ACE-inhibitors: distinction between bradykinin- and histamine-mediated angioedema and treatment strategies

- 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

The product information for all ACE inhibitors is being updated to strengthen the warnings on the risk of delayed-onset angioedema, which may still occur after weeks to years of use. Healthcare professionals, particularly in emergency departments, should be aware of the potential for delayed onset of angioedema and the distinction between bradykinin- and histamine-mediated cases, as treatment strategies differ significantly and bradykinin-mediated angioedema does not respond to standard treatment.

ACE inhibitors are indicated for the treatment of hypertension, heart failure, post-myocardial infarction management, diabetic nephropathy, and cardiovascular risk reduction.

Angioedema is characterised by localised swelling of subcutaneous or submucosal tissues. Unlike histamine-mediated (allergic) angioedema, bradykinin-mediated angioedema usually occurs without urticaria and typically has a slower onset. Symptoms may involve the tongue, lips, and upper airway, and can be life-threatening.

Although uncommon or rare, ACE inhibitors are associated with both histamine-mediated and bradykinin-mediated angioedema. Certain populations, including older adults, women, people who smoke and patients of Black  or African Caribbean ethnicity, may be at increased risk of angioedema.

Data review

A review of UK Yellow Card data up to and including 10 June 2026  identified that approximately one-half of angioedema cases with reported time-to-onset occurred 30 days or more after initiation of treatment. Manufacturer data indicated that around 20–30% of reported cases occurred after at least 30 days of therapy. This pattern of delayed onset is more associated with bradykinin-mediated angioedema. Fatal cases, although rare, have involved airway compromise and have occurred after prolonged ACE inhibitor treatment.