Patients presenting to the ED are tending to get older, have more co-morbidities and take more medications. As this happens, in my experience we seem to see more patients with complications of those medications. Something we often see in the ED is angioedema1 in patients who are taking ACE inhibitors. This is said to be caused by an accumulation of bradykinin. The angio-oedema usually affects the face and we often see patients with quite severe airway swelling, particularly of the lips and tongue. This is a topic we’ve covered on St.Emlyn’s in the past2 as it can be pretty serious and may even be so severe that we intubate patients to protect their airways.
The problem with this condition is that there’s no recognised treatment. We don’t have an antidote to ACE inhibitors. The mechanism is very different to anaphylaxis, so epinephrine, steroids and antihistamines aren’t likely to help. Some people have tried giving FFP (fresh frozen plasma) but there isn’t really much evidence. So, the arrival of icatibant some years ago was very promising. Icatibant is a bradykinin antagonist. We use it in patients with hereditary angio-oedema, to good effect. Logically, you’d think that this should be a fantastic treatment for patients with ACE inhibitor induced angio-oedema too.
In fact, a small RCT from Germany suggested that it could be fantastic3. That was a phase 2 trial – so that means it wasn’t fully powered to look at the most meaningful outcomes. However, in 32 patients who were randomized to either icatibant or placebo, those who got icatibant recovered much more quickly. The time to complete resolution of oedema fell from 27 hours (placebo) to 8 hours (icatibant), which was statistically significant (p=0.002). Fantastic!
Of course, that’s not quite enough evidence to say that icatibant definitely works. It was a phase 2 trial. We really needed a phase 3 trial that’s large enough to look at meaningful clinical outcomes in more detail. Well, that’s exactly what has just been published4. You may not have seen it – as the trial is published in the Journal of Allergy and Clinical Immunology – but it’s important for those of us working in EM and Critical Care to know about it. Here’s the abstract…
The full text is also open access at this link.
What was the trial design?
I was privileged to be involved in this trial, which was sponsored by the manufacturer of the drug (Shire). They’ve conducted themselves really well, as you’ll see. The trial was a multi-centre, international prospective RCT, which ran at 59 centres internationally including four centres in the UK. (Central Manchester, Royal Devon & Exeter, Nottingham and Brighton and Sussex). We included patients who presented within 12 hours of the onset of angio-oedema that we believed had been caused by ACE inhibitors. They were randomized to receive icatibant or placebo by subcutaneous injection.
How were patients followed up?
Here’s why delivering this trial is a really great achievement. After we’d treated patients, they had to be regularly reviewed by a senior doctor after 30 minutes, 1 hour and then every hour for the first 8 hours. If they weren’t better, we had to continue assessing them every 2 hours until they did get better. You can tell that this often meant people stayed pretty late! In Manchester, we were really lucky that people like Rachel Jenner and Omar Amin went above and beyond the call of duty to stay very late reviewing patients. Our research nurses also had to stay for the whole thing – so they too went above and beyond.
Icatibant often causes a reaction at the injection site, and this has to be monitored carefully. Obviously, if you see a reaction then you can probably guess which treatment the patient had – and then the trial is no longer blinded, which is a problem. Therefore, we had TWO research nurses review every patient at follow up. One was blinded. The other looked at the injection site and was therefore unblinded. They weren’t allowed to communicate. I can honestly say that, in Central Manchester, our research nurses were so professional at this.
What were the key results?
There were 121 patients in this trial, recruited at 31 of the 59 centres that took part. But here’s the sad part. Sadly there was no difference between icatibant and placebo. For the primary outcome of time to meeting discharge criteria, there was a median time of 4 hours in each group (p=0.62). This outcome was defined using a validated score based on several criteria. Even when we looked at the individual components of that score – e.g. difficulty swallowing, difficulty breathing, tongue swelling – there was no difference. We couldn’t find any evidence of difference in various subgroups, either.
What does it mean?
It’s really interesting that our findings are so different to those in the German phase 2 RCT. When we look at the differences between trials, we can see that blinding was better in this trial. Time to recovery was shorter in this trial. We also allowed other medications to be given in this trial (e.g. epinephrine, steroids), whereas they weren’t allowed in the German trial. However, the big difference is that this trial is a larger, phase 3 trial. The German trial was smaller and phase 2. Ultimately, we have to consider that the findings of this trial are much more likely to reflect the reality. It seems that icatibant is no more effective than placebo (on top of other standard treatments) for treating ACE inhibitor induced angio-oedema.
A striking finding from this trial is that the prognosis for these patients was pretty good! A median time to meeting discharge criteria of 4 hours isn’t bad. There were no deaths. Patients usually just got better, and it probably didn’t matter what we did. (Although stopping the ACE inhibitor is probably quite important!) That being said, we don’t know whether other measures such as steroids and epinephrine were effective or not. There’s no evidence that we shouldn’t give those treatments – but perhaps there’s a need for an RCT. It would be difficult to deliver without the backing of a multi-national pharma company – but helpful to the field.
Is there any place at all for icatibant?
The only time I would consider icatibant is in patients with very severe angio-oedema, where the situation may be immediately life-threatening. We couldn’t include such patients in the study, for ethical reasons. (Lack of informed consent). So, we don’t actually know how it works in that group. We studied patients with moderate to severe angio-oedema, not very severe. If your patient has immediately life-threatening angio-oedema, there’s no evidence that icatibant will help. However, there’s no evidence of harm either. That’s the situation when I’d probably still reach for icatibant. But for others, I wouldn’t.
Editors note – I would also ask you to reflect on how a small phase 2 trial that was inconclusive ended up published in the New England Journal of Medicine (impact factor 55.598), and yet the better RCT ended up in a much smaller journal (impact factor 12.4). This is something we will no doubt cover at dasSMACC in the future of medical publishing panel discussion.