Comparative Risk for Angioedema Associated With the Use of Drugs That Target the Renin-Angiotensin-Aldosterone System

Study Questions:

What is the risk for angioedema associated with the use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), and the direct renin inhibitor aliskiren?


The investigators conducted a retrospective, observational, inception cohort study of patients 18 years or older from 17 health plans participating in the Mini-Sentinel program who had initiated the use of an ACEI (n = 1,845,138), an ARB (n = 467,313), aliskiren (n = 4867), or a beta-blocker (n = 1,592,278) between January 1, 2001, and December 31, 2010. They calculated the cumulative incidence and incidence rate of angioedema during a maximal 365-day follow-up period. Using beta-blockers as a reference and a propensity score approach, the investigators estimated the hazard ratios of angioedema separately for ACEIs, ARBs, and aliskiren, adjusting for age, sex, history of allergic reactions, diabetes mellitus, heart failure, or ischemic heart disease, and the use of prescription nonsteroidal anti-inflammatory drugs.


A total of 4,511 angioedema events (3,301 for ACEIs, 288 for ARBs, 7 for aliskiren, and 915 for beta-blockers) were observed during the follow-up period. The cumulative incidences per 1,000 persons were 1.79 (95% confidence interval [CI], 1.73-1.85) cases for ACEIs, 0.62 (95% CI, 0.55- 0.69) cases for ARBs, 1.44 (95% CI, 0.58-2.96) cases for aliskiren, and 0.58 (95% CI, 0.54-0.61) cases for beta-blockers. The incidence rates per 1,000 person-years were 4.38 (95% CI, 4.24-4.54) cases for ACEIs, 1.66 (95% CI, 1.47-1.86) cases for ARBs, 4.67 (95% CI, 1.88-9.63) cases for aliskiren, and 1.67 (95% CI, 1.56-1.78) cases for beta-blockers. Compared with the use of beta-blockers, the adjusted hazard ratios were 3.04 (95% CI, 2.81-3.27) for ACEIs, 1.16 (95% CI, 1.00-1.34) for ARBs, and 2.85 (95% CI, 1.34-6.04) for aliskiren.


The authors concluded that compared with beta-blockers, ACEIs or aliskiren was associated with an approximately three-fold higher risk for angioedema.


This study reports that the risk for angioedema associated with the use of ACEIs or aliskiren was 3 times the risk with beta-blockers, a drug class not thought to be linked to angioedema, although the number of exposed events for aliskiren was small. The risk for angioedema was lower with ARBs than with ACEIs or aliskiren. This study is the largest of its kind and the first to examine the aliskiren-angioedema association using routinely collected clinical data, and raises awareness of this serious side effect with aliskiren. Given the small number of exposed events with aliskiren, further investigations are needed to better characterize the association.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Acute Heart Failure

Keywords: Angiotensin Receptor Antagonists, Myocardial Ischemia, Vitamin E, Mineralocorticoid Receptor Antagonists, Apolipoprotein A-I, Renin-Angiotensin System, Fumarates, Heart Failure, Cardiovascular Diseases, Confidence Intervals, Diabetes Mellitus

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