In this episode, I’ll discuss the treatment of ACE inhibitor induced angioedema.
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Angioedema due to Angiotensin-converting enzyme (ACE) inhibitors is a rare event. Because of the high frequency of ACE inhibitor use, many patients will go on to develop ACE inhibitor induced angioedema.
Angioedema is the swelling of deep dermis, subcutaneous, or submucosal tissue due to vascular leakage. When this swelling involves the upper airway, angioedema can be life-threatening. ACE inhibitor induced angioedema is related to elevated levels of bradykinin.
Swelling usually develops over minutes to hours, peaks, and then resolves over 24 to 72 hours. There are no definitive tests to confirm ACE inhibitor induced angioedema. One unique characteristic (besides a medication history including an ACE inhibitor) that helps make the clinical diagnosis of ACE inhibitor induced angioedema is the absence of itching or urticaria.
Treatment
When you encounter a patient with ACE inhibitor induced angioedema that involves the upper airway, the first and only priority is to protect the patient’s airway.
If you hear stridor, see that the patient is drooling, using accessory muscles to breathe, or has edema of the tongue or floor of the mouth, assume that the physician will want to immediately intubate the patient and obtain the necessary medications to assist with this process. I discussed medications used during intubation in episode 15.
Because ACE inhibitor induced angioedema results from bradykinin and not histamine release, therapies that work for histamine induced angioedema are not considered effective.
If the diagnosis of ACE inhibitor induced angioedema is clear, don’t waste time with epinephrine, glucocorticoids, and antihistamines as they do not effect bradykinin or alter the course of ACE inhibitor induced angioedema.
Depending on the location of the angioedema, the physician may choose a nasal rather than oral approach to intubation.
Other treatments
Avoiding intubation and mechanical ventilation is desired when possible. To this end, some treatments for ACE inhibitor induced angioedema have been employed to attempt to avoid intubation.
Plasma
Fresh frozen plasma (FFP) may degrade high levels of bradykinin, which may in turn allow angioedema to resolve. Evidence for this treatment is limited to case series.
Icatibant
Small studies have used icatibant 30 mg subcutaneously for ACE inhibitor induced angioedema. Icatibant is a bradykinin receptor antagonist and is FDA approved for use in hereditary angioedema. When given within 10 hours of symptom onset for ACE inhibitor induced angioedema, icatibant shortened the time to complete resolution of edema. Unfortunately the cost of this therapy is $11,000 USD and the study was too small to reach any conclusions on safety or clinically meaningful endpoints.
Ecallantide
Ecallantide is also approved for hereditary angioedema. It differs from icatibant in that it inhibits the unregulated production of bradykinin by inhibiting kallikrein. It appears that ecallantide is not effective for the treatment of ACE inhibitor induced angioedema.
Re-challenge & recurrence
Patients who experience ACE inhibitor induced angioedema should permanently discontinue all ACE inhibitor use and not be re-challenged. Symptoms can persist for up to 6 weeks after stopping ACE inhibitors, and this complicates the assessment of cross-reactivity with other medications such as angiotensin receptor blockers (ARB).
It is generally recommended that patients with ACE inhibitor induced angioedema should only switch to an ARB if they also have a compelling indication such as heart failure or chronic kidney disease.
Summary
In summary, when you encounter a patient with ACE inhibitor induced angioedema involving the upper airway, focus all of your attention on interventions that assist with establishing a protected airway for the patient. Once the patient’s airway is protected, the angioedema will resolve after a few days have passed.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
Joe,
Thanks again for a great review. What are your thoughts on the use of a C1 Esterase Inhibitors such as Berinert for ACEI Angioedema involving the airway? We have used it in my ER with success. Costly obviously and only used on a case by case basis. The way I understand it is that Icatibant is probably superior to Berinet but Berinet will still ‘get the job done’. Unfortunately at my institution we do not carry Icatibant so if treatment is required I give Berinert. Your thoughts?
Thanks again,
Ash
Thank you!
That is an interesting option. I only see 2 case reports describing it’s use.
I really lean towards just establishing an airway and waiting out the 24-72 hours. At such great expense I want to see evidence of a hard outcome like mortality or length of stay being improved.
First of all you should let your government bargain the prices of medication like most civilized countries. We pay $2500 for Firazyr in Norway, same price as Berinert which in my experience also gets the job done. The need to subject patients to a potential difficult airway situation and mechanical ventilation due to this exorbitant pricing is a disgrace. Anyway, a day or two in the ICU costs way more than Firazyr or Berinert.
I’ve been to Norway several years ago – beautiful country! It is interesting to see how practice is different between countries and how policies factor into that.
There was a fair amount of buzz for icatibant use in ACEi-Induced angioedema after the Bas article in NEJM. That was a small phase 2, industry-funded study in a homogeneous population. A recently completed but not yet published phase 3 study funded by the makers of icatibant showed no difference in any of the primary or secondary outcomes. Save your $$$. Manage the airway. To date there is no solid evidence for any medications in ACEi-induced angioedema. This is an area that is ripe for future research.
(disclosure- I was a site PI on the phase 3 study)
Cheers,
Gentry
@gentrywmd
Thank you for your comments, that is interesting about the phase 3 study!
https://www.emrap.org/episode/springforward/theinsidescoop
Hot off the press…
Thank you!