Icatibant … Can’t?

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”

Dexamethasone Dilemma

Look! On Twitter! Two highly-respected medical minds taking the same trial publication and producing two, very different responses:

The controversy stems from a small study examining the relatively common practice of treating pharyngitis with an oral steroid – usually dexamethasone – for its anti-inflammatory effect. Most pharyngitis does not require antibiotics, and physicians understandably prefer to try something to provide relief from suffering.

This study enrolled 576 patients in a randomized, placebo-controlled, double-blind trial in an outpatient general practice setting. Patients were provided either 10mg of oral dexamethasone or an identical lactose placebo. Patients could only enter into the trial if immediate antibiotics were not prescribed, but physicians were allowed to give a “delayed” prescription for failure to improve.

The trial is statistically negative for the primary outcome, complete resolution of sore throat at 24 hours. Of those assigned to dexamethasone, 22.6% had complete symptom resolution at 24 hours, compared with 17.7% of placebo, an absolute risk difference of 4.7% (-1.8 to 11.2)[sic]. The effect size is slightly larger at 48 hours, 8.7%, which does reach statistical significance – and thus the NNT noted above by Ian Stiell. Nearly all the other secondary outcomes – resource utilization, subsequent antibiotic use, use of pain relief – favor dexamethasone, but generally range in effect size between 1-4%.

Does the failure to meet statistical significance for the primary outcome refute this therapy as effective? Not hardly – but it certainly calls into question whether the difference is reproducible or clinically meaningful. Plug these data into Ioannidis’ framework regarding the reliability of research findings, and we see this is precisely the sort of work where both conclusions are reasonable. Is there a signal for a symptomatic benefit? Absolutely. The strength of the signal, however, is not strong enough to overcome whatever pre-study odds you placed on the treatment being successful. If, like many, you feel this is a treatment likely beneficial, this study appears confirmatory. If, like many, you feel systemic steroids for symptomatic pharyngitis is inane, this study does little to change your view of the inadequate risk/benefit ratio.

Another possible interpretation of these data is the possibility of variable effects within subgroups, where the entire small effect size seen in these data results from a more substantial effect size in some fraction of the cohort. For example, the mean duration of symptoms was ~3.9 days, with a SD of ~1.7 days. Could the recency of symptoms be associated with likelihood of benefit? Any secondary analyses such as these, particularly in a small trial like this, would only serve as fodder for future investigations.

I have seen, however, other folks using this as an opportunity to link to the recent BMJ publication regarding adverse events and corticosteroid exposures. Without delving into that publication in detail, it would be a mistake to generalize those data to this population. That said, systemic corticosteroids are certainly not harmless. These authors rather ludicrously state “Short courses of oral steroids have been shown to be safe, in the absence of contraindications” – justified by a citation from 1982.

The final answer is somewhere in between our two friends above. Dexamethasone will help some patients with symptom relief from pharyngitis, and it will harm some.  Teasing out a prediction of the optimal risk/benefit for a patient is substantially challenging – and wide practice variation is justifiable from these data, as long as it is acknowledged the uncertainty in the evidence base.

“Effect of Oral Dexamethasone Without Immediate Antibiotics vs Placebo on Acute Sore Throat in Adults”

Icatibant for ACE-Inhibitor Angioedema

Oropharyngeal angioedema can be one of the true Emergency Department airway disasters.  Massive and rapidly progressive edema can engulf all usable landmarks and views, necessitating surgical intervention.  No one enjoys these cases – least of all the patient.

This small trial, replete with heavy sponsor involvement, details the utility of icatibant, a selective bradykinin receptor antagonist, for treatment of ACE inhibitor-induced angioedema.  27 patients were randomized either to icatibant or steroids plus an antihistamine.  The mean times to symptom relief were reduced substantially by use of icatibant – with reported total symptom resolution reduced from 27 hours to 8 hours.

Of course, for the three placebo patients meeting the protocol definition of worsening clinical status, the authors arbitrarily set their time to symptom resolution to 61.8 hours – exaggerating (unnecessarily) the difference measured for the primary outcome.  Finally, bizarrely, 4 of these 27 patients were lost to follow-up – all in the placebo cohort.  What sort of effect this would have on the integrity of the results is uncertain.

But, all such misbehaviors aside, icatibant probably works, along with C1-esterase inhibitor and ecallantide.  However, each use of these medications costs between ~$7,000-$10,000 per administration.  Therefore, restraint is necessary to prevent indication creep – and such medications should not be given to all perioral angioedema presentations, and be reserved only as a final option to fend off impending upper airway obstruction.

“A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema”

TMJ Dislocations: A Better Mousetrap?

Anterior temporomandibular dislocations are generally quite satisfying closed reductions.  Patients, understandably, are exceedingly grateful to have their function restored.  However, it typically requires parenteral analgesia, sometimes procedural sedation, and puts the practioner at risk of injury from inadvertent biting.

This interesting pilot describes a technique in which the patient, essentially, self-reduces the TMJ dislocation by using a syringe held between the posterior molars as a rolling fulcrum.  I’d describe it in more detail, but I think, from the image reproduced here, you’ll get it:

These authors used this technique for 31 cases, and only one was ultimately unsuccessful.

While this is not the intended use for a syringe, I can’t hardly imagine any terrible harmful adverse effects from materials failure – and they don’t exceed the risks of procedural sedation.  I certainly find it reasonable to experiment with this technique.

“The ‘Syringe’ technique: a hands-free approach for the reduction of acute nontraumatic temporomandibular dislocation in the Emergency Department.”

The Myth of “Sinus Headache”

Here’s a simple truth to take away: incidentally-noted “chronic sinusitis” on CT should not be used as a scapegoat for acute atraumatic headache symptoms in the ED.

This is a retrospective review of non-contrast head CT at a single center in Boston, comparing 234 patients undergoing CT for atraumatic headache and 266 undergoing CT for minor head injury.  22.2% of atraumatic headache patients received radiologic diagnoses of “chronic sinusitis”, while 17.7% of minor head injury patients had a similar radiologic finding.  The authors conclude, within the limitations of this retrospective review, that findings of “chronic sinusitis” are purely incidental, and unlikely to be related to an Emergency Department visit for acute atraumatic headache, and should not be diagnosed with “sinus headache”.

This fits in with multiple other investigations demonstrating most “sinus headaches” outside the context of acute upper respiratory infection meet criteria for migrane, and respond to serotonin-receptor agonists.  Do not treat these patients with antibiotics, and do not correlate these incidental radiologic findings with acute pathology.

“Findings of chronic sinusitis on brain computed tomography are not associated with acute headaches.”

Kids with Tubes and Otitis Media Get Drops not Pills

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the last decade, researchers have sought to determine the usefulness, or lack there of, for systemic antibiotics in a number of infectious etiologies previously thought to require antibiotics for resolution. This includes strep throat, sinusitis, bronchitis and, more recently, diverticulitis. Acute otitis media (AOM) has long been a target for such studies and recently, the guidelines have changed. The American Academy of Pediatrics now endorses a “wait and see” approach for many children with AOM while also recommending a more stringent definition of the disease.

What about for patients with tympanostomy tubes who present with signs of AOM? These patients typically present with otorrhea (pus from the tympanostomy tube). Is the presence of drainage adequate to treat or should these patients be placed on oral or topical antibiotics? Small trials have shown good efficacy of topical antibiotics but Pediatricians and Emergency Physicians continue to prescribe oral antibiotics in the face of inadequate evidence.

The researchers here attempt to answer this question. They performed a fairly large study of 230 children who were randomized to either observation, oral antibiotics or topical antibiotic-glucocortocoid drops in an open-label fashion. The primary endpoint was resolution of otorrhea at 2 weeks. The results are surprising. Resolution was seen in 95% in the group given drops, 56% in the oral antibiotic group and 45% in the observation group. These numbers yield a miniscule NNT = 3 for resolution of otorrhea with topical antibiotics-glucocortocoids vs. oral antibiotics.

A couple of notes are important. All of the patients had otorrhea for up to 7 days prior to entering the study and the presence of a fever excluded them from the study. Additionally, tubes couldn’t be recently placed (< 2 weeks) there couldn’t be recent antibiotic use (< 2 weeks) or otorrhea (< 4 weeks).

As evidence mounts to the harms of inappropriate and unnecessary systemic antibiotic use, it’s important to tailor therapy based on the available literature. Many patients with tympanostomy tubes that develop otorrhea will resolve with simple observation. However, treatment with topical antibiotic-glucocortocoid drops should be the first line treatment as they are superior to oral antibiotics with fewer side effects.

“A trial of treatment for acute otorrhea in children with tympanostomy tubes.” 

Tranexamic Acid for Epistaxis

Well, it’s not the major hemorrhage of CRASH-2 – but, as every Emergency Physician knows, refractory epistaxis is burdensome and significantly irritating to all involved.  Luckily, there are a variety of methods available to manage bleeding, mostly successful.

You may now add tranexamic acid to this list.  TXA, an antifibrinolytic agent, already used to reduce hemorrhage-associated coagulopathy, has been used in many different forms for minor bleeding as well.  These folks from Iran randomized, in unblinded fashion due to differences in odor, folks presenting with severe epistaxis to “conventional control” with cotton pledgets soaked in lidocaine + epinephrine versus pledgets soaked with 500mg of TXA.  Sadly, they do not declare a primary outcome – rather, the authors list several “efficacy variables” – but, whichever they would have chosen, it would have favored the TXA group.  71% of TXA patients had cessation of bleeding within 10 minutes, versus 31% with lidocaine+ epinephrine, faster discharge from the ED, less rebleeding in 24 hours, and less rebleeding at a week.

It seems physiologically plausible, in any event, considering lidocaine+epinephrine isn’t truly directly therapeutic for hemostasis.  As any Emergency Physician knows, it’s all about Plan B, C & D for every situation – and TXA seems another reasonable tool for the box.

“A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial”