SGEM#188: Icatibant Bites the Dust – For ACE-I Induced Angioedema

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Date: September 12th, 2017

Reference: Sinert et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract 2017.

Guest Skeptic: Dr. Anand Swaninathan is an Assistant Professor of Emergency Medicine at NYU/Bellevue Hospital in the Department of Emergency Medicine. He is also part of REBEL EM, The Teaching Course, EMRAP and CoreEM.

Case: As you walk in to your shift, the nurses grab you and bring you in to bed four where a patient has just presented with tongue swelling. In the room is a 53-year-old woman who, though, not in any particular distress, has got a swollen tongue and lower lip. After a bit of history, you find out that she is taking lisinopril and you determine that this is likely angiotensin converting enzyme inhibitor (ACE-I) induced angioedema. The patient’s swelling started about three hours ago and hasn’t changed much. You place her on a monitor in a high acuity area and bring your airway equipment to the bedside and then return to your computer to take sign out. You discuss with the resident a bit on ACE-I induced angioedema and settle on a plan to observe the patient. Your resident tells you that they recently read an article in the NEJM that argued for the administration of icatibant to usher along resolution of symptoms in ACE-I induced angioedema and asks whether you should consider this treatment.

Background: ACE-I are prescribed to millions of patients in the US. Though they are relatively safe, upper airway angioedema is one of the life-threatening adverse effects that we see frequently in the Emergency Department. Though this disorder is routinely treated with medications for anaphylaxis (i.e. epinephrine, histamine blockers, corticosteroids) the underlying mechanism of action predicts that these medications will not work.

There is no well-established treatment algorithm other than airway control if the angioedema is severe and appears to be causing a mechanical obstruction and cessation of the medication.

A 2015 phase 2 study published in the NEJM (Bas et al) touted the role for icatibant in the treatment of these patients. Icatibant is a selective bradykinin B2 receptor antagonist so it acts by blocking the production of bradykinin.

Despite being heralded as “the cure,” the data set in this article was small (n=27) questioning the validity of the findings.

We covered ACE-I induced angioedema and reviewed the 2015 icatibant study on SGEM#110. Our bottom line at that time was that icatibant was an expensive drug that appears to work well for the off-label use of ACE-I induced angioedema but should be reserved for those rare cases of impending airway compromise.

Enter the CAMEO study which attempts to further elucidate whether there are going to be benefits or not of this medication.

Clinical Question: Does the administration of icatibant to patients with ACE-I induced angioedema improve outcomes?

Reference: Sinert et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract 2017.

Population: Patients 18 years of age or older who were being treated with an ACE-I and presenting with ACE-I induced angioedema of the head and/or neck within 12 hours of symptom onset.
Intervention: Conventional treatment plus icatibant 30 mg subcutaneously
Comparison: Conventional treatment plus placebo subcutaneously
Outcome:
- Primary: Time to meeting discharge criteria “defined as time from study drug administration to earliest time that difficulty breathing and difficulty swallowing were absent and voice change and tongue swelling were mild or absent.”
- Secondary: Occurrence of airway intervention, admission to hospital, use of corticosteroids, antihistamines or epinephrine and number/proportion of subjects meeting the primary endpoint at 4, 6 and 8 hours post-drug administration.

Authors’ Conclusions: “Icatibant was no more efficacious than placebo in at least moderately severe ACE-I-induced angioedema of the upper airway”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the ED. YES
The patients were adequately randomized. YES (computer generated randomization was performed)
The randomization process was concealed. YES
The patients were analyzed in the groups to which they were randomized. YES. The analysis was done on intention to treat
The study patients were recruited consecutively (i.e. no selection bias). UNSURE
The patients in both groups were similar with respect to prognostic factors. YES
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. YES, probably
All groups were treated equally except for the intervention. YES. Standard anaphylaxis/allergy treatment was at discretion of MD but were fairly equal across groups.
Follow-up was complete (i.e. at least 80% for both groups). YES. 100% for primary outcome and only 1 patient did not complete 3-day follow up.
All patient-important outcomes were considered. YES
The treatment effect was large enough and precise enough to be clinically significant. NO. There was no treatment effect.

Key Results: There were 147 patients screened and 121 patients included in the study with a mean age of about 60 and more than 2/3 were black or African American. Greater than 90% of patients received conventional treatment medications (corticosteroids, antihistamines, or epinephrine) an average of 3.5 hours before the study drug. There were 118 patients who received treatment a median of 7.8 hours from symptom onset.

Primary Outcome: Time to meeting discharge criteria – No Difference

Primary Outcome: Median time to discharge in both groups was 4.0 hours
Secondary Outcomes:
- Airway Intervention: No significant difference between treatment arms. One patient in icatibant arm required an airway intervention (none in placebo arm).
- Hospitalization: No significant difference between treatment arms
- (45.8% vs. 45.8%)
- Use of Adjunct Medications: No significant difference between treatment arms (58.3% vs. 60.3%)
- Stratified Time to Discharge: No significant difference between treatment arms at any point (4, 6 or 8 hours)

Exclusions: There were 147 patients screened but only 121 were randomized. What happened to the other 26 patients? They excluded patients needing immediate airway intervention as they could not consent. We will talk about this group more in point number two. Patients with hereditary angioedema were also excluded. In this group, icatibant is an accepted treatment. Another excluded group was patients who responded to allergic reaction/anaphylaxis medications. The rationale was that these medications should not help in ACE-I angioedema and thus, response calls the diagnosis into question. A final point to make is the diagnosis of ACE-I angioedema is subjective.
External Validity: As mentioned, the study excluded patients who required immediate airway management as this group could not consent. Does this represent a group in whom we should consider administering the drug? This is possible and is a major critique from the icatibant supporters. In many cases, interventions show the greatest benefit in those at greatest risk of adverse outcomes. Hence, by excluding the population with the most to benefit, one reduces the chance of detecting an effect. Also, there’s really no evidence to support the use of the drug in these circumstances. A much larger study of this group of severely ill patients would be required to get a recommendation for this indication. This is unlikely to happen as angioedema patients requiring airway control are rare (this study collected just 121 patients over 1.5 years at 59 sites). Of note, in the Bas article published in 2015, there were 3 patients in the control arm who were decompensating and were then given icatibant. One of these three progressed after icatibant and needed a tracheostomy.
Blinding: We answered “yes” but we could have also answered “unsure” What’s the deal? Their approach to blinding was excellent and clinicians, assessors and patients were blinded to group allocation. However, icatibant is two times more likely to cause a local reaction at the injection site. This may have caused some unblinding, but you would think that any unblinding would have favored the intervention.
Dr. Rick Body

Publication Bias: The study by Bas and colleagues was published in the NEJM while this article is in the Journal of Allergy and Clinical Immunology Practice. Doesn’t the fact that the article touting the utility of this drug appeared in a high impact factor journal mean I should take those recommendations over the ones from this author group? No. The Bas article was a very small (n = 27) phase II RCT performed in a homogenous patient group which limits external validity. Because the study was small, the confidence intervals around the point estimates are wide so it’s hard to know what the actual benefit is. Despite these issues, the high impact journal NEJM agreed to publish the trial. In contrast, the CAMEO study was a much more robust study with superior methodology and a negative outcome. It too was submitted to the NEJM but rejected. Dr. Rick Body was one of the authors on the CAMEO study. He has agreed to provide some more insight into the study. Listen to the SGEM podcast on iTunes to hear Rick’s comments.
Conflicts of Interest: Both studies were funded by industry. We have repeatedly stated that just because a study is funded does not make the results wrong. However, there is data to suggest that industry funded studies more often have a positive interpretation of the results. Because this better study did not find efficacy in using icatibant for patients with ACE-I angioedema it makes us believe these results more than the other earlier study.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions. This well done, RDCT shows no benefit to the addition of icatibant in the treatment of ACE-I-induced angioedema. There may be a role for the drug in patients with severe, immediately airway-threatening angioedema but we have no data on that issue and further high-quality studies looking at this population would be required.

SGEM Bottom Line: We do not have good evidence that icatibant improves outcomes in patients with ACE-I induced angioedema.

Case Resolution: After discussing the NEJM article as well as the recent CAMEO study, you and your resident decide not to administer icatibant and, instead, to admit the patient for observation overnight.

Clinical Application: The excitement of some for the purported benefits of icatibant for this indication based on the small NEJM study was unfounded. Currently, there is no reason to add icatibant in the treatment of ACE-I induced angioedema.

If we are not going to give icatibant, how should we manage these patients with angioedema Swami?

Dr. Anand Swaminathan

Airway control if indicated
Observe and reassess
Anaphylaxis meds aren’t helpful unless the patient has utricaria or hives with their angioedema. In these cases, epinephrine is likely to help
I used to tout FFP as the treatment of choice but it’s really not. FFP does have ACE so you can see how theoretically it can help but FFP also contains bradykinin and kininogen which can worsen symptoms
Cessation of the drug is critical to make sure this doesn’t happen again

ACE-I induced angioedema remains a disorder without a viable treatment modality for reduction of symptoms. For now, the primary therapeutic interventions remain the same – airway management when indicated, observe and removal of the offending agent.

What do I tell my patient? You are currently suffering from angioedema which is a swelling of the skin and it’s likely due to a medication you’re taking. We don’t currently have a medication that fixes this problem but, for most people, the swelling stabilizes and recedes without any complications. Because you have swelling of the mouth and the tongue, we’re going watch you in the hospital and make sure this doesn’t progress. We’ll also be taking you off the medication that caused this swelling.

Keener Kontest: Last weeks’ winner was Dave Lemonick from Pittsburgh. He knew the story of how barefoot doctors are connected to acupuncture (Victor W Sedil NEJM 1972).

Listen to the SGEM podcast on iTunes to hear this weeks’ question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

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