Angioedema is a rare, potentially life-threatening adverse event of renin-angiotensin system inhibitors. The objective of the present study was to determine the risk of
angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on
angiotensin-converting enzyme (
ACE) inhibitors,
angiotensin receptor blockers (ARBs), or
direct renin inhibitor (DRI). Trials with a total number of patients ≥100 and a duration of ≥8 weeks were included for analysis. Incidence of
angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the
ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of
angioedema with
ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With
ACE inhibitors and ARBs, incidence of
angioedema was higher in
heart failure trials compared to
hypertension or
coronary artery disease trials without
heart failure (p <0.0001). Weighted incidence of
angioedema with
ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of
angioedema with ARBs and DRI was <1/2 than that with
ACE inhibitors and not significantly different from placebo. Incidence of
angioedema was higher in patients with
heart failure compared to those without
heart failure with
ACE inhibitors and ARBs.