In a small, problematic, Phase 2 trial, icatibant – a selective bradykinin B2 receptor antagonist – seemed promisingly efficacious for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema. Considering the catastrophic and potentially fatal complications relating to airway angioedema, the prospect of having an effective rescue medication is of substantial clinical importance.
Sadly, and first picked up by Bryan Hayes, the phase 3 trial was a wash. Published with great fanfare in the Journal of Allergy and Clinical Immunology: In Practice, this multi-center study enrolled 121 patients with presumed, and at least moderately severe, ACE-I-induced angioedema. The primary efficacy endpoint was the subjective “time to meeting discharge criteria”, which was guided by a scoring system consisting of difficulty breathing, difficulty swallowing, voice change, and tongue swelling. Secondary endpoints included time to onset of symptom relief, rescue therapy, and other safety considerations.
Almost all patients received some “conventional” therapy prior to randomization, with most (>80%) receiving antihistamines or corticosteroids and approximately one-fifth receiving epinephrine. The median time to doses of conventional therapy were ~3.5 hours, and enrolled patients received either icatibant or placebo ~3.3 hours afterwards.
The picture is worth all the words:
No difference.
Laudably – although this ought to be the default, without special recognition – the sponsor and these COI-afflicted authors unabashedly published these neutral findings with little sugarcoating. I will defer, then, to their closing sentence:
In conclusion, icatibant was no more effective than placebo in treating at least moderately severe ACE-Ieinduced angioedema in this phase III trial.
“Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor Induced Upper Airway Angioedema”
http://www.sciencedirect.com/science/article/pii/S2213219817301721
I wonder if we’re over diagnosing ACE inhibitor induced angioedema? Basically if a patient presents with angioedema and they are on an ACE inhibitor we label it as ACE inhibitor induced angioedema even if they have tolerated the ACE inhibitor for years. However, we know that many cases of angioedema are idiopathic. ACE inhibitors are widely used drugs and while there is a pathway that explains ACE inhibitor induced angioedema and statistical evidence that ACE inhibitor users are at higher risk of angioedema, that does not mean that every case of angioedema in a patient using an ACE inhibitor is directly a result of the ACE inhibitor. It’s not surprising that cases of angioedema due to other etiologies may not respond to a relatively specific antagonist.
I don’t deny the existence of ACE inhibitor induced angioedema but in a complicated and poorly understood process such as angioedema it is likely an oversimplification to believe that every time a patient on an ACE inhibitor experiences angioedema that it is due to the ACE inhibitor.
I agree – I think the key element here is not that this bradykinin antagonist fails to do what it claims, but, rather, that we necessarily must make a clinical diagnosis of presumed ACE-I angioedema before reaching for an expensive drug like this. Unfortunately, we’re just not able to make those sorts of precise determinations between different precipitants of angioedema at the bedside.