[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.207.106.142. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Original Investigation
Nov 12, 2012

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

Author Affiliations

Author Affiliations: Department of Population Medicine, Harvard Medical School, and Harvard Pilgrim Health Care Institute, Boston, Massachusetts (Drs Toh and Li); Office of Surveillance and Epidemiology (Drs Reichman, Houstoun, McCloskey, Wu, and Zornberg), Office of New Drugs (Dr Ross Southworth), Office of Translational Sciences (Drs Ding and Levenson), and Office of Medical Policy (Ms Shoaibi), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland; Division of Cardiology, Duke University School of Medicine, Durham, North Carolina (Dr Hernandez); and Center for Clinical Epidemiology and Biostatistics and Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Dr Hennessy).

Arch Intern Med. 2012;172(20):1582-1589. doi:10.1001/2013.jamainternmed.34
Abstract

Background Although certain drugs that target the renin-angiotensin-aldosterone system are linked to an increased risk for angioedema, data on their absolute and comparative risks are limited. We assessed the risk for angioedema associated with the use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and the direct renin inhibitor aliskiren.

Methods We 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 β-blocker (n = 1 592 278) between January 1, 2001, and December 31, 2010. We calculated the cumulative incidence and incidence rate of angioedema during a maximal 365-day follow-up period. Using β-blockers as a reference and a propensity score approach, we 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.

Results A total of 4511 angioedema events (3301 for ACEIs, 288 for ARBs, 7 for aliskiren, and 915 for β-blockers) were observed during the follow-up period. The cumulative incidences per 1000 persons were 1.79 (95% 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 β-blockers. The incidence rates per 1000 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 β-blockers. Compared with the use of β-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.

Conclusions Compared with β-blockers, ACEIs or aliskiren was associated with an approximately 3-fold higher risk for angioedema, although the number of exposed events for aliskiren was small. The risk for angioedema was lower with ARBs than with ACEIs or aliskiren.

×