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Author: Kristin Watson, PharmD, BCPS-AQ Cardiology

Angioedema, edema of subcutaneous or submucosal tissues, occurs as a result of an increase in microvascular permeability secondary to elevations in histamine or bradykinin concentrations. This edema can form in the lips, oral cavity, face, neck, gut and/or extremities. Partial or complete airway obstruction can occur. Several hereditary and acquired causes of angioedema exist.  The focus of this piece will be on selecting an appropriate alternative in the setting of angiotensin converting enzyme inhibitor (ACEi)-induced angioedema.1

Angioedema has been reported to occur in up to 0.7% of patients who receive ACEi therapy. 2,3 While the rate of this adverse effect is very low, one should consider that ACEis are the most commonly prescribed antihypertensive class in the United States.4 In 2015, there were over 112 million prescriptions for lisinopril alone.5 A large proportion of angioedema-related emergency room visits are secondary to ACEi therapy. 6,7

Symptoms of angioedema develop and progress over several hours and can last up to 48 to 72 hours.8 These symptoms can be self-limiting; however, patients should be counseled to seek medical attention even if initial symptoms are minor since upper airway obstruction could ensue. Death due to ACEi- angioedema has been reported.

Angioedema secondary to ACEi therapy is proposed to be secondary to elevations in bradykinin. Administration of ACEi therapy prevents the degradation of bradykinin. Bradykinin alters vascular permeability and stimulates the release of substance P; increases in substance P then leads to vasodilation and extravasation of fluid into tissues.9 The risk for developing angioedema is not dose-dependent and can occur anytime during the course of therapy .2 Recurrence of angioedema has been reported after stopping ACEi therapy, with most cases happening within a month of discontinuation.10

It has been consistently reported that black patients are at an increased risk for ACEi-induced angioedema. Other risk factors that have been proposed include, but are not limited to, prior history of drug rash, seasonal allergies, heart failure, allergy to a non-steroidal anti-inflammatory drug and smoking. Concomitant use of an antihistamine, calcium channel blocker, systemic corticosteroid or a dipeptidyl peptidase-IV (DPP-4) inhibitor have also been reported as risk factors for ACEi-induced angioedema.  1,11-14 It is not recommended to use these risk factors in determining whether ACEi therapy should be prescribed to a patient. The decision to use an ACEi, when indicated, should be based on the presence of other contraindications/precautions to use.

An ACEi should not be re-initiated once angioedema occurs, regardless of the severity of the reaction. An alternative treatment should be prescribed. The question is whether an angiotensin II receptor blocker (ARB) can or should be substituted for an ACEi if angioedema occurs. In general, the risk of angioedema with an ARB is reported to be lower than ACEi therapy.15,16  Owing to the low incidence of ACEi-induced angioedema, there is limited information on the rate of cross-reactivity with ARBs.  However, data do suggest that most patients with ACEi-induced angioedema will not develop angioedema with an ARB. It is estimated that the risk of cross-reactivity is < 10%.17-21

One may consider an ARB as an alternative to ACEi if the indication for an ARB can be justified. In other words, the use of an ARB should be deemed to be superior and demonstrate clinically significant improvements in outcomes compared to other potential therapies. For example, the use of ACEi or ARB therapy has been shown to decrease the risk of death and heart failure hospitalization in patients with heart failure with a reduced ejection fraction (HFrEF). Alternative therapies would not achieve this same benefit in this patient population. Hydralazine/nitrate therapy is considered an alternative to ACEi or ARB therapy in this population, but this therapy does not exhibit the same reduction in clinical outcomes. Therefore, an ARB should be considered in a patient with HFrEF and a history of ACEi-induced angioedema. In patients with hypertension, several other medication classes are available that can reduce blood pressure and improve clinical outcomes (e.g., thiazide-like diuretics, calcium channel blockers); thus, an alternative agent to an ACEi or ARB is usually considered.

Patients who are prescribed an ARB after developing ACEi-induced angioedema should be educated on the risk for angioedema since this rare adverse effect can still occur with an ARB. The patient should be instructed to seek medical attention if symptoms develop.


Did You Know?
Sacubitril/valsartan is contraindicated in patients who develop angioedema with either an ACEi or ARB.

In Canada, the use of aliskiren is contraindicated in patients who develop angioedema with aliskiren, an ACEi or ARB.


Kristin Watson, PharmD, BCPS-AQ Cardiology

Dr. Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal



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Quick Guide: ACE Inhibitor-induced Angioedema

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