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Three Part Question

In [patients presenting to the Emergency Department with ACE-inhibitor angioedema] is [bradykinin B2 receptor antagonist icatibant more effective than standard supportive therapy or placebo] at [reducing severity of angioedema attacks]?

Clinical Scenario

A 64-year-old woman is brought to your Emergency Department with acute onset isolated lip and tongue swelling. Despite having no other symptoms of anaphylaxis, she quickly receives intramuscular epinephrine and intravenous methylprednisolone without any effect. Her history reveals that she has been taking ramipril for two years to treat her hypertension. You suspect a bradykinin-mediated ACE-inhibitor angioedema and have heard that icatibant may help this patient, but you’re not sure if there is convincing evidence for its use.

Search Strategy

Medline 1946-06/10/22 using the OVID interface.
[exp bradykinin B2 Receptor Antagonist/ or icatibant.mp or firazyr.mp or sajazir.mp] and [exp Angioedema/ or (ace inhibitor adj5 angioedema).mp]

Search Outcome

The search yielded 332 papers, however, only three studies met inclusion criteria comparing icatibant to either standard treatment for angioedema or placebo. Case reports and case series with fewer than 20 patients were excluded.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bas M, Greve J, Stelter K et al. 2015 Germany	27 patients ages 18-95 who were taking an ace-inhibitor and presented to the Emergency Department with ace-inhibitor-induced angioedema affecting the upper aerodigestive tract.	Phase 2 RCT	Time to complete resolution of angioedema.	Icatibant (N=13) median 8.0hrs, standard therapy (N=14) median 27.1 hrs. (p=0.002).	Small study with only 27 patients included in the analysis. Patients were exclusively white Europeans, despite ace-inhibitor-induced angioedema being more common among black patients taking ace inhibitors. Statistical analysis for the primary endpoint was performed per-protocol, with no reported intention to treat analysis.
			Proportion of patients with complete resolution at 4 hours after treatment	Icatibant 5 of 13 patients (38%), standard therapy 0 of 14 patients (0%)
			Time to onset of symptom relief	Icatibant (N=13) median time to symptom relief 2.0 hours, standard therapy (N-14) median time to symptom relief 11.7 hours standard therapy (p=0.03)
Straka BT, Ramirez CE, Byrd JB et al. 2017 USA	33 patients ages 18-65 presenting with ace-inhibitor-associated angioedema (defined as swelling of the lips, pharynx, or face while taking an ace-inhibitor in patients who had never experienced angioedema while not taking an ace-inhibitor)	RCT	Time to resolution of symptoms	No difference between icatibant and placebo (p=0.20)	This was a small study with only 33 patients enrolled, a number of whom had significant unbalanced comorbid conditions including previous organ transplant, chronic high dose steroid use, and autoimmune disorders. Though written as a multicentre study, all but one patient were enrolled at a single centre, and the remaining patient was excluded from the analysis. The study required administration of drug within 6 hours of presentation, but the mean time between onset of symptoms and administration of medication was 10.3 hours in the icatibant group. This is a substantially longer delay than for the patients in whom icatibant has been found to be effective (ie. hereditary angioedema).
			Improvement in symptoms over time	No difference between icatibant and placebo (p=0.95)
			Incidence of intubation	No difference between icatibant and placebo. (p value not reported)
			Incidence of ICU admission	No difference between icatibant and placebo. (p value not reported)
Sinert R, Levy P, Bernstein JA, et al. 2017 USA, UK, Canada, Israel	121 adults > 18 years who were taking an ace-inhibitor and presented with ace-inhibitor-induced angioedema of the head and/or neck.	Phase 3 RCT	Time to meeting discharge criteria	IQR 2.0-6.0 hrs), Placebo 4.0 hrs (IQR 1.0-6.0 hrs). No statistically significant difference (p=0.63)	This study was funded by Shire, the manufacturer of Firazyr. The time to resolution of symptoms and time to symptom relief in the placebo group was substantially shorter than the natural course of ace-inhibitor-induced angioedema reported in the literature (though there is significant variability in this), raising concerns that some of the randomized patients may have presented with histamine-mediated rather than bradykinin-mediated angioedema.
			Time to onset of symptom relief	No statistically significant difference between icatibant and placebo for any symptom. (p>0.08) Results reported by individual symptom in supplementary materials.
			Occurrence of airway intervention	1 patient receiving icatibant and no patients receiving placebo required airway intervention after receiving study drug.

Comment(s)

Prior to the publication of these three RCTs, a number of case reports and case series had been published suggesting a possible role for icatibant in the treatment of ACE-inhibitor induced angioedema. A meta-analysis including the three RCTs summarized above was published by Jeon et al. in 2017 (reference below), finding no significant effect of icatibant when compared with placebo or conventional treatment. The above RCTs were used in this BET to provide a more granular understanding of the current state of evidence for icatibant.

Clinical Bottom Line

The current evidence from RCTs does not demonstrate a beneficial effect of icatibant in the treatment of ace-inhibitor-induced angioedema when compared with standard care or placebo.

References

1. Bas M, Greve J, Stelter K et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. New England Journal of Medicine. January 2015; 372:418-425.
2. Straka BT, Ramirez CE, Byrd JB et al. Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema. Journal of Allergy and Clinical Immunology. July 2017; 140:242-248.
3. Sinert R, Levy P, Bernstein JA, et al. Randomized trial of icatibant for angiotensin converting enzyme inhibitor-induced upper airway angioedema. Journal of Allergy and Clinical Immunology: In Practice. September/October 2017; 5:1402-1409.