Angioedema associated with ACE inhibitors

This side effect occurs in approximately 0.1 to 0.7% of users (1) with an increased risk in elderly individuals, females, and the African American population with a prior history of cutaneous drug eruptions, allergy reactions, and patients on immunomodulatory agents (2).

The mechanism underlying the angio-oedema is likely to be the increased availability of bradykinin; this effect may also aggravate the angio-oedema associated with HAE. Angio-oedema associated with angiotensin receptor blockers has been reported infrequently and hence their use in individuals with ACE inhibitor-related angio-oedema has been questioned but is not contra-indicated (3)

• this side effect most commonly affects the face and mucous membranes, lips, tongue and larynx (3)
  
• angioedema is a known uncommon or rare side-effect of ACE inhibitor treatment (4)
  • can either be allergic (histamine-mediated) or less commonly non-allergic (bradykinin-mediated)
  • certain populations, including older adults, women, people who smoke and patients of Black or African Caribbean ethnicity, may be at increased risk of angioedema

Advice for Healthcare Professionals (4):

• angioedema is a known uncommon or rare side-effect of ACE inhibitor treatment. This can either be allergic (histamine-mediated) or less commonly non-allergic (bradykinin-mediated). Healthcare professionals should consider bradykinin-mediated mechanisms as a cause when standard anaphylaxis treatment is ineffective
• angioedema can occur at any time during treatment, including after weeks to years of use
• swelling of the tongue, lip, face, or larynx which may cause difficulty in breathing or swallowing may progress and can lead to airway compromise. Other symptoms can include gastrointestinal pain and cramps
• bradykinin-mediated angioedema is unlikely to respond to standard anaphylaxis treatments including adrenaline (epinephrine)
• lack of response to standard anaphylaxis treatments should prompt consideration of bradykinin-mediated angioedema, with treatment informed by clinical protocols
• if angioedema is suspected in a patient taking an ACE inhibitor, discontinue the ACE inhibitor immediately and do not restart

Notes:

• symptoms are generally self-limiting and resolve spontaneously within 48 to 72 hours (5)
• individuals of Afro-Caribbean origin are at increased risk of ACE inhibitor-induced angio-oedema and as these drugs are less effective in such individuals, an alternative antihypertensive may be prudent (2)
• interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results (5)
  • there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients
• individuals who do not improve even after several months of stopping the ACE inhibitor, probably have idiopathic angio-oedema and are coincidentally taking an ACE inhibitor (1)
  • there are no routine investigations to distinguish responders from non-responders to ACE inhibitor withdrawal
  • if the ACE inhibitor is responsible but is not withdrawn, the attacks may become more frequent and severe. ACE inhibitors are contra-indicated in subjects with a history of chronic angio-oedema, and alternative drugs should be used

Reference:

1. Ameer M. et al. Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A Case Report With a Review of Management Options. Cureus. 2023 Jun; 15(6): e40320.
2. Kostis WJ et al. ACE inhibitor-induced angioedema: a review. Curr Hypertens Rep. 2018;20:55.
3. Maurer M, Magerl M. Differences and similarities in the mechanisms and clinical expression of bradykinin-mediated vs. mast cell-mediated angioedema. Clin Rev Allergy Immunol. 2021;61:40–49.
4. MHRA Drug Safety Update volume 19, issue 11: June 2026: 1.
5. Montinaro V, Cicardi M. ACE inhibitor-mediated angioedema. Int Immunopharmacol. 2020 Jan;78:106081.