Angiotensin receptor blockers (ARBs) and
angiotensin-converting enzyme (ACE) inhibitors are highly utilized classes of
medications that affect the renin-angiotensin-aldosterone system (RAAS). Both
have been shown to be beneficial in the treatment of disease states--such as
hypertension, chronic heart failure, chronic kidney disease, and myocardial
infarction--in which the RAAS system plays a significant role.1-4
ACE inhibitors and ARBs have similar pharmacologic actions, with the primary
effect being interference of angiotensin II via either receptor inhibition
(ARBs) or decreased production (ACE inhibitors). Angiotensin II is a potent
vasoconstrictor that increases sodium reabsorption, contributes to ventricular
hypertrophy, and produces reactive oxygen species.5 Due to their
similar pharmacologic action, ACE inhibitors and ARBs are thought to have
equivalent efficacy for many indications; however, significant differences
exist with regard to tolerability. Cough and angioedema occur significantly
less frequently with ARBs than they do with ACE inhibitors.
Up to 39% of patients taking ACE inhibitors
experience cough,6-8 presumably related to increased levels of
bradykinin, a potent vasoactive peptide inactivated by ACE (Figure 1).
5,9,10 Since ARBs do not affect ACE, the incidence of cough in patients
taking these agents is much lower and has been found to be comparable to that
of placebo in large clinical trials.11,12 It has become common
practice to substitute ARBs for ACE inhibitors to alleviate cough.13
Controversy exists, however, with regard to caring for patients with ACE
inhibitor–induced angioedema. Given the known mortality benefit of using ACE
inhibitors and ARBs in both heart failure and post–myocardial infarction,
identifying the incidence of ARB-induced angioedema, specifically the
cross-reactivity of ARBs with ACE inhibitor–induced angioedema, carries
important ramifications for clinical practice.
Angioedema is a localized, noninflammatory, nonpruritic swelling of the skin
characterized by a buildup of fluid in the interstitial tissue. It is often
benign but can result in asphyxiation when affecting the skin around the
larynx. It can also involve the lips, tongue, intestine, and other peripheral
tissues, particularly those containing less connective tissue. Genetic
disorders, such as C1 esterase inhibitor protein deficiency, and seasonal
allergies are also risk factors for the development of angioedema.14,15
The common cellular mechanism among these causes appears to be activation of
the complement system and/or other pro-inflammatory cytokines such as
prostaglandins and histamine, which can result in rapid vasodilatation and
edema.16 In addition to ARBs and ACE inhibitors, multiple
medications, including aspirin and nonsteroidal anti-inflammatory medications,
can also induce angioedema.
ACE inhibitor–induced angioedema accounts for 17%
of all patients admitted to medical centers for the treatment of angioedema.
17,18 Studies report that anywhere from 13% to 22% of patients with ACE
inhibitor–induced angioedema will require airway intervention. It has been
theorized that ACE inhibitor–mediated angioedema results from an elevation in
bradykinin levels, similar to cough.9 As in other causes of
angioedema, elevated bradykinin levels in the peripheral tissues results in
rapid fluid accumulation. Currently, this is the most accepted theory for why
ACE inhibitors cause angioedema, but it has not been definitively proven. It
also offers a scientifically sound hypothesis for why ARBs are less likely to
cause angioedema and might serve as potential alternatives in patients with
ACE inhibitor–induced angioedema.19,20 Instances of
ARB-induced angioedema without ACE inhibitor exposure have also been
described. Since ARBs do not increase bradykinin levels to the same degree as
ACE inhibitors, the mechanism by which angioedema occurs with these
medications is largely unknown. One theory is that stimulation of the
angiotensin II receptor activates the bradykinin-prostaglandin-nitric oxide
cascade, resulting in bradykinin-mediated side effects from both ARBs and ACE
inhibitors; however, the angiotensin II function has not been fully elucidated.
19 Thus, until the exact mechanism of angioedema induced by these
medications is known, patients must be monitored for symptoms associated with
either ACE inhibitors or ARBs. Given the potential life-threatening nature of
angioedema, a review of case reports, case series, clinical trial data, and
scientific literature will help determine if hesitancy over cross-reactivity
Incidence of ACE Inhibitor– and ARB-Induced
The first case report of ACE inhibitor–induced angioedema occurred in 1980,
and now, 2 to 10 per 1,000 patients reportedly experience this adverse effect.
15,21 More than 40 million people receive ACE inhibitors worldwide, 60%
of whom develop ACE inhibitor–induced angioedema during the first week of
medication administration.16 This early initiation period has also
been associated with a 14-fold increase in the incidence of angioedema.
9,16,21 The elevated risk persists during the first month of therapy,
accounting for a ninefold increase in incidence.16 There are,
however, case reports of angioedema beyond one year of therapy, possibly
resulting from nonadherence or dose escalation.16 The risk of
developing angioedema has also been associated with smoking, advanced age,
being female or black, and having seasonal allergies.21,22
The exact prevalence and incidence of ARB-induced
angioedema are not known, but are thought to be significantly lower than those
of ACE inhibitors.17 In fact, in 1995, when the first ARBs were
approved for the treatment of hypertension, the risk of angioedema was
considered negligible;23 however, postmarketing surveillance has
shown that this reaction can occur with ARBs. The majority of cases of
ARB-mediated angioedema have been associated with administration of losartan.
It is unclear at this time, however, if all ARBs within the class affect
bradykinin to the same extent, or if another mechanism exists.10 In
one study, Johnsen and colleagues searched a hospital discharge registry of
more than 1.4 million individuals for the incidence of first hospitalization
for nonhereditary angioedema.17 Using prescription databases, they
identified 641 cases of angioedema and cross-referenced these patients to
determine the number of individuals who were currently receiving or had been
receiving ACE inhibitors or ARBs. These cases were then matched with 6,264
control patients from the general population. The incidence of angioedema was
highest in patients who were currently receiving or had received an ACE
inhibitor. Past or present ARB use was not associated with an increase in
first-time hospitalization for angioedema in this study. Although the risk of
angioedema might be lower with ARBs as initial therapy, these findings do not
confirm whether ARBs are appropriate in a patient who has already experienced
ACE inhibitor–induced angioedema. The remainder of this paper will focus on
the literature surrounding this particular question.
Literature Review of Cross-Reactivity
The issue of ARB and ACE inhibitor cross-reactivity has been addressed in
several case reviews. A MEDLINE search conducted by Warner and colleagues
reported findings from one case series and six case reports between 1966 and
1999 that addressed angio edema in patients previously experiencing this
adverse reaction with an ACE inhibitor.21 The case series in their
review included 13 patients with losartan-induced angioedema. Three of the
patients had experienced reactions to an ACE inhibitor.14 Since the
publication of this review, other case reports have echoed the same concern of
cross-reactivity. Cha and Pearson described a 62-year-old black woman who was
admitted for the management of hypertension.13 The patient was
initially treated with beta-blockade and ACE inhibition, and developed
angioedema four days after initiation of captopril. Losartan was then
substituted for captopril, and the patient developed a similar swelling after
only one dose. Likewise, in 2002, a case report described a 27-year-old female
patient with type 1 diabetes who was being treated with enalapril for
microalbuminuria.7 She developed angioedema, which resolved with
discontinuation of enalapril. At her follow-up two months later, she was
prescribed losartan. After three days, she developed a swollen throat and
tongue and was diagnosed again with angioedema. These articles and others have
prompted the initiation of several clinical trials to investigate if an ARB
can be used as a therapeutic alternative in ACE inhibitor–intolerant patients,
including those with angioedema.
Case reports demonstrate that there is some degree
of angioedema cross-reactivity between ACE inhibitors and ARBs; however, the
reports fail to describe the incidence of or identify the mechanism for this
reaction. A trial of 54 patients, all of whom experienced ACE
inhibitor–induced angioedema, was performed to determine the safety of using
other antihypertensive medications in this population.24 After
discontinuing the offending agent, 26 patients were switched to an ARB, 14 to
a calcium channel blocker, and 14 to other various antihypertensive
medications. The patients were followed for one to 80 months, and 81% of the
patients who received an ARB had complete resolution or reduction of
angioedema, compared with 78% of those receiving calcium channel blockers. The
authors reported recurrence of angioedema in only two of 26 patients (8%)
receiving ARBs. A similarly low cross-reactivity was demonstrated in the
angioedema subgroup of patients enrolled in the Candesartan in Heart Failure:
Assessment of Reduction in Mortality and Morbidity–Alternative trial
(CHARM-Alternative), in which 2,028 patients with systolic heart failure who
were ACE inhibitor–intolerant were randomized to receive candesartan or
matching placebo.25 Of the 83 patients who had previously
experienced ACE inhibitor–induced angioedema or anaphylaxis, 39 received
candesartan. During the 38 months of follow-up, angioedema recurred in three
patients (7.7%), and only one patient (2.6%) required discontinuation of
candesartan. On the basis of these two trials, cross-reactivity appears to be
less than 10%, but given the frequency of treatment with these two classes of
medications, further data are needed to validate these results. Currently, the
Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with
Cardiovascular Disease (TRANSCEND) trial, another trial of ARBs in patients
who are ACE inhibitor–intolerant, is underway.26 The
TRANSCEND trial is recruiting patients from 730 centers and 40 countries and
is projected to enroll more than 6,000 subjects who will receive either
telmisartan or placebo. The study's primary outcome is the composite end point
of cardiovascular death, myocardial infarction, stroke, or hospitalization for
heart failure. Depending on the number of patients recruited who have a
history of ACE inhibitor–induced angioedema, the trial might provide more
conclusive data on the incidence of cross-reactivity between ACE inhibitors
A major limitation of postmarketing surveillance and adverse event reporting
is the lack of data on successful actions in clinical practice. There are
multiple case reports, case series, and adverse event data to suggest using
caution when initiating ARBs in patients who previously developed angioedema
with ACE inhibitor therapy. It is not known, however, how many times this
substitution is performed successfully and without adverse effect to the
patient in day-to-day clinical practice. We do know that ARBs and ACE
inhibitors have demonstrated a reduction in mortality for several patient
populations, including those with heart failure and those who have experienced
myocardial infarction. We also know that these classes of medications have
been shown to slow progression of diabetic nephropathy and chronic kidney
disease. To date, the best data on using ARBs in patients with ACE
inhibitor–induced angioedema have come from the prospective, randomized
CHARM-Alternative trial, with cross-reactivity angioedema resulting in
discontinuation of therapy in less then 3% of patients.25 Since
recurrence of angioedema was not a primary outcome, and only 4% of the patient
population had previous angioedema, results of the CHARM-Alternative trial
cannot be considered definitive. It is hoped that the TRANSCEND trial will
corroborate these results with an even larger patient population and further
substantiate the role of ARBs in ACE inhibitor–intolerant patients.
Further study is needed on the mechanism for
angioedema jointly induced by these agents. Pharmacologically, it seems an ARB
should be safe to use in a patient with ACE inhibitor–induced angioedema;
however, we know from the case reports and literature review that
cross-reactivity does occur, albeit at a relatively low frequency. It is
possible that there are common pathways for ACE inhibitor– and ARB-induced
angioedema beyond bradykinin that have yet to be discovered.
Based on the relatively low prevalence of
cross-reactivity in the literature (<10%), and the benefits of angiotensin II
inhibition for certain disease states, ARBs should be considered in patients
with ACE inhibitor–induced angioedema. Thus far, this stance has been adopted
by the National Kidney Foundation guidelines and the American College of
Cardiology and American Heart Association (ACC/AHA) consensus guidelines for
the treatment of heart failure, acute myocardial infarction, and the secondary
prevention of cardiovascular disease.27-30 Given the strong
potential for harm with drug-induced angioedema, however, close monitoring is
necessary to ensure that repeat angioedema does not occur. As new information
regarding the mechanism of drug-induced angioede ma or the
cross-reactivity of ACE inhibitor–induced angioedema with ARBs becomes
available, this issue will require further scrutiny. For now, populations that
have demonstrated a clear benefit from angiotensin II antagonism who have no
alternative--such as those with heart failure or chronic kidney disease, or
those who have had a myocardial infarction--require the best efforts of the
practitioner to initiate these life-prolonging therapies.
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