hospitals/
Standards/09_FAQs/default.htm. Accessed April 22, 2010.
www.americantherapeutics.com