Angioedema Associated With Angiotensin-Converting Enzyme Inhibitor Use:  Outcome After Switching to a Different Treatment FREE

Angioedema is a self-limiting, nonpitting edema that occurs in the skin and mucous membranes. Drugs are among the multiple precipitating factors.¹ In drug-induced angioedema, the close temporal relationship between drug intake and appearance of angioedema is usually the key element that makes obvious identification and subsequent withdrawal of the offending medication.

Angiotensin-converting enzyme (ACE) inhibitors have long been recognized to cause angioedema,² with reported incidence varying from 0.1% to 1%, although most of the large studies indicate incidence of about 0.1% to 0.2% of treated patients.³ Unlike other cases of drug-related angioedema, this adverse reaction of ACE inhibitor use is frequently missed because it can start years after beginning the treatment and recur inconstantly while the drug is continued. However, it has been shown that continuing use of ACE inhibitors after the first episode of angioedema results in a markedly increased rate of angioedema recurrence with serious morbidity.⁴ Six cases of fatal airway obstruction caused by angioedema related to ACE inhibitor use have been recently reported.⁵ It is therefore mandatory to recommend that patients presenting with angioedema while taking ACE inhibitors withdraw such treatment.

Inhibition of ACE blocks angiotensin conversion and reduces catabolism of bradykinin, a potent vasoactive peptide, which is degraded by ACE.⁶ Hence, it has been speculated, and there is now some experimental evidence, that ACE inhibitors induce angioedema by increasing availability of bradykinin.^7- 9 For this reason it has been assumed that drugs not affecting bradykinin metabolism should not present a risk of angioedema for patients who had this complication while taking ACE inhibitors.

Angiotensin II receptor blockers (ARBs), introduced in 1995 for treatment of hypertension, have a pharmacological profile similar to ACE inhibitors in blocking the renin-angiotensin system. Because they do not theoretically affect bradykinin, they are good candidates to substitute for ACE inhibitors in patients with bradykinin-related adverse reactions to these drugs.^10- 11 Nevertheless, occurrence of angioedema with different ARBs has been reported and the safety of these drugs for this indication is now debated.^12- 22

The reports that describe large series of patients with angioedema during treatment with ACE inhibitors or ARBs are reviews of data from institutes for pharmacovigilance or from hospital files, and do not contain information on the recurrence of angioedema after treatment was changed. Thus, they lack a main clue to substantiate the diagnosis of drug-related angioedema. Actually, it is possible that angioedema will continue independent of the treatment, either because of the presence of a preexisting condition causing the angioedema²³ or because the association with the drug was fortuitous.

We report on the outcome of 64 consecutive patients with ACE inhibitor–related angioedema after discontinuing ACE inhibitor treatment and on the safety of using ARBs.

From January 1993 through June 2002 we saw at our outpatient clinic 1168 patients for symptoms of angioedema with or without urticaria. Sixty-four of these patients were receiving treatment with an ACE inhibitor and had no other obvious causes for angioedema; 38 were men and 26 were women. Median age was 63 years (range, 46-84 years). Known causes of angioedema were excluded by clinical history that included detailed information about personal and familial allergies; relationship of angioedema to potential causative agents (eg, food, drugs, and chemicals); and complete physical examination. If known causes were excluded, patients were simply recommended to discontinue the ACE inhibitor and, after obtaining informed consent to participate to this study, to return for follow-up.

To rule out the possibility of a deficiency of C1 inhibitor (C1-INH) as the cause of angioedema, all patients were tested for C1-INH function, as measured by chromogenic assay (Baxter), and for C1-INH, C4, C3, and C1q antigens, as measured by radial immunodiffusion (NOR-Partigen, LOW-Partigen for C1q; Behringwerke AG, Marburg, Germany).

The ACE inhibitors used by the 64 patients at the time of onset of angioedema are shown below.

Scattered but unequivocal symptoms of angioedema before starting the ACE inhibitor therapy were recorded in 6 patients, and in 4 patients it could not be clarified whether angioedema or urticaria had previously been present. These patients were included in the study because the frequency of angioedema clearly worsened after starting ACE inhibitor therapy. Fifty-four patients denied any previous symptoms of urticaria or angioedema. The median length of ACE inhibitor treatment before the appearance of angioedema was 12 months (range, 0-156 months) and the median duration of ACE inhibitor use after the appearance of the first angioedema episode was also 12 months (range, 0-120 months). Grouping of the patients according to the duration of ACE inhibitor use after the first episode of angioedema is as follows: less than 1 month, 14 patients; 1 to 6 months, 12 patients; 6 to 12 months, 11 patients; and longer than 12 months, 27 patients. For patients continuing to take ACE inhibitors for 1 year or more after the first episode of angioedema, 7 (22%) had recurrences after 12 years; 9 (28%) had recurrences for 6 to 11 years; and 16 (50%) had recurrences between 1 and 5 years.

The face was the site most commonly involved (55 patients), followed by the tongue (25 patients). Other cutaneous locations were rare (9 patients) as well as abdominal symptoms referable to edema of the bowel mucosa (3 patients). Six patients had episodes of dyspnea due to laryngeal involvement. One of them underwent endotracheal intubation.

Withdrawal of the ACE inhibitor was recommended to all patients. Ten patients did not return for the follow-up visit and therefore are not further considered. Of the remaining 54 patients, 26 switched to an ARB, 14 to a calcium antagonist, and 14 to other treatments (β-blocker [5], α-lytic [1], diuretic [3], no treatment [5]). In these 3 groups, patients were not significantly different in terms of age, sex, duration of ACE inhibitor treatment before and after appearance of angioedema symptoms, presence of angioedema and/or urticaria before starting the ACE inhibitor use, or frequency of angioedema recurrence. The median length of the follow-up was 11 months (range, 1-80 months). Withdrawing the ACE inhibitor resulted in complete disappearance of angioedema in 37 patients (69%) and in drastic reduction in frequency and severity, so that the patients considered them negligible, in additional 9 patients (17%). Eight patients (15%) did not experience any improvement. Evolution of angioedema by means of the new therapeutic regimen is reported in Table 1.

The 8 patients who did not benefit from stopping ACE inhibitor use (5 who switched to ARBs and 3 to calcium antagonists) underwent further evaluation consisting of a second physical examination and laboratory tests aimed to discover other causes of angioedema such as infections, autoimmune disorders, or mailignancies. In 6 patients it was concluded that angioedema was not due to the antihypertensive treatment. In 1 patient, the angioedema disappeared after removal of a dental granuloma; in another patient, following a histamine-free diet resulted in angioedema disappearance; and in the remaining 4 patients, angioedema continued without recognizable etiology and regardless of changing or discontinuing the antihypertensive regimen. In the last 2 patients there is the possibility that the ARB, substituted for the ACE inhibitor, could have been causing angioedema. In the first patient, angioedema first appeared 3 months after starting treatment with enalapril and recurred over the course of 2 years while taking this drug. Episodes of angioedema continued for 2 months after candesartan was substituted for enalapril and then stopped after switching to a β-blocker. The other patient, receiving hemodyalisis for 3 years and taking enalapril for 5 years, had one angioedema episode that involved the face and upper airway, necessitating endotracheal intubation. After this episode he stopped taking enalapril and started losartan. Six months later he had a second angioedema episode of the face that resolved in 3 days without complications. Losartan use was stopped and nifedipine started. At the latest follow-up, 18 months later, he had not had any further episodes. All patients had normal complement parameters.

Occurrence of angioedema has been reported with the use of all ACE inhibitors and it is considered a class-related side effect.³ Our data confirm this finding, listing 10 different ACE inhibitors used at the time of onset of angioedema. The strikingly higher rate of recurrence with enalapril (55%) is remarkable. However, this is by far the most commonly used ACE inhibitor in Italy. Although we cannot exclude that enalapril carries a higher risk for angioedema compared with other preparations, it is still likely that our finding is just the consequence of its prominent position on the market. Angioedema related to ACE inhibitor use belongs to the group of angioedema that occurs in absence of significant rush of urticaria.²⁴ The best recognized example in this group is hereditary angioedema, which is due to C1-INH deficiency, and likely is mediated by bradykinin.²⁵ Along with these clinical and pathogenetic analogies, ACE inhibitor–related and hereditary angioedema share the emblematic, unexplained feature of recurrence of symptoms at randomly variable frequency, despite the constant persistence of the etiologic factor (C1-INH deficiency on one hand, ACE inhibitor treatment on the other).^26- 27 Efforts to identify the additional condition(s) that could link up with the initial cause in order to have angioedema to emerge remain unconvincing. A partial C1-INH deficiency has been hypothesized to be the predisposing factor for ACE inhibitor–related angioedema,³ but this supposition has never been confirmed; moreover, our patients' complement parameters were normal.

The severity of a condition characterized by angioedema depends on the rate of recurrences rather than on the risk of fatalities. Analysis of patients who remained on the ACE inhibitor for 1 year or longer after the first angioedema episode shows that in half of them symptoms recurred from a minimum of one every other month up to a weekly frequency. Considering that each attack lasts 48 to 96 hours, it results in disability of 10 to 120 days per year. This fact, along with the mentioned risk of fatality (in our series 1 patient underwent tracheostomy), emphasizes the importance of recognizing ACE inhibitors as a cause of angioedema. Unfortunately, the knowledge of this important adverse effect of ACE inhibitor use among practitioners is still lacking. The median of 10 months between appearance of angioedema and withdrawal of the drug should be regarded as an unacceptable medical error that needs to be corrected because it exposes patients to severe risks.

We examined the outcome of patients upon withdrawal the ACE inhibitor. In most, angioedema recurrence stopped or was drastically reduced, thereby reinforcing the evidence of a cause-effect relationship between the side effect and the treatment. The beneficial effect of stopping the drug was also verified in patients with a previous history of angioedema, which is an acknowledged risk factor for developing ACE inhibitor–related angioedema. A favorable outcome upon stopping the treatment was recorded in all 6 patients with such a history. Thus, since 85% of the patients solved the problem just upon stopping the drug, we recommend that this simple measure, without further assessments, should be immediately taken in patients who experience angioedema while taking ACE inhibitors.^28- 29

The final relevant point from this study concerns the safety of ARBs. As highlighted, these drugs appear the more obvious substitutes for ACE inhibitors, but reports of angioedema with their use suggest to reserve their use for patients with ACE inhibitor–related angioedema. Based on animal studies showing that the hypotensive effect of ARBs could be realized in part through release of vasodilators such as bradykinin,³⁰ it also has been postulated that with these drugs angioedema could be bradykinin dependent.¹³ However, we found that these drugs do not worsen the frequency and the severity of symptoms in patients with hereditary angioedema, as one would expect with a drug that increases bradykinin levels or activity, and as it occurs with ACE inhibitors.^29,31 Six of our patients with hereditary angioedema are taking an ARB for hypertension or renal disease since 6 months or more without effect on angioedema recurrences.

In the case of patients with ACE inhibitor–related angioedema, our overall experience on using ARBs as substitutive therapy is largely favorable, and this confirms another recent report³² on this issue. Twenty percent of patients in both the group taking calcium antagonists and ARBs did not benefit from just stopping the ACE inhibitor. However, this percentage also comprises patients in whom the association between antihypertensive drug and angioedema was shown to be just fortuitous. That an ARB could have sustained angioedema was a possibility for 2 (8%) of the 26 patients who switched to this class of drugs. This limited percentage does not seem a strong argument to consider ARBs as a contraindication in patients with ACE inhibitor–related angioedema.

Corresponding author and reprints: Marco Cicardi, MD, Dipartimento di Medicina Interna, Via Pace 9, 20122 Milan, Italy (e-mail: marco.cicardi@unimi.it).

Accepted for publication June 20, 2003.