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ACE inhibitor-induced angioedema

ACE inhibitor-induced angioedema
Authors:
Autumn Chandler Guyer, MD
Aleena Banerji, MD
Section Editor:
Sarbjit Saini, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Nov 07, 2022.

INTRODUCTION — Angiotensin-converting enzyme (ACE) inhibitors are the leading cause of drug-induced angioedema in the United States because they are so widely prescribed. Patients most commonly present with swelling of the lips, tongue, or face, although another presentation is episodic abdominal pain due to intestinal angioedema. Urticaria and itching are notably absent.

This topic reviews the clinical features, diagnostic evaluation, differential diagnosis, pathophysiology, risk factors, and management of ACE inhibitor-induced angioedema. The use of angiotensin-receptor blockers (ARBs) and related medications in patients who have past angioedema to an ACE inhibitor is also reviewed. An overview of angioedema from all causes is found separately. (See "An overview of angioedema: Clinical features, diagnosis, and management" and "An overview of angioedema: Pathogenesis and causes".)

EPIDEMIOLOGY — ACE inhibitors induce angioedema in 0.1 to 0.7 percent of recipients, with data suggesting a persistent and relatively constant risk over time [1-11]. The incidence of ACE inhibitor-induced angioedema is up to five times greater in people of African descent [12-14].

Although the risk to an individual is relatively low, the large number of people taking these medications means that ACE inhibitors are the leading cause of drug-induced angioedema in the United States, accounting for 20 to 40 percent of all emergency department visits for angioedema each year [15-17]. Approximately 35 percent of all prescriptions written for antihypertensive medications in the United States are for ACE inhibitors [18], and more than 40 million patients globally are taking these agents [1]. ACE inhibitors are routinely used in patients with hypertension, myocardial infarction, heart failure, diabetes, and chronic kidney disease.

CLINICAL FEATURES — Angioedema is an asymmetric, nonpitting swelling of the subcutaneous or submucosal tissues that most commonly affects nondependent areas. There is an absence of itching or urticaria in ACE inhibitor-induced angioedema, and the presence of urticaria suggests a different group of etiologies [19]. The different mechanisms of angioedema and the etiologies associated with each mechanism are reviewed separately. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Types of angioedema'.)

Affected areas — ACE inhibitor-induced angioedema most commonly affects the lips, tongue, face, and upper airway. The intestine can also be involved, presenting as acute abdominal pain with diarrhea or other gastrointestinal symptoms, but this presentation may be less well recognized. The reason that these particular parts of the body are more often affected is not known.

Face, mouth, and upper airway — The edema that occurs from ACE inhibitors usually affects the lips, tongue, and face (picture 1) [20]. Angioedema of the pharynx, larynx, and subglottic area have also been reported. Early signs of laryngeal edema may include hoarseness of the throat and inspiratory stridor, which may progress to airway obstruction in up to 10 percent of cases [15,21]. Rarely, fatalities due to massive tongue swelling and asphyxiation are reported [15,16,22].

Intestine — Visceral angioedema due to ACE inhibitors has been described in a handful of case reports and reviews [23-29]. Most commonly, this presents as diffuse abdominal pain and diarrhea [23-28,30-36]. Other symptoms include vomiting, anorexia, or ascites [37]. In most of these reports, diagnosis was delayed by months to years, because clinicians were not as aware of this potential presentation of ACE inhibitor-induced angioedema [23-27].

In more than one-half of the case reports of visceral angioedema, symptoms began within 72 hours of starting ACE inhibitor therapy, although in other reports, angioedema developed after weeks or years of therapy [29,30,36]. The jejunum is most often involved, followed by the ileum and duodenum. At least one case report documented swelling of the distal antrum and pylorus of the stomach [38].

Findings on imaging — Visceral angioedema can usually be visualized using either abdominal computed tomography (CT) or ultrasound. Typical findings include dilated bowel loops, a "doughnut" or "stacked coin" appearance, thickened mucosal folds, mesenteric edema, perihepatic fluid, and/or ascites [25,39].

Time course — ACE inhibitor-induced angioedema occurs episodically, but each episode follows a relatively predictable time course of two to five days in duration. Swelling usually develops over minutes to hours, peaks, and then resolves over 24 to 72 hours, although complete resolution may take days in some cases [15,31,38]. The pathophysiologic reasons for this pattern are not known. A history of preceding episodes with long symptom-free intervals is not unusual, especially in the case of abdominal or visceral angioedema [23,30]. If the ACE inhibitor is not discontinued, the episode will still resolve, although the frequency and severity of future episodes appears to escalate, and the condition can become life-threatening. (See 'Discontinue ACE inhibitor' below.)

In more than one-half of cases, angioedema occurs during the first week of exposure, although it may occur any time during the course of therapy from hours to years after treatment [10,32,40,41]. In the large retrospective study mentioned previously, two-thirds of angioedema episodes occurred within the first three months of therapy [6]. However, case reports have documented episodes of angioedema related to ACE inhibitor use after years of stable therapy [33,34], with data suggesting a persistent and relatively constant risk annually [10].

Severity — In most cases, the episode of angioedema resolves without complications. However, endotracheal intubation or emergency tracheostomy may be necessary for angioedema obstructing the airway, and fatalities have been reported [42,43].

Risk of additional episodes — Some patients will have additional episodes of angioedema even after stopping the ACE inhibitor. For this reason, it is critical to explain this to patients and provide specific advice about how to proceed if another episode occurs. (See 'Recurrence' below.)

PATHOPHYSIOLOGY — The clinical features of ACE inhibitor-induced angioedema are related to elevated levels of bradykinin, an inflammatory vasoactive peptide, which leads to vasodilation of blood vessels. The pathways involved in bradykinin generation are described briefly here.

ACE inhibition — ACE inhibitors block the effects of the enzyme ACE, also known as kininase II, and impact both the renin-angiotensin-aldosterone (RAA) pathway and the degradation of bradykinin. The RAA cascade is important for regulating renal blood flow and blood pressure. Angiotensinogen, produced in the liver, is converted by renin in the kidney to produce angiotensin I. Angiotensin I is then metabolized to angiotensin II in the lungs by the enzyme ACE (kininase II). Angiotensin II acts as a vasoconstrictor through stimulation of angiotensin I and II receptors.

ACE (kininase II) is the primary peptidase involved in the degradation of bradykinin [44]. Bradykinin is a peptide made of nine amino acids that increases capillary permeability and acts as a potent vasodilator. The production of bradykinin occurs after the precursor kininogen is cleaved by kallikrein, which leads to production of the active form of bradykinin (figure 1).

Bradykinin has a very short half-life (approximately 17 seconds) and is metabolized primarily by ACE (kininase II), neutral endopeptidase (NEP), and aminopeptidase P (APP) and secondarily by the enzymes dipeptidyl peptidase-4 (DPP-4) and kininase I. Des-Arg9-BK is an active metabolite of bradykinin formed primarily due to the kininase I enzyme. The pharmacologic activities of des-Arg9-BK, similar to those of bradykinin, are short-lived because of its breakdown by ACE and APP.

Thus, ACE inhibitor therapy has the following effects in all patients:

Initially, vasodilation due to inhibited production of angiotensin II

Chronically, angiotensin II returns to pretreatment levels through alternative pathways of production by tissue chymases [45]

Bradykinin levels become elevated due to impaired metabolism, which leads to release of nitric oxide and prostaglandins and results in vasodilatation and hypotension [46]

Levels of des-Arg9-BK, the breakdown product of bradykinin, become elevated

In addition, a small study found that serum levels of 6-keto-prostaglandin F1-alpha, a breakdown product of prostaglandins with a longer half-life, increased significantly with 10 mg/day doses as a result of ramipril therapy [47]. Further studies are necessary to determine if this will be a clinically useful biomarker in the future.

Role of bradykinin in angioedema — Elevated plasma bradykinin activity has been demonstrated in patients with ACE inhibitor-induced angioedema [48]. A case report demonstrated a 10-fold increase in bradykinin levels during an episode of angioedema due to use of the ACE inhibitor captopril and returned to normal levels during remission [49,50]. High levels of bradykinin stimulate vasodilation and increased vascular permeability of the postcapillary venules and allows for plasma extravasation into the submucosal tissue, leading to angioedema [49,51]. Substance P can also increase vascular permeability, leading to angioedema.

ACE inhibitor-induced angioedema is thought to result from defective degradation of at least three vasoactive peptides: bradykinin, des-Arg9-BK (a metabolite of bradykinin), and substance P [52,53].

Normally, bradykinin is inactivated by ACE, APP, DPP-4, and NEP, as mentioned previously. The APP-inactivated bradykinin metabolite, des-Arg9-BK, is also degraded by DPP-4 [54]. Substance P is inactivated primarily by the enzyme DPP-4, although ACE and NEP play a secondary role [54,55]. Decreased activity of DPP-4 correlated to a prolonged half-life of substance P but only in the presence of ACE inhibition, suggesting a requirement for multiple enzyme defects to inhibit degradation.

When ACE is inhibited by drug therapy, the secondary bradykinin metabolic enzymes (APP, kininase I, NEP, and DPP-4) play a relatively larger role in degrading bradykinin, des-Arg9-BK, and substance P. Thus, defects or deficiencies in these enzymes theoretically predispose patients to developing angioedema when taking an ACE inhibitor. Studies that support this mechanism include the following:

Decreased APP activity was demonstrated in the sera of 39 White patients with a history of ACE inhibitor-induced angioedema, as compared with 39 ACE inhibitor-exposed controls [56].

Decreased DPP-4 antigen and activity levels were found in the sera of 50 patients with a history of ACE inhibitor-induced angioedema, as compared with 176 ACE inhibitor-exposed controls [57].

In addition to the above, approximately one-half of patients experiencing ACE inhibitor-induced angioedema also have an enzyme defect involved in des-Arg9-BK metabolism, leading to its accumulation when ACE is inhibited [58].

RISK FACTORS — Both environmental and genetic factors have been shown to influence the development of ACE inhibitor-induced angioedema [12-15,54-57,59-63]. However, there is no standardized genetic or laboratory evaluation that can identify (in advance) individual patients who are at an increased risk for developing ACE inhibitor-induced angioedema.

Possible risk factors — Potential risk factors include the following:

History of previous episodes of angioedema [12,15,59].

Age older than 65 years [12].

Aspirin or other nonsteroidal anti-inflammatory (NSAID) use [12,15,59].

History of angioedema related to NSAID use [10].

Female sex [12,15,59].

Smoking [57].

Seasonal allergies [12].

Use of the mechanistic target of rapamycin (mTOR) inhibitors, sirolimus or everolimus, has been shown to predispose to angioedema when combined with ACE inhibitor use in renal transplant recipients, due to reduced metabolism of bradykinin [60,64]. Increased rates of angioedema have also been reported in cardiac transplant patients taking everolimus and ACE inhibitors [65]. Ramipril was restarted at lower doses in all patients at lower sirolimus levels with no adverse effects, suggesting a dose-dependent effect of this combination of drugs on the development of angioedema. In general, transplant patients are thought to be at increased risk of ACE inhibitor-induced angioedema because of the effects of immunosuppressants on decreasing the activity of circulating levels of dipeptidyl peptidase-4 (DPP-4) [66].

Underlying C1 inhibitor deficiency or dysfunction predisposes individuals to episodes of bradykinin-mediated angioedema, independently of ACE inhibitors, although some patients are asymptomatic until exposed to these drugs [48]. Both hereditary (hereditary angioedema [HAE]) and acquired forms of C1 inhibitor disorders exist. Patients already known to have these rare disorders should not be given ACE inhibitors. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

History of ACE inhibitor-induced cough was found to be an independent risk factor for developing ACE inhibitor-related angioedema in one retrospective cohort study [48]. The mechanism of ACE inhibitor-induced cough is not precisely known, although it may involve increases in bradykinin, prostaglandins, thromboxanes, and/or substance P [67,68]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Cough'.)

In contrast, the risk of angioedema is not related to the specific agent administered or to dose [2,41]. There appears to be a reduced risk of angioedema due to ACE inhibitors in people with diabetes [3,57].

Predisposing genetic factors — The following genetic factors are believed to impact the risk of ACE inhibitor-induced angioedema:

The incidence of ACE inhibitor-induced angioedema is up to five times greater in people of African descent, as mentioned previously [12-14]. (See 'Epidemiology' above.) One possible explanation for this heightened susceptibility is the presence of genetic polymorphisms in the enzymes aminopeptidase P (APP) and neutral endopeptidase (NEP), which occur at a greater rate in African Americans [56]. These polymorphisms lead to lower circulating levels of these enzymes, which are responsible for degradation of bradykinin and its active metabolite, des-Arg9-BK [54]. Levels of bradykinin are further increased in the presence of an ACE inhibitor [54,57]. Despite these polymorphisms, ACE inhibitors are considered beneficial in the treatment of hypertension in patients of African descent.

In other populations, genetic polymorphisms in the gene that encodes APP (XPNPEP2) lead to decreased APP activity and higher levels of bradykinin and des-Arg9-BK, which have been associated with a higher prevalence of ACE inhibitor-induced angioedema [61,62,69].

Insertion/deletion polymorphisms have been described in the ACE gene and have been associated with reduced expression of ACE and a decrease in the degradation of bradykinin. Although theoretically relevant, there does not appear to be a link between ACE gene polymorphisms and the occurrence of ACE inhibitor-induced angioedema [63].

Genetic variations in the enzyme neprilysin have been preliminarily implicated. In a genome-wide association study (GWAS) of 175 individuals with ACE inhibitor-induced angioedema and 489 ACE inhibitor-exposed controls, genotyping was performed for polymorphisms in genes encoding the bradykinin-degrading or substance P-degrading enzymes (carboxypeptidase N, neprilysin, APP, DPP-4, bradykinin B1-receptor, and the neurokinin 1 [NK1] receptor) [70]. No single gene appeared to have a large effect size, suggesting that ACE inhibitor-induced angioedema behaves like a complex trait. There were two single nucleotide polymorphisms (SNPs) that were modestly associated with an increased rate of angioedema. Using a candidate gene approach, a polymorphism in the first intron of the neprilysin gene was detected that was associated with an increased risk of angioedema in two subjects. Additional evidence implicating neprilysin was found in the OCTAVE trial (discussed above) [5]. Patients treated with omapatrilat, a combined inhibitor of ACE and neprilysin, demonstrated a threefold increased risk of angioedema, compared with those treated with enalapril alone. (See 'Epidemiology' above.)

DIAGNOSIS — The diagnosis of ACE inhibitor-induced angioedema is made clinically, based on the presence of angioedema, without itching or urticaria, affecting a characteristic anatomic site, in a patient taking ACE inhibitors. In this scenario, the ACE inhibitor should be discontinued and assumed to be the cause until proved otherwise.

The diagnosis is confirmed when the ACE inhibitor is discontinued and no further angioedema episodes occur. However, the impact of discontinuation may only be clear after several months, as some patients will have a small number of recurrent episodes, particularly in the first few months after the ACE inhibitor was discontinued. (See 'Recurrence' below and 'Referral' below.)

Laboratory evaluation — There are no definitive laboratory tests to diagnose ACE inhibitor-induced angioedema. ACE inhibitor-induced angioedema is far more common than any of the other rare angioedema disorders [71]. However, obtaining a serum level of complement protein 4 (C4) is reasonable if there is any clinical suspicion that another cause of bradykinin-mediated angioedema could be present. A C4 is definitely indicated if the patient has a family history of angioedema or has an underlying lymphoproliferative disorder (such as monoclonal gammopathy of uncertain significance or lymphoma) or other malignancy [71,72]. In addition, patients with rare angioedema disorders are at higher risk of developing angioedema with ACE inhibitor therapy, such that ACE inhibitors can "unmask" an underlying disorder. A low C4 level requires further evaluation. (See 'Referral' below.)

A low C4 should prompt a more complete laboratory evaluation, including C1 inhibitor function and protein levels, C4 level, and C1q levels. The complement abnormalities seen in these different angioedema disorders are summarized in the table (table 1).

Studies to date have been unsuccessful at identifying specific laboratory biomarkers for ACE-inhibitor induced angioedema, although a study looking at patients with both bradykinin-mediated angioedema and histamine/mast cell-mediated angioedema identified significantly increased levels of fibroblast activation protein alpha (FAP-alpha) and tissue-type plasminogen activator (tPA) in both types of angioedema compared with controls. Only bradykinin-mediated angioedema showed increased levels of serum E-selectin and angiopoietin-2 compared with controls. Additional studies are needed to determine the clinical relevance of these findings [73].

Discontinuation of the ACE inhibitor and monitoring for resolution of symptoms confirms the diagnosis. However, the impact of discontinuation may only be clear after several months, as some patients will have a small number of recurrent episodes, particularly in the first few months after the ACE inhibitor was discontinued. Such patients should remain off ACE inhibitors. Referral to an allergy expert should be considered for patients who continue to have episodes of angioedema after six months. (See 'Recurrence' below and 'Referral' below.)

Evaluation of abdominal symptoms — If visceral angioedema is suspected in a patient taking an ACE inhibitor and presenting with acute abdominal pain, noninvasive imaging, such as ultrasonography or computed tomography (CT), should be performed to confirm bowel edema and/or ascites [38]. CT or abdominal ultrasound are diagnostic in most cases. Magnetic resonance imaging (MRI) and invasive endoscopy should be reserved for cases in which ultrasound and CT are nondiagnostic and there is still a high clinical suspicion [23]. (See 'Findings on imaging' above.)

DIFFERENTIAL DIAGNOSIS — In general, angioedema can be caused by either the generation of bradykinin or by activation of mast cells and release of various mast cell mediators (including histamine). Mast cell-mediated angioedema is reviewed separately. (See "An overview of angioedema: Pathogenesis and causes", section on 'Causes'.)

Other rare disorders of bradykinin-mediated angioedema present similarly to ACE inhibitor-induced angioedema, and include (algorithm 1):

Hereditary angioedema (HAE) (see "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis")

HAE with normal C1 inhibitor (see "Hereditary angioedema with normal C1 inhibitor")

Acquired angioedema with deficiency of C1 inhibitor, which is associated with lymphoproliferative disorders (see "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis")

Angioedema induced by other medications [74]

MANAGEMENT — The primary treatments of ACE inhibitor-induced angioedema are acute airway management if the mouth or throat is involved (until the angioedema episode has resolved) and discontinuation of the drug.

Airway monitoring — If the mouth or throat is involved, the airway should be immediately evaluated and repeatedly monitored until the swelling is clearly resolving. Prompt intubation and mechanical ventilation may be required. (See "Approach to the anatomically difficult airway in adults outside the operating room" and "Devices for difficult emergency airway management in adults outside the operating room" and "Approach to the failed airway in adults outside the operating room".)

Discontinue ACE inhibitor — Angioedema caused by ACE inhibitors usually resolves within 24 to 72 hours. If ACE inhibitors are continued, there is an increased and unpredictable rate of angioedema recurrence, and attacks may become more severe or life-threatening [35,75]. Patients who have experienced angioedema attributed to an ACE inhibitor should never again be treated with this group of medications.

If the cause of a patient's angioedema is unclear, we would still advise discontinuation of ACE inhibitors. If the patient experiences recurrent episodes of angioedema beyond several months, then the cause of the angioedema is likely not the ACE inhibitor, and other etiologies should be explored. (See 'Referral' below.)

Therapies of unproven efficacy — There are several therapies that are effective for aborting attacks of angioedema in hereditary angioedema (HAE), which is the best studied form of bradykinin-mediated angioedema. These include C1 inhibitor concentrate, ecallantide, icatibant, and possibly fresh frozen plasma. In theory, these therapies should also be helpful in ACE inhibitor-induced angioedema, but available studies are conflicting [76-79]. There may be several reasons for this:

There is no quick diagnostic test to determine if a patient's angioedema is bradykinin-mediated or mast cell/histamine-mediated. The diagnosis of ACE inhibitor-induced angioedema is presumptive in a patient with angioedema who is taking an ACE inhibitor, so there are likely patients in each of these trials who are incorrectly categorized as having ACE inhibitor-induced angioedema.

Although both HAE and ACE inhibitor-induced angioedema are believed to be bradykinin-mediated, the angioedema attacks are likely different in other ways. Patients with HAE have repeated attacks of angioedema and learn to recognize prodromal symptoms and self-administer treatment or seek emergency care in the earliest stages of an attack. Studies demonstrating efficacy of HAE therapies have required that patients present in the first few hours of symptoms. In contrast, most patients with ACE inhibitor-induced angioedema have not experienced angioedema before and thus present significantly later for care.

For these reasons, the utility of HAE therapies for patients with ACE inhibitor-induced angioedema may be limited, and we cannot recommend their use in most situations. However, we propose that there are uncommon scenarios in which the clinician may consider their use. As an example, if a patient presents with severe angioedema that is threatening the airway and actively worsening, has no history of previous angioedema, is on ACE inhibitor therapy, and can receive one of the HAE therapies within the first few hours from symptom onset, then we would advocate its use.

A more detailed discussion of each of the therapies, including dose, administration, and adverse effects, is found separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'First-line agents: Dosing, efficacy, and adverse reactions'.)

Tranexamic acid — A retrospective review evaluated 33 patients presenting for emergency care with severe angioedema while taking an ACE inhibitor, who were treated with either intravenous or oral tranexamic acid as an initial therapy [80]. Doses ranged from 0.5 grams to 4 grams, with most patients receiving 1 gram. Improvement was observed within one hour in 13 of 33 patients, and tranexamic acid was sufficient to manage the angioedema in 27, while 6 showed partial improvement and were then given either icatibant (5) or C1 inhibitor concentrate (1). None required intubation [81,82].

Ecallantide — Ecallantide is a recombinant protein that is approved for use in acute treatment of HAE attacks. Ecallantide inhibits the conversion of high molecular weight kininogen to bradykinin by inhibiting plasma kallikrein (figure 1). However, ACE inhibitor-induced angioedema is caused by the persistence of bradykinin due to lack of metabolism, rather than overproduction, so it is not entirely intuitive that ecallantide would be effective [33]. The evidence that ecallantide is of benefit in the treatment of ACE inhibitor-induced angioedema is mixed [83,84]:

One randomized trial found no difference in the amount of time required for patients to be safely discharged following treatment with either ecallantide (at doses of 10 mg, 30 mg, or 60 mg) or placebo [84]. The study included 76 adults who developed angioedema while taking an ACE inhibitor and presented for emergency care within 12 hours of symptom onset.

Another randomized trial of 50 adults assigned subjects to ecallantide (30 mg) or placebo (in addition to conventional therapy with glucocorticoids and antihistamines), required that subjects presented within 12 hours of symptom-onset and developed worsening symptoms or did not improve during two hours of initial observation [83]. The primary endpoint was eligibility for discharge within four hours of treatment. Discharge criteria were met in 31 versus 21 percent of subjects receiving ecallantide and placebo, respectively (95% CI, –14 to 34 percent). Thus, there appeared to be some benefit to therapy, although confidence intervals overlapped no effect.

(See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Kallikrein inhibitor (United States only)'.)

Purified C1 inhibitor concentrate — Purified C1 inhibitor concentrate has appeared helpful for ACE inhibitor-induced angioedema in case reports [85-89]. One of the functions of C1 inhibitor is the inhibition of kallikrein. Similar to icatibant, this therapy is most likely to be beneficial if given within a few hours of symptom onset. (See 'Icatibant' below.)

Dosing is reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'C1 inhibitor (plasma-derived)' and "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Recombinant C1 inhibitor'.)

Fresh frozen plasma — Plasma (solvent detergent-treated plasma or fresh frozen plasma) contains the enzyme ACE, and the administration of plasma is thought to degrade high levels of bradykinin with subsequent resolution of angioedema. The usual dose of plasma is 2 units for adults. In the reports described, swelling usually resolved within two to four hours of plasma administration. Case reports have described administration of fresh frozen plasma leading to rapid improvement of ACE inhibitor-induced angioedema without further recurrence of symptoms [90-92]. However, the levels of ACE in individual units of plasma can vary significantly [93]. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Plasma'.)

Icatibant — Icatibant is a synthetic bradykinin B2-receptor antagonist that is approved for the acute treatment of HAE attacks (figure 1). Case reports, small series, and one randomized trial initially provided initial support for the use of icatibant for ACE inhibitor-induced angioedema [64,76,94-100]. However, this was followed by two larger randomized trials with negative results, such that the cumulative data do not support the use of icatibant [77,78].  

DISCHARGE COUNSELING — Patients who have experienced ACE inhibitor-induced angioedema should be educated about the following:

The need to avoid all ACE inhibitors in the future.

The risk of recurrent episodes of angioedema in the first few months after the ACE inhibitor is discontinued. (See 'Recurrence' below.)

The need to determine if a replacement therapy is needed for the condition that the ACE inhibitor was treating.

Written instructions — A handout for patients who have experienced ACE inhibitor-induced angioedema is provided. (See 'Information for patients' below.)

RECURRENCE — Some patients experience one or more recurrent angioedema episodes in the months after the causative ACE inhibitor has been discontinued. In a long-term retrospective study, 111 patients with ACE inhibitor-induced angioedema were followed for at least 1 year and up to 14 years [35]. After stopping the ACE inhibitor, 46 percent had recurrences of angioedema. In 88 percent of patients with recurrences, episodes occurred within the first month after the ACE inhibitor was discontinued, although recurrences continued for six months or more in other patients. However, in cases where angioedema persisted beyond several weeks, it is also possible that ACE inhibitors were not the true culprit or that the patient had an underlying predisposition to develop angioedema that was exacerbated (but not entirely caused) by the presence of an ACE inhibitor.

FUTURE USE OF RELATED DRUGS — Drugs mechanistically related to ACE inhibitors include angiotensin-receptor blockers (ARBs), the combination of an ARB and a neprilysin inhibitor (known as angiotensin receptor-neprilysin inhibitor or ARNI), renin inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors.

Angiotensin II receptor blockers — Angiotensin-II receptor blockers (ARBs) have cardioprotective effects that are similar to those of ACE inhibitors. Although earlier systematic reviews described a 1.5 to 10 percent rate of recurrent angioedema in patients with a history of ACE inhibitor-induced angioedema who were switched to an ARB [101,102], subsequent studies have not found ARBs to be associated with higher rates of angioedema than other antihypertensives (eg, beta blockers) [6,9,103]. The findings of earlier studies may be attributable to the phenomena discussed previously, ie, that patients with ACE inhibitor-induced angioedema who are switched to ARBs may have one or more additional episodes of angioedema in the ensuing weeks to months that are still due to the lingering effects of the discontinued drug. (See 'Recurrence' above.)

From a pharmacologic perspective, ARBs do not interfere as directly with bradykinin metabolism (figure 1). Therefore, we do not believe that ARBs should be avoided in patients with ACE inhibitor-induced angioedema if ARB therapy offers an advantage over other antihypertensives for that individual patient.

The following studies found a low incidence of angioedema in patients receiving ARBs [6,9,103]:

A nationwide cohort study found that among 5507 patients with prior ACE inhibitor-induced angioedema, the incidence of angioedema was significantly lower in patients treated with ARBs than in those treated with other antihypertensive agents (beta blockers, calcium channel blockers, or thiazides) (adjusted hazard ratio 0.39; 95% CI 0.30-0.51) [103].

In a meta-analysis of data from 19 trials, the overall incidence of angioedema with ARBs was not significantly different from placebo [9]. This analysis included 35,479 patients (mean age 61 years, 59 percent men) of whom 52 developed angioedema during a mean duration of 120 weeks, for a weighted incidence of 0.11 percent (95% CI 0.09-0.13).

When changing patients from an ACE inhibitor to an ARB, we specifically explain that they could have a recurrence of angioedema and review with them how to proceed if this should occur. Written instructions are provided. (See 'Information for patients' below.)

Another approach is to wait four to six weeks after an ACE inhibitor is discontinued before starting an ARB. However, this is only appropriate if the patient can safely go without the medication for this period of time.

ARNIs — Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor combination drug (ARNI) used in the management of heart failure with reduced ejection fraction. ARNIs should not be given to patients with previous angioedema to an ACE inhibitor, because they cause angioedema at rates similar to ACE inhibitors (0.5 percent versus 0.2 percent with enalapril in the PARADIGM-HF trial) [104]. The incidence of angioedema in Black patients was significantly higher (2.4 percent with sacubitril-valsartan and 0.5 percent with enalapril). (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)

Renin inhibitors — More clinical experience with the use of renin inhibitors is needed to understand the risk of angioedema with these agents. Until more information is available, caution is warranted. Aliskiren was the first oral direct-renin inhibitor approved by the US Food and Drug Administration (FDA) in 2007 for the treatment of hypertension, and several other direct-renin inhibitors are in the early stages of development [105]. Renin inhibitors are thought to provide a more comprehensive inhibition of the renin-angiotensin system compared with ACE inhibitors and ARBs and appear to have different safety profiles. Theoretically, aliskiren should not confer a risk of bradykinin-induced angioedema, because unlike ACE inhibitors, it has no known effect on bradykinin metabolism. In a case series, a patient with life-threatening angioedema while receiving an ACE inhibitor did not experience subsequent angioedema episodes when treated with long-term aliskiren [106].

Despite the above conceptual differences between ACE inhibitors and renin inhibitors, angioedema has been reported with aliskiren [6,9,107,108]:

In a meta-analysis that pooled data from 12 randomized-controlled trials of 12,188 patients treated with aliskiren for hypertension, the incidence of angioedema with aliskiren treatment was 0.4 percent and similar to the risk with ACE inhibitors [108].

A subsequent study followed 4867 adult patients initiated on aliskiren therapy, among whom there were seven associated angioedema events and one case of serious angioedema [6].

In a meta-analysis of 5141 patients on aliskiren, 7 developed angioedema during a mean duration of 24 weeks with an incidence of 0.13 percent (95% CI 0.07-0.19) [9].

(See "Renin-angiotensin system inhibition in the treatment of hypertension", section on 'Direct renin inhibitors'.)

Dipeptidyl peptidase-4 inhibitors — The dipeptidyl peptidase-4 (DPP-4) inhibitors are a group of medications used in the management of type 2 diabetes. Sitagliptin, saxagliptin, and linagliptin are available in the United States and often used in combination with ACE inhibitor and ARB therapy [109,110]. The incidence and prevalence of DPP-4 inhibitor-associated angioedema is unknown. However, health care providers should be aware that angioedema has been associated with DPP-4 inhibitors, either alone or when used concomitantly with certain classes of medications, including ACE inhibitors and ARBs [109,111-113]. The proposed mechanism is reduced clearance of bradykinin, because DPP-4 is an enzyme that is involved in bradykinin metabolism (figure 1). (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)

NSAIDs — Nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate some bradykinin-mediated forms of angioedema, but clear evidence of this in patients with an episode of ACE inhibitor-induced angioedema is lacking. Therefore, we do not counsel patients to avoid NSAIDs in the future, unless the episodes of angioedema continue to occur after approximately six months. (See 'Recurrence' above.)

REFERRAL — Indications for referral to an allergy specialist include the following:

Patients in whom complement protein 4 (C4) levels were measured and found to be low.

Patients in whom angioedema continues to occur beyond the first few months after ACE inhibitor discontinuation, as such patients may have underlying disorders that predispose to angioedema (eg, acquired C1 inhibitor deficiency). (See 'Differential diagnosis' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Angioedema caused by ACE inhibitor medicines (The Basics)")

SUMMARY AND RECOMMENDATIONS

Incidence – The overall incidence of angioedema in patients receiving angiotensin-converting enzyme (ACE) inhibitors is between 0.1 and 0.7 percent. ACE inhibitors are the leading cause of drug-induced angioedema, accounting for up to 40 percent of emergency visits for angioedema. (See 'Epidemiology' above.)

Clinical features and timing – ACE inhibitor-induced angioedema usually affects the lips, tongue, and face, although visceral edema presenting as acute abdominal pain is also possible. Urticaria and itching are absent. Symptoms typically begin during the first week of treatment, although some cases develop after years of uneventful therapy. (See 'Clinical features' above.)

Pathophysiology and risk factors – The clinical features of ACE inhibitor-induced angioedema are related to elevated levels of bradykinin, an inflammatory vasoactive peptide, which leads to vasodilation of blood vessels. The risk of angioedema with an ACE inhibitor is not related to agent or dose. Lower levels or defects in enzymes that degrade bradykinin and similar compounds may predispose certain patients to angioedema, which is one identified reason that patients of African descent are more susceptible. (See 'Pathophysiology' above and 'Risk factors' above.)

Diagnosis is clinical – The diagnosis of ACE inhibitor-induced angioedema is made clinically, as there are no definitive laboratory tests that are routinely available to diagnose ACE inhibitor-induced angioedema. Resolution following discontinuation of the ACE inhibitor confirms the diagnosis. (See 'Diagnosis' above.)

Management

The primary acute treatment of ACE inhibitor-induced angioedema is supportive care until the angioedema resolves. (See 'Management' above.)

Careful attention to the airway is critical if tongue or laryngeal swelling is present, because airway obstruction occurs in up to 10 percent of cases. Intubation and mechanical ventilation may be required. (See 'Airway monitoring' above.)

Therapies for hereditary angioedema (HAE), a disorder that is also bradykinin-mediated, may be beneficial in ACE inhibitor-induced angioedema, but studies are conflicting and early administration appears to be critical, such that the real-world utility of these agents is limited. Thus, we do not advocate using them in most situations. However, for the rare patient who presents with severe and worsening angioedema potentially compromising the airway, in whom symptoms began no more than approximately six hours earlier, bradykinin-targeting therapies may be beneficial. (See 'Therapies of unproven efficacy' above.)

Patient education – Patients should be counseled that angioedema can recur in the first few months after stopping an ACE inhibitor and given advice about how to proceed if symptoms develop again. A patient handout is provided. (See 'Information for patients' above.)

Future use of related medications

In patients with a history of ACE inhibitor-induced angioedema, we suggest not avoiding angiotensin-receptor blockers (ARBs) if an ARB has advantages over other agents for that patient (Grade 2C). (See 'Angiotensin II receptor blockers' above.)

Angioedema has been reported with angiotensin receptor-neprilysin inhibitor (ARNIs) at rates comparable with those with ACE inhibitors, and ARNIs should not be given to patients with previous ACE inhibitor-induced angioedema. Caution is warranted with several other related drugs, including renin inhibitors and dipeptidyl peptidase-4 (DDP-4) inhibitors (eg, sitagliptin, saxagliptin, and linagliptin), although data are limited. (See 'Future use of related drugs' above.)

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