title: Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system.
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.
authors.affiliation: Department of Population Medicine, Harvard Medical School, Boston, MA 02215, USA. darrentoh@post.harvard.edu
authors.forename: Sengwee
authors.initials: S
authors.lastname: Toh
authors.forename: Marsha E
authors.initials: ME
authors.lastname: Reichman
authors.forename: Monika
authors.initials: M
authors.lastname: Houstoun
authors.forename: Mary
authors.initials: M
authors.lastname: Ross Southworth
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Hernandez
authors.forename: Mark
authors.initials: M
authors.lastname: Levenson
authors.forename: Lingling
authors.initials: L
authors.lastname: Li
authors.forename: Carolyn
authors.initials: C
authors.lastname: McCloskey
authors.forename: Azadeh
authors.initials: A
authors.lastname: Shoaibi
authors.forename: Eileen
authors.initials: E
authors.lastname: Wu
authors.forename: Gwen
authors.initials: G
authors.lastname: Zornberg
authors.forename: Sean
authors.initials: S
authors.lastname: Hennessy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000799:Angioedema / Q000139:chemically induced* / Q000453:epidemiology*; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors