D1.402 - Angiotensin-Converting Enzyme Inhibitor–Induced Bradykinin-Mediated Angioedema: Three Cases of Sustained Remission Following Definitive Discontinuation and the Critical Role of the Prescribing Physician

Angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema affects ~0.7% of ACEI users, carries a risk of fatal laryngeal obstruction. The mechanism is bradykinin-mediated. The diagnosis of ACEI-induced angioedema can be made by clinical exclusion and normal complement levels. Genetic analysis is not required. De-challenge is both diagnostic and therapeutic in the vast majority of patients. Re-challenge is absolutely contraindicated and may provoke more severe, potentially fatal reactions. Yet preventable morbidity persists, largely because of re-exposure.

One female and two male patients aged 52–78 years were followed up as case studies and randomly selected for a retrospective chart review. All three patients received a perindopril-based regimen for about 24 months, each with recurrent non-urticarial orolingual angioedema and normal C1q and C4 levels throughout. De-challenge resulted in complete remission in all three patients. Following definitive withdrawal, all three patients remained event-free in 12 months of follow-up, yielding long-term remission in these cases.

The most instructive case involved a man whose general practitioner reintroduced the original ACEI preparation two weeks after our categorical recommendation to discontinue permanently; within 26 days the patient developed massive laryngeal angioedema requiring intensive care unit admission – constituting an inadvertent but irrefutable positive re-challenge. 

Data from large observational  cohorts report recurrence in 46–71% following ACEI discontinuation, and isolated attacks beyond 6 months post-discontinuation are not uncommon. However, thorough pharmacovigilance evaluations indicate that a proportion of so-called “late recurrences” may reflect continued exposure, drug re-initiation, or switch within the ACEI class rather than pharmacodynamic persistence. Given the short plasma half-life of most ACEI and the reversibility of bradykinin accumulation once ACE degradation normalizes - pharmacological persistence is biologically unlikely beyond a few weeks and when angioedema recurs within 6 months of reported discontinuation, ongoing exposure should be assumed until excluded. 

Educating referring physicians  is as important as the medication discontinuation itself. These cases illustrate that the gap between guideline recommendations and clinical reality is not in the pharmacology – but in prescriptions that the patients received.