What is the cause of angioedema in patients treated with Angiotensin-Converting Enzyme (ACE) inhibitors?

From the Guidelines

ACE inhibitor-induced angioedema is caused by bradykinin accumulation rather than an allergic mechanism, which explains why it can occur after years of uneventful use and why antihistamines have limited effectiveness. This condition requires immediate discontinuation of the ACE inhibitor and permanent avoidance of all drugs in this class. The management of ACE-I–associated angioedema is discontinuation of the ACE-I 1. If a patient develops angioedema while taking an ACE inhibitor like lisinopril, enalapril, or ramipril, the medication should be stopped immediately and never restarted.

Some key points to consider in the management of ACE inhibitor-induced angioedema include:

• Discontinuation of the ACE inhibitor is the cornerstone of therapy for these patients 1
• Treatment with antihistamines, corticosteroids, or epinephrine has not been shown to be efficacious 1
• Efficacy of icatibant and fresh frozen plasma have been described for ACE-I–associated angioedema; however, no controlled studies have been reported 1
• African American subjects are at a substantially higher risk of experiencing ACE-I–induced angioedema than white subjects 1
• Other factors that increase the risk of angioedema from ACE-Is include a history of smoking, increasing age, and female sex 1

For patients still requiring blood pressure or heart failure management, alternative medications should be considered. Angiotensin receptor blockers (ARBs) like losartan or valsartan can be used, though there is a small cross-reactivity risk (about 2% to 17%) 1. Calcium channel blockers, thiazide diuretics, or beta-blockers are safer alternatives with no cross-reactivity. Patients should be educated about this reaction and instructed to inform all healthcare providers about their ACE inhibitor intolerance to prevent accidental re-exposure.

From the Research

Cause of Angioedema in Patients Treated with ACE Inhibitors

• The exact cause of angioedema in patients treated with Angiotensin-Converting Enzyme (ACE) inhibitors is not fully understood, but it is believed to be related to the increased levels of bradykinin, a potent vasodilator 2, 3.
• ACE inhibitors block the conversion of angiotensin I to angiotensin II, but they also inhibit the breakdown of bradykinin, leading to increased levels of bradykinin in the body 3, 4.
• The increased levels of bradykinin can cause blood vessels to dilate, leading to increased permeability and swelling of the tissues, which can result in angioedema 3, 4.
• Other factors that may contribute to the development of angioedema in patients treated with ACE inhibitors include:
  • Genetic predisposition 3
  • Female sex 3, 4
  • African American ethnicity 3, 4
  • History of drug rash, seasonal allergies, or immunosuppressive therapy 4
  • Smoking 4
  • Older age 4

Pathophysiology of ACE Inhibitor-Induced Angioedema

• The pathophysiology of ACE inhibitor-induced angioedema involves the inhibition of bradykinin and substance P degradation by ACE (kininase II), leading to vasodilatation and plasma extravasation 4.
• The increased levels of bradykinin and substance P can cause increased permeability of blood vessels, leading to swelling of the tissues and angioedema 4.

Incidence and Risk Factors

• The incidence of angioedema in patients treated with ACE inhibitors is estimated to be between 0.1% and 0.7% 2, 3, 5, 4.
• The risk of angioedema is higher in certain populations, including African Americans, women, and older individuals 3, 4.
• Patients with a history of drug rash, seasonal allergies, or immunosuppressive therapy may also be at higher risk of developing angioedema 4.