Off-label C1 Inhibitor Concentrate May Be Effective in ACEI-induced Acute Angioedema

Off-label C1 inhibitor concentrate successfully treated people with severe acute angioedema triggered by the use of so-called ACE inhibitor medications, a small study has found.

The study, “Effectiveness of C1-INH therapy in angiotensin converting enzyme inhibitor induced angioedema,” was published in the journal Allergy, Asthma & Clinical Immunology.

Angioedema often occurs as an allergic reaction to various allergens, but it also can be triggered by medications such as angiotensin-converting enzyme inhibitors (ACEIs), which often are prescribed for treating high blood pressure, heart failure, diabetes, and chronic kidney disease.

Angioedema is a well-documented side effect of ACEIs, affecting about 1% of those who receive them, and is the leading cause of therapy-induced angioedema emergency room visits.

Without treatment, ACEI angioedema typically resolves over one to five days. However, when symptoms threaten the patients’ airways, C1 esterase inhibitor (C1-INH) concentrate has been prescribed and used off-label when other treatments have failed. 

C1-INH is a protein with anti-inflammatory properties whose levels are diminished in people with hereditary angioedema. Concentrates of this protein, such as CSL Behring’s Haegarda, are currently approved to treat those with this particular condition.  

However, there is no consensus on the best approach to treat people with ACEI-induced angioedema, and there are no approved therapies. Given the number of emergency room visits, further investigation into the efficacy of C1-INH concentrate for this particular condition is needed.

Scientists in Canada recently reviewed the medical records of people who experienced ACEI-induced angioedema and were treated with C1-INH concentrate at local hospitals. 

After consulting records from three academic hospitals in Manitoba, investigators identified a total of nine people, ages 57–80, with ACEI-induced angioedema, who received C1-INH concentrate from 2010 to 2020.

From these, six were women and eight were Caucasian. The only patient who was not Caucasian was of Filipino descent. All were diagnosed with high blood pressure; five also had diabetes. 

Less than half (four of nine) of the patients included in the analyses were treated with nonsteroidal anti-inflammatory drugs (NSAIDs), which are used routinely to ease pain and inflammation. 

All of them experienced acute angioedema attacks involving the upper airways or face, including lips, tongue, soft palate, or cheeks. Most patients (seven of nine) required mechanical ventilation for airway protection.

All patients were treated immediately with the intravenous (into-the-vein) steroid methylprednisolone, the antihistamine diphenhydramine, as well as epinephrine (adrenaline), which is used to treat life-threatening allergic reactions caused by, for example, insect bites or stings, foods, or medications. 

In the emergency room, the time to receive C1-INH concentrate was highly variable, ranging from one to 25 hours. The first dose of C1-INH concentrate was 20 international units per kilogram (IU/kg), with doses ranging from 1,000 to 1,500 IU. Three patients received additional C1-INH, including one who received an extra dose of 500 IU, and two who received an additional dose of 1,000 IU.

In one participant, ACEI-induced angioedema improved after one dose (1,500 IU) of C1-INH concentrate. Yet, four hours later, the patient had to be treated with Firazyr (icatibant injection), an approved treatment for acute angioedema attacks, due to lack of response to C1-INH concentrate.

About 26 hours after receiving both treatments the patient was well enough to be removed from ventilation. 

Angioedema was resolved in four of the nine patients (44%) after 12 to 14 hours, with no recurrence. One participant had partial symptom resolution after 14 hours, but angioedema recurred 24 hours later, requiring re-ventilation. The remaining four patients were cleared of angioedema after 22 to 72 hours. 

In two patients, an additional dose of C1-INH concentrate after a lack of response from the first dose did not improve the time to resolution of symptoms, which finally occurred after 35 and 72 hours, suggesting “that if a response to C1-INH concentrate treatment will be seen, it will be with the first dose,” the team wrote. 

Additionally, “there was a trend that patients being treated with NSAIDs at the time of developing the angioedema, responded slower to the C1-INH treatment,” they added. “This raises the question of whether there was [multiple causes] or [an] alternative explanation of the angioedema in these patients.” 

The researchers concluded: “Although our preliminary findings suggest that C1-INH concentrate administration may shorten the time spent in the intensive care unit in a subgroup of patients, this conclusion must be met with caution given multiple confounding variables. Ultimately, further research into characterizing this subgroup of patients needs to be completed.”