Abstract
Several reports on angioedema (AE) related to the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have been published recently. This study reports on the experience gained at the Ear, Nose, and Throat (ENT) Clinic of the University Hospital of Heraklion, Crete. A retrospective chart review of the patients admitted to this clinic, in a 42-month period (1999–2003), and discharged with a diagnosis ENT code for AE was performed (14 eligible patients). A complementary telephone survey was conducted during January 2005. Ten patients responded to our invitation. Of those patients, five were under ACE-I and one was under ARB treatment during the AE episode. The mean length of time between the onset of symptoms and presentation to the hospital was 4.5 hours (range 0.5–12 hours). The mean duration between the initiation of antihypertensive treatment and AE episode was 26.2 months (range 1–60 months). Patients reported that no information was provided about the possible adverse effects of these drugs. Although AE introduced by ACE-I and ARBs is an uncommon side effect, this case series conveys a key message to primary care physicians.
Introduction
The use of certain drugs, including angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB), useful agents for the management of hypertension, heart failure, and diabetic nephropathy, has been associated with episodes of angioedema (AE). AE is an indurated, well-demarcated swelling of the skin and mucosa. It may present as facial, lip, and oropharyngeal mucosa swelling with potential progression to supraglottic areas resulting in airway compromise Citation[1]. AE related to the use of ACE-I seems to be secondary to the effects on bradykinin levels Citation[2]. The occurrence of ACE-I-induced AE has been estimated between 0.1% and 0.2% Citation[3], Citation[4]. Several cases of AE episodes related to ARBs have also been reported Citation[5–7] despite the different mechanism of ARB action. The exact mechanism of AE related to both pharmacologic agents is unknown. There has been an important increase of prescriptions of both drugs in primary care in Greece, and their adverse effects seem to be underreported. Thus, we were interested to explore the potential adverse effects from the use of these drugs at the University Hospital of Heraklion, Crete, and to discuss their implications on daily practice.
Methods
A medical audit study based on a retrospective chart review of patients admitted to the Ear, Nose, and Throat (ENT) Clinic at the University Hospital during a 42-month period (1999–2003) and discharged with a diagnosis ENT code for AE was carried out. Fourteen patients were identified. A telephone survey was conducted during January 2005, and information relevant to patients’ medical history before and after their hospitalization was recorded.
Results
Of the 10 patients who agreed to participate and responded by phone, five were under ACE-I treatment and one was under ARB therapy during the episode of AE. The mean patient age was 68.5 years (range 55–76 years), and the male-to-female ratio was 2:1. The ACE-I agents used were lisinopril (two cases), enalapril, ramipril, and quinapril. The ARB agent found to induce an episode of AE was valsartan in a patient who was previously under ACE-I treatment. More than half of the cases were observed during winter. The main anatomical sites of involvement and the most frequently reported complaints are depicted in . The mean length of time between the onset of symptoms and presentation to the hospital was 4.5 hours (range 0.5–12 hours). The mean duration between the initiation of ACE-I and ARB therapy and AE episode was 26.2 months (range 1–60 months). All patients had a history of AE (episode average per patient: 2.7) during the treatment. Cardiologists made out two-thirds of the prescriptions. Patients reported that no information was provided about the possible adverse effects of these drugs. The personal physicians of the affected patients complied with the discharge recommendation given for drug discontinuation, but in two patients there was a switch to ARB agents. Four out of six patients who received drugs from different classes of antihypertensives, such as diuretics, calcium-channel blockers, and beta-blockers, were free of new AE episodes (between treatment switching and phone interviews).
Table I. Main anatomical involvement during the medical examination and most frequently reported symptoms by patients with facial or mucosal angioedema related to ACE-I or ARB treatment.
Discussion
Despite the small sample, this study suggests that AE and the use of ACE-I may be more commonly related than thought. AE may occur after long-term use of these agents, as previous studies have shown Citation[1], Citation[8]. Our observation that AE secondary to ACE-I or ARBs is frequently diagnosed after several episodes is in agreement with other studies Citation[1], Citation[7], Citation[8]. In some cases of AE, there was a switch from ACE-I to ARBs due to the recommended discontinuation of ACE-I therapy. However, prescribing ARBs to such patients is also unsafe and not advisable Citation[6–8]. It seems that the physicians involved may not be aware of this potentially life-threatening complication. Our study has certain implications for the quality of care, since it implies that clearer messages need to be given to the providers of primary care services in Greece. They are advised to offer to their patients all the necessary information concerning the potential side effects when they prescribe these drugs, and to diagnose these effects as early as possible when they occur. illustrates some simple questions that might be of help when physicians treat patients with facial or mucosal angioedema related to ACE-I or ARBs.
Box I. Six questions for the recruitment of patients with facial or mucosal angioedema related to ACE-I or ARB treatment.
Conclusions
Although AE induced by ACE-I and ARBs is a non-frequent side effect, primary care physicians should be aware of it, informing their patients about these complications and diagnosing it as early as possible.
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