Causality assessment · Causality: well established

Lisinopril (ACE inhibitors) and Angioedema: is the FAERS signal real?

n=6,693 co-reports · PRR 12.2 · ROR 12.4

Lisinopril (ACE inhibitors) side-effect profile All assessments See in the full list

A written Bradford Hill assessment of one drug–event pair. The grade is a judgement about the signal, not a statement that this drug causes this event in any one person; FAERS counts are reports, not rates.

Causality: well established

Lisinopril (ACE inhibitors) ↔ Angioedema

n=6,693 co-reports · PRR 12.2 · ROR 12.4

Angioedema is the classic non-cough serious adverse effect of ACE inhibitors: swelling of the lips, tongue, face, or upper airway that can compromise breathing. The mechanism is well defined — ACE (kininase II) inhibition reduces bradykinin breakdown, and bradykinin accumulation increases vascular permeability. The reaction is a class effect, estimated in the low single-digit per-thousand range, may occur at any time (including months or years into therapy), and is disproportionately reported in patients of African ancestry. Because no ACE inhibitor is clearly safer than another, the labeling carries a class-wide warning and patients who develop it are switched to an ARB. The high FAERS count reflects the enormous population on ACE inhibitors and the severity that drives reporting.

Regulatory basis: ACE-inhibitor class labeling (angioedema warning; contraindication with hereditary/idiopathic angioedema). ONTARGET trial (2008) quantified the ACEI-vs-ARB angioedema difference in practice.

Bradford Hill viewpoint	Status	Note
Temporality (necessary)	met	Occurs during exposure, often early but sometimes after prolonged use
Strength	met	PRR 12 on a large co-report count
Consistency	met	Reproduced across ACE inhibitors and in randomized comparisons (ONTARGET)
Specificity	met	Notably more common with ACE inhibitors than with ARBs
Biological gradient	partial	Not clearly dose-related; risk varies more by ancestry than by dose
Plausibility	met	Bradykinin accumulation from ACE inhibition — a well-characterized mechanism
Coherence	met	Coheres with the class-wide effect and the ARB-switch practice
Experiment	met	Randomized ONTARGET showed ACEI angioedema exceeding ARB, with rechallenge evidence off-drug
Analogy	met	Analogous to ACE-inhibitor cough (same kinin mechanism)

This page's own qualitative read, not an automated/citation-gated assessment.

✗ Searched; the trial that surfaced was not evidence either way. The top results-posting ACE-inhibitor study (VA NEPHRON-D, NCT00555217) tracked only generic oedema/swelling terms — not angioedema specifically — with a handful of events in each arm. Angioedema is rare enough (and trials of this size too small) that the risk was established from the randomized ONTARGET comparison and large observational cohorts, not from a trial’s adverse-event table.