Risk of Angioedema with Drug Therapy

Abstract & Commentary

By Michael H. Crawford, MD, Editor

Source: Toh S, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med 2012;172:1582-1589.

Angioedema is an infrequent, but serious, adverse event from drug therapy. Drugs that affect the renin-angiotensin-aldosterone system have been linked to angioedema, but the relative frequency of this complication with these drugs is poorly understood. Thus, this group of investigators used the FDA’s Mini-Sentinel Distribution Database (MSDD) to explore this issue. The MSDD is a pilot program involving 17 health plans for an eventual national system for monitoring the safety of medical products. An inception cohort design was used to assess patients > 18 years old receiving only an angiotensin-converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB), aliskiren, or a beta-blocker (reference group). The primary endpoint was a new diagnosis of angioedema and the secondary outcome was serious angioedema (airway obstruction requiring in-patient care). The study was censured if angioedema occurred, the drug was stopped, another drug in this group was started, or 1 year had passed. There were approximately 1.8 million initiated on ACEIs, 467,000 on ARBs, 4867 on aliskiren, and 1.6 million on beta-blockers. Mean follow-up for ACEIs was 149 days, ARBs 136 days, aliskiren 112 days, and beta-blockers 126 days. Among the approximately 4 million patients studied, there were 4511 cases of angioedema and 388 cases of serious angioedema. The incidences per 1000 persons were 1.79 for ACEIs, 0.62 for ARBs, 1.44 for aliskiren, and 0.58 for beta-blockers. Serious angioedema rates were 0.18 for ACEIs, 0.02 for ARBs, 0.21 for aliskiren, and 0.03 for beta-blockers. The authors concluded that compared to beta-blockers, the risk of angioedema is highest with ACEIs or aliskiren and lowest with ARBs.


This large, well-done retrospective, observational study has important implications for the care of patients. Angioedema and serious angioedema in patients receiving drugs that have been associated with angioedema is rare. Even patients receiving drugs not thought to be associated with angioedema (beta-blockers) have a measurable risk of angioedema. In fact, in this study, the incidence of serious angioedema was higher with beta-blockers than ARBs. The main result of this study is that compared to beta-blockers, ACEIs and aliskiren have a three-fold higher incidence of angioedema and ARBs are 16% higher. Serious angioedema is five times more common with ACEIs vs beta-blockers. This is a robust study involving about 4 million patients among whom over 50% were women. One limitation of this study is a lack of racial or ethnicity data; African Americans are known to have a higher incidence of angioedema. However, this study did confirm that women and those > age 65 years have higher rates of angioedema with ACEIs, but not ARBs. So, my question at this time is: Is there any reason to use ACEIs vs ARBs, especially in outpatients with hypertension facing decades of therapy? I think not, especially since at least one ARB is now generic.