ACE inhibitor induced angioedema

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 renin inhibitors is also reviewed.

EPIDEMIOLOGY

Angiotensin-converting enzyme (ACE) inhibitors induce angioedema in 0.1 to 0.7 percent of recipients . The incidence of ACE inhibitor-induced angioedema is up to five times greater in people of African descent .

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. Approximately 35 percent of all prescriptions written for antihypertensive medications in the United States are for ACE inhibitors  , and more than 40 million patients in the United States are taking these agents. ACE inhibitors are routinely used in patients with hypertension, myocardial infarction, heart failure with systolic dysfunction, diabetes, and chronic kidney disease.

The overall incidence of angioedema related to ACE inhibitors has been estimated between 0.1 percent and 0.7 percent . However, the lower end of this range may overlap with the background rate of angioedema in the general population. In the TRANSCEND trial of ACE inhibitor-intolerant individuals given an angiotensin II receptor blocker (ARB) or placebo, rates of angioedema were 0.07 and 0.1 percent in the ARB and placebo groups, respectively.

Studies that reported rates of angioedema in patients taking ACE inhibitors include the following:

●In the OCTAVE trial, a prospective study of over 12,500 patients with hypertension treated with enalapril or omapatrilat (an experimental agent), the calculated risk of developing angioedema related to the use of enalapril was 0.68 percent over six months.

●The ONTARGET trial compared ramipriltelmisartan, and combination therapy with both agents in over 25,000 patients with vascular disease or diabetes . The overall incidence was 0.3 percent in the 8500 patients on ACE inhibitors, with a median follow-up of 56 months.

●In a retrospective analysis of 1,845,138 patients 18 years of age and older initiating ACE inhibitor therapy, there were 3301 total angioedema events associated with the use of ACE inhibitor therapy after a mean follow-up duration of 149 days. The overall recorded rate of angioedema was 0.18 percent .

●In a meta-analysis of 26 randomized clinical trials, 394 out of 74,857 patients on ACE inhibitors developed angioedema during a mean duration of 129 weeks, with a weighted incidence of 0.30 percent (95% CI 0.28-0.32).

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 angiotensin-converting enzyme (ACE) inhibitor-induced angioedema, and the presence of urticaria suggests a different group of etiologies. The different mechanisms of angioedema and the etiologies associated with each mechanism are reviewed separately.  

Affected areas — ACE inhibitor-induced angioedema is most commonly reported to affect 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.

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. Rarely, fatalities due to massive tongue swelling and asphyxiation are reported .

Intestine — Visceral angioedema due to ACE inhibitors has been described in a handful of case reports and reviews . Most commonly, this presents as diffuse abdominal pain and diarrhea  . Other symptoms include vomiting, anorexia, or ascites . 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 angioedema .

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. 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 .

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, even if the ACE inhibitor has been discontinued . 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 . 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.  

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  . In the large retrospective study mentioned previously, two-thirds of angioedema episodes occurred within the first three months of therapy . Case reports have documented episodes of angioedema related to ACE inhibitor use after years of stable therapy .

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

Recurrence after stopping ACE inhibitor therapy — 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 . Approximately 88 percent of patients with relapses in angioedema experienced symptoms within the first month after the ACE inhibitor was discontinued, and in some cases, these relapses continued for six months or more. However, in cases where angioedema persisted beyond several weeks, it is also possible that patients had angioedema unrelated to the ACE inhibitor 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.

PATHOPHYSIOLOGY — The clinical features of angiotensin-converting enzyme (ACE) inhibitor 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 pathway (RAA) 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.

Angiotensin II is also responsible for inactivating bradykinin  , while ACE (kininase II) is the primary peptidase involved in the degradation of bradykinin. 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.

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 IV (DPPIV) and kininase I. Des-Arg9-BK is an active metabolite of bradykinin formed primarily due to the kininase I enzyme. The pharmacological 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

●Elevated levels of bradykinin due to impaired metabolism, which leads to release of nitric oxide and prostaglandins, and results in vasodilatation and hypotension

●Elevated levels of des-Arg9-BK, the breakdown product of bradykinin

Role of bradykinin in angioedema — Elevated plasma bradykinin activity has been demonstrated in patients with ACE inhibitor angioedema . 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.  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 . 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 .

Normally, bradykinin is inactivated by ACE, APP, DPPIV, and NEP, as mentioned previously. The APP-inactivated bradykinin metabolite, des–Arg9–BK, is also degraded by DPPIV . Substance P is inactivated primarily by the enzyme DPPIV, although ACE and NEP play a secondary role  . Decreased activity of DPPIV 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 DPPIV) 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 Caucasian patients with a history of ACE inhibitor-induced angioedema, as compared with 39 ACE inhibitor-exposed controls

●Decreased DPPIV 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  .

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 .

RISK FACTORS — Both environmental and genetic factors have been shown to influence the development of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema  . However, at this time, 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

●Age older than 65 years

Aspirin or other nonsteroidal antiinflammatory (NSAID) use

●Female sex

●Smoking

●Seasonal allergies

●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 . Increased rates of angioedema have also been reported in cardiac transplant patients taking everolimus and ACE inhibitors 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 IV (DPPIV) .

●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 . 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.

●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 . The mechanism of ACE inhibitor-induced cough is not precisely known, although it may involve increases in bradykinin, prostaglandins, thromboxanes, and/or substance P  .  

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

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

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. These polymorphisms lead to lower circulating levels of these enzymes, which are responsible for degradation of bradykinin and its active metabolite, des-Arg9-BK. Levels of bradykinin are further increased in the presence of an ACE inhibitor . 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 angioedema  .

●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 .

●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, DPPIV, bradykinin B1 receptor, and the neurokinin 1 (NK1 receptor)] . 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) . 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.  

DIAGNOSIS

The diagnosis of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema is made clinically, based upon the presence of angioedema in a characteristic anatomic site, without itching or urticaria, in a patient taking ACE inhibitors. There are no definitive laboratory tests to diagnose ACE inhibitor-induced angioedema.

●Some authors have advised screening all patients for underlying defects in the complement system with a serum level of complement protein 4 (C4) level , while others advocate for complete laboratory evaluation to include C1 inhibitor function and protein levels, C4 levels, and C1q levels. However, the likelihood of finding such a disorder is low  . 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. If any of these features are present, a C4 level should be obtained to screen for hereditary or acquired C1 inhibitor disorders . A low C4 level requires further evaluation.

●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, as mentioned previously. 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.  

Evaluation of abdominal pain — 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 . CT and abdominal ultrasound are diagnostic in most cases. Typical findings include dilated bowel loops, thickened mucosal folds, perihepatic fluid, ascites, mesenteric edema, and a "doughnut" or "stacked coin" appearance . Magnetic resonance imaging (MRI) and invasive endoscopy should be reserved for use only when ultrasound and CT are nondiagnostic and there is still a high clinical suspicion .

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). Other disorders of bradykinin-mediated angioedema present similarly, and include hereditary angioedema (HAE), acquired angioedema with deficiency of C1 inhibitor, and HAE with normal C1 inhibitor .

 

TREATMENT

The primary treatments of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema are discontinuation of the drug and airway management if the mouth or throat is involved. Additional therapies may be helpful for severe or persistent symptoms.

Airway management — 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.

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 . 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.

Other interventions — Antihistamines, glucocorticoids, and epinephrine are commonly used to treat allergic, histamine-induced angioedema. These medications are not known to alter levels of bradykinin and are usually considered ineffective or minimally effective in treating ACE inhibitor-induced angioedema . Despite this, a small number of studies have reported the apparent benefit with antihistamines in ACE inhibitor-induced angioedema  and intubated patients who were treated with antihistamines were extubated significantly earlier than those who were not in one small study . The data in support of glucocorticoids is even weaker and one report described a patient who was on prednisone when she developed ACE inhibitor-induced intestinal angioedema, suggesting that glucocorticoids did not have a preventative effect .

Additional therapies for severe or persistent symptoms — Additional therapies to speed the resolution of ACE inhibitor-induced angioedema should be considered if the swelling is threatening the patient's airway and does not appear to be stabilizing or improving, such that intubation seems imminent.

The agents discussed below are approved for use in hereditary angioedema (HAE). A more detailed discussion of each of the therapies, including dose, administration, and adverse effects, is found separately.  

Icatibant — Icatibant is a synthetic bradykinin B2-receptor antagonist that is approved for the acute treatment of HAE attacks and has also been shown to be effective for the treatment of ACE inhibitor-related angioedema . This agent (and the others discussed in this section) is most likely to be effective if given in the first few hours of the angioedema attack, when the swelling is increasing, compared with when after the angioedema has peaked and stabilized, based on observations in studies of patients with HAE.

The dose of icatibant is 30 mg (for adults), given by slow subcutaneous injection because of the relatively large volume (3 mL) involved, preferably in the abdominal region . Most patients require only one dose to treat symptoms adequately. However, if symptoms of angioedema are continuing to worsen after 6 hours, a second injection can be given. Exceeding three doses within 24 hours is not recommended. The cost of one 30 mg dose of icatibant was approximately USD $8000 to $9000 at the time of this review.

Efficacy was demonstrated in a randomized trial of 27 adults presenting to the emergency department with angioedema of the upper aerodigestive tract (face, lips, cheeks, tongue, soft palate or uvula, pharynx, or larynx) while taking an ACE inhibitor . To be eligible, patients must have had initial symptoms no more than 10 hours prior to presentation (median time from symptom-onset to treatment was 5 to 6 hours). Subjects received either a single subcutaneous injection of icatibant or "standard therapy" (ie, treatment for histamine-induced angioedema), consisting of the combination of intravenous prednisolone and the antihistamine clemastine. If there was no improvement within 6 hours of initial treatment, rescue therapy consisting of icatibant plus prednisolone could be given. All subjects randomized to icatibant experienced initial relief in approximately 2 hours and complete resolution of angioedema in a median time of 8 hours (interquartile range, 3 to 16). In comparison, those receiving standard therapy had resolution in a median of 27.1 hours (interquartile range, 20 to 48), with three requiring rescue therapy and one undergoing tracheotomy.

Additional small series and case reports also support the efficacy of icatibant in this setting . Icatibant was well-tolerated in the above studies with reports of only pain and local reactions at the injection site that resolved spontaneously within 4 hours of treatment.  

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 . 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  . Results from initial trials were mixed  :

●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 . The study included 76 adults who developed angioedema while taking an ACE inhibitor and presented for emergency care within 12 hours of symptom onset. Conventional therapy (glucocorticoid, antihistamine,epinephrine) could also be administered, and 86 percent received this. The mean time from symptoms onset to treatment was 7.2 hours and 72 percent of patients receiving placebo improved during that time. The primary endpoint was eligibility for discharge within six hours of receiving treatment in both groups, which was not different between the groups.

●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 2 hours of initial observation . The primary endpoint was eligibility for discharge within 4 hours of treatment. Discharge criterial 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.

Thus, the evidence that ecallantide is of benefit in the treatment of ACE inhibitor-induced angioedema is weak at present.  

Fresh frozen plasma — Plasma (solvent detergent-treated plasma or fresh frozen plasma [FFP]) contains the enzyme ACE, and the administration of plasma is thought to degrade high levels of bradykinin with subsequent resolution of angioedema. Case reports have described administration of FFP leading to rapid improvement of ACE inhibitor-induced angioedema without further recurrence of symptoms . 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.  

Purified C1 inhibitor concentrate — Purified C1 inhibitor concentrate has been shown to be effective for ACE inhibitor-induced angioedema in case reports  . One of the functions of C1 inhibitor is the inhibition of kallikrein. Dosing is weight-based and described separately.  

FUTURE USE OF OTHER RELATED DRUGS — A patient who developed angioedema from one angiotensin-converting enzyme (ACE) inhibitor should strictly avoid all other ACE inhibitors. To prevent patients from being given ACE inhibitors in the future, we suggest they obtain a medical alert bracelet (or similar device) indicating that angioedema developed in response to ACE inhibitors.

Angiotensin II receptor blockers — The rate of angioedema with angiotensin-receptor blocker (ARB) therapy is small as demonstrated in a large study  . The mechanism by which ARBs would theoretically precipitate angioedema is not clear .

The following studies evaluated the incidence of angioedema in patients receiving ARBs:

●In a large study of 467,313 patients who were initiated on ARB therapy, there were 288 angioedema events, although the cumulative incidence was similar in ARBs and beta blockers .

●In a meta-analysis of data from 19 trials, the overall incidence of angioedema with ARBs was not significantly different from placebo . 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).

Systematic reviews of the literature describe a 1.5 to 10 percent rate of recurrent angioedema in patients with a history of ACE inhibitor-induced angioedema that were switched to an ARB  . This relatively high rate of recurrence may be misleading and may be attributable to the phenomena discussed previously, ie, that patients with ACE inhibitor-induced angioedema may have one or more additional episodes of angioedema in the weeks to months after the ACE inhibitor is discontinued.

ACE inhibitors and ARBs share many of their cardioprotective effects. Given the available evidence, we do not feel that use of ARBs should be avoided in patients with ACE inhibitor-induced angioedema if ARBs offer an advantage over other antihypertensives for that individual patient. We do recommend routine monitoring of patients to evaluate for potential side effects, as should be done for any patient who is started on a new medication. In addition, we specifically counsel patients that they could have a recurrence of angioedema and review with them how to proceed if this should occur. Another approach is to wait at least four 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.

A small series of 11 patients who developed oral or airway angioedema while receiving ARB therapy found that time to remission was 5 to 7 hours in three patients treated with icatibant, compared with 24 to 54 hours in those treated with glucocorticoids and antihistamines or observation alone . The study did not specify whether these patients had any previous exposure to ACE inhibitors.

Renin inhibitors — Aliskiren was the first oral direct-rennin 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 . Renin inhibitors are thought to provide a more comprehensive inhibition of the renin-angiotensin system compared with ACE inhibitors and ARBs and are thought 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 .

Despite the above conceptual differences between ACE inhibitors and renin inhibitors, angioedema has been reported with aliskiren :

●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 .

●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.

●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)  .

Thus, 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.  

Dipeptidyl peptidase IV inhibitors — The dipeptidyl peptidase IV (DPPIV) inhibitors are a group of medications used in the management of type 2 diabetes. Sitagliptinsaxagliptin, and linagliptin are available in the United States and often used in combination with ACE inhibitor and ARB therapy . The incidence and prevalence of DPPIV inhibitor-associated angioedema is unknown. However, healthcare providers should be aware that angioedema has been associated with DPPIV inhibitors, either alone or when used concomitantly with certain classes of medications, including ACE inhibitors and ARBs .

REFERRAL — Patients with severe angioedema, as well as those in whom complement protein 4 (C4) levels were measured and found to be low, should be referred to a drug allergy expert for further evaluation. In addition, patients in whom angioedema continues to occur beyond the first few months after ACE inhibitor therapy was stopped, should be evaluated further by an allergy or hematology expert for underlying disorders that predispose to angioedema (eg, acquired C1 inhibitor deficiency).  

SUMMARY AND RECOMMENDATIONS

●The overall incidence of angioedema in patients receiving angiotensin-converting enzyme (ACE) inhibitors is between 0.1 percent 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

●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.  

●The clinical features of ACE inhibitor 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.  

●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 upon discontinuation of the ACE inhibitor confirms the diagnosis.

●The primary treatment of ACE inhibitor-induced angioedema is discontinuation of the drug and supportive care until the angioedema resolves. 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.  

●For patients with ACE inhibitor associated angioedema that is threatening the airway and does not appear to be stabilizing or improving, we recommend treatment with icatibant (Grade 1B). If icatibant is not available, we suggest administering another agent that has utility in bradykinin-mediated angioedema (Grade 2C). Options include fresh frozen plasma (FFP), purified C1 inhibitor concentrate, or ecallantide. These agents are most likely to be effective if given within the first several hours of an angioedema episode when the swelling is still increasing.  

●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). However, the risk of recurrent angioedema may be as great as 10 percent, so patients should be informed about how to proceed if symptoms develop. (See 'Angiotensin II receptor blockers' above.)

●Angioedema has been reported with renin inhibitors at rates comparable with those with ACE inhibitors, although the mechanism is likely different. Angioedema has also been reported with dipeptidyl peptidase IV (DDPIV) inhibitors (eg, sitagliptinsaxagliptin, and linagliptin), although these agents are often used in combination with ACE inhibitors and data are limited.