Angiotensin-converting enzyme inhibitors and angioedema: estimating the risk.

The angiotensin-converting enzyme (ACE) inhibitors are now widely prescribed for the treatment of hypertension as well as for providing cardiovascular and renal protection in patients with heart failure, chronic kidney disease, and at high risk of cardiovascular events. Worldwide, it is estimated that tens of millions of patients are now taking these agents. Given this widespread exposure to ACE inhibitors, it is evident that even rare events can multiply and affect significant numbers of patients.1 This certainly applies to angioedema, a serious side effect of the ACE inhibitors that has been known about since these drugs were first introduced. The article by Miller et al in this issue of Hypertension represents a careful effort to estimate the frequency of this event in contemporary clinical practice.2 One of the chief attributes of the ACE inhibitors has been their overall tolerability. By far the most commonly encountered complaint with these agents is a dry, nonproductive cough. The cause of this cough has never been established, but bradykinin—which exists in increased concentrations as a direct result of the action of the ACE inhibitors—is the most commonly cited culprit. This cough is generally not of medical significance, but can sometimes lead to increased doctor visits and costs when the explanation for a newly evident cough is being sought. This symptom is sufficiently intrusive to cause discontinuation of ACE inhibitor therapy in up to 20% of patients. Angioedema is potentially far more troubling. As with cough, bradykinin seems to be the cause of this event.3 Angioedema varies in severity. In its mildest form, it may be manifested by a transient swelling of the lips, tongue, or mouth. More serious cases, however, can cause acute respiratory distress by affecting the upper airway and larynx. Obviously, patients with these drastic manifestations of angioedema typically are hospitalized and may require intubation or even tracheostomy. These episodes can be fatal. Although most instances of angioedema are localized to the head and neck, it has been surmised that the epigastric discomfort that has been associated with ACE inhibitors may, in fact, reflect an angioedema-like effect in the gastrointestinal tract.4 ACE inhibitor–induced angioedema is more prevalent in black patients than in white. The current report by Miller and colleagues provides yet further confirmation of the heightened risk in blacks. It is possible, too, that angioedema in black people can be particularly severe. One coroner’s office actually observed, within a 3-year period, 6 fatal cases of angioedema in black patients exposed to ACE inhibitors.5 This concern has led to extraordinary labeling in the FDAapproved package inserts of all the ACE inhibitors. The labeling points out that because black patients, when treated for hypertension, tend to get lesser antihypertensive effects with ACE inhibitors than other ethnic groups, but at the same time be exposed to a higher probability of angioedema, their treatment with ACE inhibitors provides a diminished benefit risk ratio. This brings up the question as to whether ACE inhibitors should still be considered first-line therapy in black patients. When pondering this issue, however, we should remember that in hypertensive black patients with nondiabetic kidney disease, treatment based on an ACE inhibitor was superior to that with either blocker or calcium channel blocker treatments in protecting against progression of kidney disease.6 Soon after the ACE inhibitors were introduced into clinical practice, there was a wide misconception that almost all angioedema events took place within the first few days or weeks of therapy. Sadly, this reassuring statement has not turned out to be true. Reports during the past 3 years,7,8 including that of Miller et al,2 have emphasized that although a relatively high proportion of angioedema episodes occur during the early part of treatment, these serious events can be observed after months or even years of ACE inhibitor therapy. In fact, in a large clinical survey by Zingale et al the average ACE inhibitor exposure before the occurrence of angioedema was a full 12 months; remarkably, it took an additional 12 months from the occurrence of the angioedema until the ACE inhibitor therapy was discontinued.9 ACE inhibitors are by no means the only cause of angioedema. Many cases have been attributed to different foods, for example, and for many patients the stimulus for their angioedema is not evident. Clinical trials also have revealed that angioedema can occur during treatment with drug classes other than ACE inhibitors. In the Valsartan Antihypertensive Long-term Use Evaluation trial, in which the effects on major clinical end points of the angiotensin receptor blocker, valsartan, were compared with those of the calcium channel blocker, amlodipine, there was a 0.13% incidence of angioedema reported for each drug across the 5 years of the study.10 Similarly, another clinical outcomes study, the LoThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the SUNY Downstate College of Medicine and St. Luke’s – Roosevelt Medical Center, Columbia University College of Physicians and Surgeons, New York. Correspondence to Michael A. Weber, MD, SUNY Downstate College of Medicine, 308 E 38th St, Ste 201, New York, NY 10016. E-mail [email protected] (Hypertension. 2008;51:000-000.) © 2008 American Heart Association, Inc.