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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 21-April-2006, Vol 119 No 1232

Oral angioedema secondary to ACE inhibitors, a frequently overlooked association: case report and review
Miriam Hurst, Marianne Empson
Angioedema is a common problem; in clinical practice it is usually either idiopathic or secondary to allergens or medications. Angiotensin converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory medications (NSAIDs) are the most common medications responsible for angioedema. ACE inhibitor-induced angioedema can occur at any stage of treatment and is potentially life-threatening. However, this condition is under-recognised, and many patients who present to immunology outpatients clinics with typical histories of ACE inhibitor-induced angioedema are still receiving these medications. We present an illustrative case of ACE inhibitor-induced angioedema from Auckland, New Zealand, followed by a discussion aimed at helping doctors recognise and manage this association.

Case report

A 71-year-old European woman was referred to Auckland City Hospital’s Immunology Clinic for investigation of angioedema. Some months earlier, she woke with tongue swelling that impaired her speech and made breathing difficult. An ambulance was called and she received three doses of intramuscular adrenaline but with no improvement.
At the emergency department she was given nebulised adrenaline, steroids, and antihistamines, with gradual resolution of her symptoms, and she was observed in intensive care overnight. She was discharged with a prescription for an EpiPen® (a self-injecting adrenaline device, DEY L.P., Napa, California); no other changes were made to her medication.
She also reported three milder episodes of angioedema over the preceding 2 years, one episode affecting the tongue and the other two her cheeks. No other triggers had been identified. She had been diagnosed with hypertension 3 years previously and started on cilazapril 5 mg once daily and pindolol 15 mg once daily. Other medical problems included a history of osteoarthritis, osteoporosis, eczema, and hay fever. She had no history of food or drug allergies.
ACE inhibitor-induced angioedema was thought to be the most likely diagnosis for all her episodes of angioedema. Her beta-blocker therapy could have contributed to the severity of her reaction and lack of response to adrenaline. This diagnosis was discussed with her GP and arrangements were made for her to alter her current antihypertensive medications under his guidance.
The patient was informed of her diagnosis and its implications, and instructed in the use of her EpiPen.

Causes of angioedema

Angioedema is a nonpitting oedema involving deeper layers of the cutaneous and mucosal tissues caused by allergic or nonallergic reactions.1,2 Although any part of the body may be affected, the commonest sites for skin involvement are the perioral and periorbital tissues.2 Angioedema involving the tongue and throat can be fatal due to asphyxia.1 Gastrointestinal angioedema may present with abdominal pain, nausea, and diarrhoea; other organ systems are rarely affected.1
A good clinical history is essential in establishing the diagnosis and determining possible causes. Factors to consider include timing and duration of the episode(s), particularly in relation to any possible triggers such as foods or environmental stresses (e.g. heat, cold, exercise). Drug history, especially new medications or over the counter agents such as NSAIDs, is also important, as are any associated symptoms (such as urticaria), other diseases (autoimmune or atopic), and family history.
Angioedema can be part of an IgE-mediated allergic reaction (most commonly to foods such as peanuts, tree nuts, or shellfish; or medications such as penicillin) or non-allergic as with ACE inhibitors, most NSAID reactions, and chronic idiopathic urticaria/angioedema.3 Rare causes include congenital or acquired deficiencies in C1 esterase inhibitor (C1-INH).2 Most cases of angioedema in adult clinical practice are not IgE-mediated—a significant proportion of cases are due to ACE inhibitors.

ACE inhibitors in clinical practice

ACE inhibitors are used widely in New Zealand. According to New Zealand’s drug-buying agency, PHARMAC, in the year ending June 2004, just over 1 million prescriptions were filled for ACE inhibitors (value estimated from graph).4 The main clinical indication for ACE inhibitors is hypertension; however, ACE inhibitors are also used to treat congestive heart failure and diabetic nephropathy, and to significantly decrease morbidity and mortality after myocardial infarction.5

Adverse effects

ACE inhibitors are generally well tolerated. Significant adverse effects include hypotension, renal impairment, and cough. Cough is a side-effect specific to ACE inhibitors, reported in 5 to 20% of patients; it is thought to result from bradykinin and/or prostaglandin accumulation.6
Angioedema is a less common reaction that has been associated with all ACE inhibitors. Most ACE inhibitor-induced angioedema involves the tongue, pharynx, or perioral tissues. No diagnostic test exists at present; the diagnosis is made on the classical history and ingestion of the ACE inhibitor. Visceral angioedema with ACE inhibitors is rare, but has been reported, and needs to be considered in the context of recurrent abdominal pain where no other cause has been identified.7

ACE inhibitors and angioedema

Incidence—Initial estimates of the incidence of angioedema during ACE inhibitor treatment were around 0.1%,6 although rates of up to 2% have subsequently been observed.8 Observational studies suggest a rate of 0.1% per year of treatment, resulting in an overall risk of up to 1% after 10 years of treatment.1 The majority of reactions are in the first week of treatment but they can occur at any time; in addition, episodes of angioedema have been reported after stopping ACE inhibitor treatment.1 Although these episodes are predominantly in the first month after treatment cessation, we have observed episodes up to 3 months afterwards.
People with a history of idiopathic angioedema are at an increased risk of ACE inhibitor-induced angioedema.6 For unknown reasons, studies indicate a higher incidence in African-Americans (4.5-fold more that in white Americans).9 There are no Maori or Pacific Island data. Episodes of angioedema may also be triggered by trauma, such as intubation or endoscopy.10 Patients experiencing ACE inhibitor-associated cough are not significantly more likely to develop ACE inhibitor-associated angioedema.
One case series indicated that ACE inhibitor-associated angioedema may account for up to 40% of all angioedema presentations to the emergency department.11 Despite this, the role of ACE inhibitors may be overlooked. In one study, patients presenting with recurrent angioedema while taking ACE inhibitors had their ACE inhibitors stopped on only 3 of 14 occasions;12 in another series of 6 patients with ACE inhibitor-associated angioedema who presented on 9 occasions, ACE inhibitors were identified as a possible cause only once.13 Our clinical experience also suggests that a significant number of patients referred to us for investigation of angioedema are still on ACE inhibitors at the time of referral.
Severity—Studies suggest hospitalisation for ACE inhibitor-induced angioedema patients was necessary in roughly half of all cases.12,14 Intubation or tracheostomy was required in 5–16% of hospitalised patients12,14,15 and 4 deaths were reported in one early study, although 2 were thought to be unrelated to ACE inhibitor usage.14 In a United States study, a coroner’s review of 2000 autopsies from 1998 to 2000 found 7 deaths from ACE inhibitor-induced angioedema of the tongue, all in African Americans aged 51 to 65 years.16
Failure to identify ACE inhibitors as a cause and cease treatment may be associated with increasing severity of the reaction. In one study of 82 patients with ACE inhibitor-induced angioedema, 45% required hospitalisation for their initial presentation with angioedema; however, 64% required hospitalisation for recurrent reactions, and rates of intubation also increased from 5% to 18%.12
Proposed mechanisms—The exact mechanism of ACE inhibitor-associated angioedema is not yet certain. Immunological and complement-based mechanisms are thought to be unlikely, as there is no increase in IgE levels and a lack of other allergic phenomena. Significant complement or C1-INH deficiencies have not been demonstrated. Current theories focus on the effects of the ACE inhibitor on the renin-angiotensin-aldosterone system.
Normally, ACE converts angiotensin I to angiotensin II (ATII); see Figure 1. It also catalyses the breakdown of bradykinin and other vasoactive substances such as substance P.1 Blocking ACE with an ACE inhibitor decreases levels of ATII and increases levels of bradykinin, a vasoactive peptide which acts on a constitutively-expressed B2 receptor (found on smooth muscle and vascular endothelium) to cause vasodilation and increased vascular permeability. The increase in bradykinin is thought to be responsible for the angioedema seen in ACE inhibitor-induced angioedema.
Figure 1. The renin-angiotensin-bradykinin system and sites of drug action
ACE=Angiotensin converting enzyme, AT-II=Angiotensin II receptor blocker, BK=Bradykinin.
Some studies have shown increased levels of bradykinin in patients with ACE-induced angioedema versus controls; however, patients with ACE dysfunction do not have increased rates of angioedema.1 Acute external trauma can increase concentrations of vasoactive substances and may be responsible for the connection between intubation and angioedema.1
In addition to being metabolised by ACE, bradykinin is also metabolised by the specific peptidases aminopeptidase P, carboxypeptidase N, and dipeptidyl peptidase IV (DPPIV).18,19 Studies in small numbers of patients have shown lower levels of carboxypeptidase N,19 aminopeptidase P,19 or DPPIV18,20 in patients experiencing ACE inhibitor-induced angioedema, compared with controls; however, results have not been consistent across all studies.

Management of ACE inhibitor-induced angioedema

Acute attack—Angioedema sparing the airway can usually be managed conservatively with antihistamines with or without steroids and discontinuation of the causative medication. However, when the tongue and upper airway are involved, intramuscular adrenaline should be used (although its efficacy is uncertain as there are no controlled trials) and some patients may even require an artificial airway (e.g. intubation or cricothyroidectomy).
Fresh frozen plasma has been successfully used in treating patients with severe ACE inhibitor-induced angioedema that has not responded to other treatments.21,22 C1 esterase inhibitor concentrate has also been used successfully in one case,23 although the reason for this is uncertain, as patients with ACE inhibitor-induced angioedema have normal C1 esterase inhibitor levels.
Long term—ACE inhibitor-induced angioedema is a class effect, so patients experiencing angioedema with a particular ACE inhibitor should not be switched to another ACE inhibitor.1,6 Calcium channel blockers and/or thiazides are appropriate as alternative antihypertensives. Beta blockers are contraindicated in the initial setting because of the risk of recurrent episodes and their antagonistic effects on adrenaline; however, they could be used once it has been established that the angioedema has not recurred after stopping the ACE inhibitor. Generally an interval of at least 6 months would be recommended to exclude the possibility of idiopathic or non-ACE inhibitor-related causes of angioedema.
Patients with other causes of angioedema may have their episodes exacerbated by concurrent ACE inhibitor usage so these should still be avoided in these patients.
Patients with a history of laryngeal oedema or life-threatening reactions should be given an EpiPen in case of recurrence and a MedicAlert® bracelet should be considered.
Alternative medications: are AT II receptor blockers safe?—ATII receptor blockers have been used as alternatives to ACE inhibitors in patients unable to tolerate these drugs because of cough.8 However, literature reviews indicate several cases of angioedema associated with ATII receptor blockers,8,24,25 with at least one case requiring emergency tracheotomy,25 although the overall incidence appears lower than that with ACE inhibitors. There is a predominance of cases associated with losartan, although this may represent prescribing bias.
In one paper, 6 of 19 patients with angioedema associated with ATII blockers had previous histories of ACE inhibitor-associated angioedema,24 hence suggesting that ATII blockers may not be an acceptable alternative to ACE inhibitors in patients with ACE inhibitor-induced angioedema.
A recent retrospective review of 64 consecutive patients with ACE inhibitor-related angioedema found that 2 of the 26 patients commenced on an ATII blocker had further angioedema secondary to the ATII blocker.26 The potential benefits of the ATII blocker need to be considered against the risks of further angioedema when deciding whether a trial of these medications is warranted.

The future

Usage of ACE inhibitors is likely to increase and consequently the number of patients experiencing ACE inhibitor-induced angioedema will also increase. Observational studies indicate that ACE inhibitors are currently significantly under-prescribed in certain patient populations, such as those who have experienced acute myocardial infarctions.5 Combination therapy with both ACE inhibitors and ATII blockers has been suggested in patients with diabetic nephropathy as a way to limit proteinuria and delay (or prevent) disease progression;27 it is not clear how common angioedema will be with this combination.
Newer agents currently in development for treatment of hypertension and/or heart failure include omapatrilat, which inhibits both ACE and neutral peptidases; rates of angioedema with this medication are currently unknown.28 However, if the pathogenesis of ACE inhibitor-induced angioedema can be identified, it may be possible to screen patients before treatment and identify those at higher risk of this significant complication.29
New agents such as icatibant30(a selective bradykinin receptor B2 antagonist) and DX-8831 (a kallikrein inhibitor) are currently in clinical trials for the treatment of acute attacks of hereditary angioedema, and may in the future have a role to play in the treatment of ACE inhibitor-induced angioedema.
Author information: Miriam Hurst, Immunology Registrar, Clinical Immunology Department, Liverpool Hospital, Sydney, NSW, Australia; Marianne Empson, Clinical Immunologist, Auckland City Hospital, Auckland
Correspondence: Marianne Empson, Clinical Director Immunology, Level 6 Support Building, Auckland City Hospital, Private Bag 92024, Auckland 1001. Fax: (09) 307 4998; email: MarianneE@adhb.govt.nz
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