Angioedema During ACE Inhibitor Therapy

Angiotensin-converting enzyme (ACE) inhibitors are used in the management of many conditions, including hypertension, heart failure, myocardial infarction, and diabetic nephropathy. Around 30% of individuals are intolerant to these medications, most commonly due to symptomatic hypotension or the development of a persistent dry cough. Angioedema is a less frequent but potentially serious adverse effect associated with this class.

Angioedema is characterised by non-pitting oedema of subcutaneous or submucosal tissues. It often affects the face, lips, tongue and throat. Where angioedema affects the bowel wall, gastrointestinal symptoms, may also be present. While some cases are mild and self-limiting, airway involvement can be life-threatening.

There are many potential causes of angioedema, including:

• Allergic reactions;
• Genetic disorders (e.g. hereditary angioedema);
• Acquired disorders (e.g. B cell lymphoproliferative disorders);
• Autoimmune disorders;
• Certain infections; and
• Medications (via allergic and non-allergic mechanisms).

Medication-induced angioedema

Allergic causes of angioedema are related to mast cell degranulation and may also be referred to as histaminergic angioedema. This may be accompanied by other signs and symptoms of mast cell mediator release, e.g. urticaria, flushing, generalised pruritus, and hypotension. Allergic angioedema may also be accompanied with anaphylaxis. In general, mast-cell mediated angioedema begins within minutes of exposure to an allergen, peaks within a few hours, and resolves in 24 to 48 hours.

In contrast, symptoms of non-allergic angioedema tend to develop over a more prolonged period. These reactions are related to activation of the kallikrein-kinin cascade (a key regulatory system involved in the maintenance of blood pressure, haemostasis, inflammation, and renal function). Bradykinin, a potent vasodilator produced in this cascade, increases vascular permeability and contributes to angioedema. Non-allergic angioedema is typically not associated with urticaria, bronchospasm, or other symptoms of allergic reactions.

ACE inhibitors

All medications in the ACE inhibitor class are associated with non-allergic angioedema. This is an infrequent adverse event, with an estimated incidence of around 0.1-0.42%. However, as ACE inhibitors are widely prescribed, they represent a significant cause of non-allergic angioedema.

One small Australian study found that 32% of patients presenting to the emergency department with angioedema were taking an ACE inhibitor. While causation was not confirmed in this study, the attributable risk factor for ACE inhibitors in patients with ACE-inhibitor-associated angioedema is thought to be 80%.

Bradykinin accumulation is thought to be the cause as ACE inhibitors block bradykinin degradation. Symptoms of ACE inhibitor-associated angioedema typically affect the face, lips, tongue, and upper airway. Gastrointestinal involvement is less common but may present with abdominal pain, vomiting, or diarrhoea.

Angioedema can occur at any stage during ACE inhibitor therapy. Around half of all cases occur in the first month of treatment. However, a first presentation can occur after months or years of therapy without incident. This variability can lead to the ACE inhibitor being overlooked as the causative agent.

Before the cause is correctly identified, patients may experience multiple episodes of angioedema with long symptom-free periods. If administration of the ACE inhibitor continues, the episodes will usually get worse. Patients with mild initial presentations can go on to develop life-threatening angioedema. Therefore, early recognition is crucial to prevent serious events.

Risk factors

While ACE inhibitors can cause angioedema on their own, combination with other medications may increase the risk.

Medications associated with a heightened risk include:

• Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin);
• Mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, sirolimus); and
• Neprilysin inhibitors (i.e. sacubitril – combination contraindicated by manufacturer).

Other factors that may increase the risk of ACE inhibitor-induced angioedema include:

• Smoking;
• History of ACE inhibitor-induced cough (~9x increased risk); and
• African American background (~4x increased risk).

Management

As ACE inhibitor-induced angioedema is mediated by bradykinin rather than histamine, it often does not respond to standard treatments used for histaminergic angioedema. However, initial management may still include these therapies, as distinguishing between the two forms can be challenging at presentation.

The primary management of ACE inhibitor-induced angioedema is airway management (if required) and discontinuation of the drug. Mild cases may not require treatment. However, patients should be monitored for several hours in case of symptom progression. Antihistamines are sometimes used to relieve symptoms, although their efficacy in this setting is likely limited.

Angioedema caused by ACE inhibitors typically resolves within 24-72 hours. Some patients may experience recurrent episodes in the weeks to months after discontinuing the ACE inhibitor due to lingering effects of the discontinued drug. However, if the angioedema persists, alternative causes should be considered.

When a patient presents with angioedema and is taking an ACE inhibitor, discontinuation is generally recommended even if the cause is unclear. This is because continuing the ACE inhibitor puts the patient at risk of more frequent and severe episodes.

Alternatives

Patients who experience angioedema attributed to an ACE inhibitor should not be rechallenged with any other ACE inhibitor in the future. A history of ACE inhibitor-induced angioedema is also listed as a contraindication for the angiotensin receptor neprilysin inhibitor, sacubitril with valsartan.

An angiotensin II receptor blocker (ARB) may be considered as a replacement for the discontinued ACE inhibitor. While angioedema has been reported with ARBs, recent studies suggest that these drugs do not have a higher risk compared with other antihypertensives.

A large registry-based cohort study investigated the safety of ARBs in people with a history of angioedema during ACE inhibitor therapy. The study included over one million users of ACE inhibitors, and angioedema was reported to occur in 0.5% of users. Of the individuals who experienced angioedema during ACE inhibitor therapy, the highest recurrence rate was seen in the group who continued to take an ACE inhibitor (adjusted hazard ratio of 1.45 (95% CI, 1.19 to 1.78)). However, the lowest incidence occurred in patients switched to an ARB (adjusted hazard ratio, 0.39; 95% CI, 0.30 to 0.51).

Summary

While ACE inhibitor-induced angioedema is infrequent, this adverse effect is potentially serious. Prompt recognition and management is essential to improve patient outcomes and prevent progression to life-threatening complications. ACE inhibitors may be overlooked as the cause of angioedema due to the highly variable timing of the initial event. Discontinuation of the ACE inhibitor is recommended for all patients with ACE inhibitor-associated angioedema. Alternative therapies, such as ARBs, may be considered in these patients.