Angioedema Rare With RAAS Inhibitors in Real World

October 18, 2012

October 17, 2012 (Boston, Massachusetts) — The risk of the potentially life-threatening side effect angioedema differs between different classes of drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), according to the largest-ever study to examine this [1]. ACE inhibitors and aliskiren (Tekturna, Novartis) have an approximately threefold higher risk of angioedema compared with the reference drug class, beta blockers--a higher rate than the other group examined, angiotensin-receptor blockers (ARBs), say Dr Sengwee Toh (Harvard Medical School, Boston, MA) and colleagues in the Archives of Internal Medicine.

However, the researchers caution that the occurrence of angioedema is uncommon. "In absolute terms, angioedema is still a pretty rare event. Out of 1000 users, maybe only two will develop any angioedema, and the risk for a severe episode is even rarer," Toh told heartwire . "Angioedema is one of the many potential adverse drug reactions that physicians and patients should consider, but it is only one consideration. Our findings should not warrant any change in practice."

In absolute terms, angioedema is still a pretty rare event. Out of 1000 users, maybe only two will develop any angioedema.

Toh notes that this is the first report of angioedema with aliskiren, and the number of events for this newer agent, a direct renin inhibitor, was small, so caution should be exercised in the interpretation of this finding. This is also the first time that the risk of angioedema has been able to be precisely quantified for individual ARBs, he said.

And Toh and colleagues show that the risk of developing angioedema seems to be greatest in the first month after treatment is started. "This side effect is most likely to occur in the first 30 days. After that there is still a risk, it doesn't go away entirely, but it diminishes over time," he observed.

In an accompanying editor's note [2], deputy editor Dr Mitchell H Katz (Los Angeles County Department of Health Services, CA) says, "As editors, we were particularly happy to see this article by Toh et al for its content and for its methods."

Working out the comparable risks for unusual adverse events with a group of medications having similar indications can be "challenging, because most phase 3 efficacy trials are not powered to accurately estimate or even detect the incidence of unusual occurrences. We believe careful postmarketing surveillance, like this project, is essential for us to learn the risks and benefits of medications in real-world practice."

Magnitude of Effect With ACE Inhibitors in Line With Other Studies

Toh and colleagues conducted a retrospective study of adult patients from 17 health plans participating in the US FDA's Mini-Sentinel program, representing what they say is "a large, diverse, population-based cohort who received these drugs in real-world clinical settings."

Of the patients, 1 845 138 patients had started on an ACE inhibitor, 467 313 had begun ARB therapy, and 4867 were taking aliskiren between January 1, 2001 and December 31, 2010. They were compared with 1 592 278 patients taking beta blockers--which are not thought to increase the risk of angioedema--as a reference, over the same period.

They calculated the cumulative incidence and incidence rate of angioedema during a maximal 365-day follow-up period. Using a propensity-score approach, they estimated the hazard ratios of angioedema separately for ACE inhibitors, 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 agents.

Among individual ARBs, losartan appears to be associated with the greatest risk, but information on several individual ARBs was limited.

"In this study, the risk for angioedema associated with the use of ACE inhibitors and aliskiren was three times the risk with beta blockers, a drug class not thought to be linked to angioedema," Toh and colleagues state.

They note that the risk of this side effect with ACE inhibitors was already known, and their findings here are broadly in line with those of other studies in terms of the magnitude of this effect.

And "among individual ARBs, losartan appears to be associated with the greatest risk, but information on several individual ARBs was limited," they observe.

Angioedema Events by Study Drug Use During a Maximum of One-Year Follow-up

Drug No of events Cumulative incidence of angioedema per 1000 persons HR*
ACE inhibitors 3301 1.79 3.04
ARBs 288 0.62 1.16
Candesartan 4 0.33 0.95
Eprosartan (Teveten, Abbott) 0 -- --
Irbesartan 24 0.54 1.11
Losartan potassium 94 0.88 1.53
Olmesartan (Benicar, Daiichi Sankyo) 39 0.42 0.88
Telmisartan (Micardis, Boehringer Ingelheim) 11 0.42 0.86
Valsartan (Diovan, Novartis) 110 0.60 1.08
Aliskiren 7 1.44 2.85
Beta blockers 915 0.58 1 [reference]

*Propensity-score adjusted

Further Work Needed to Properly Characterize Risk for Aliskiren

The association between aliskiren use and angioedema was previously "not well quantified," Toh and colleagues say, but there is a warning in the aliskiren label about this side effect, similar to that found with ACE inhibitors, because there were some reports of this in the premarket development program, including cases of serious angioedema in which patients required intubation.

However, in this new analysis, the risk for angioedema and urticaria had to be assessed as a combined outcome, and the analyses did not allow for the examination of angioedema separately, they note. Therefore "further investigations are needed to better characterize this association," they state.

Toh said it has also previously been suggested that African American patients may be at greater risk of angioedema than others, but he and his colleagues were unable to analyze their data by race, he explained.

Toh has no conflicts of interest. Disclosures for the coauthors are listed in the paper. No disclosure is listed for Katz.