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”
http://jamanetwork.com/journals/jama/fullarticle/2618622

7 thoughts on “Dexamethasone Dilemma”

  1. Nice one Ryan…

    But this is hardly the first study looking at a single dose of oral dex for pharyngitis. There seems to be a reasonably consistent signal in the literature. It might help a bit. Let’s face it, steroids probably works more in the subset of more severe pharyngitis… but this is more extrapolated common sense than science.

    Perhaps the steroids would work better if we combined it with Vitamin C and Thiamine…

    1. I’d say the “reasonably consistent signal” is the product of multiple, small, low-quality studies, as well.

      There’s a benefit out there for some. There’s probably harm out there for some. Patient selection is important, but we don’t have great evidence to guide that.

  2. NNT is nice although I wouldn’t take it . NNT 12 for a minor benefit.
    As usual nothing anout NNH ?

    In the BMJ paper I read “within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07)”
    I fail to see how a short course of steroids could increase fracture rates within 30 days. Unless it would cause falls. Maybe a fluke result out of a myriad association tested, and retrospective anyhoo.

    Wisdom sayeth steroids are dangerous drugs. I haven’t seen much to counter that wisdom. Have you ?

    1. You know as well as I do the misery of acute pharyngitis. For a primary outcome of complete symptom relief, that hardly rules out some symptom relief for those without complete.

      And, the BMJ steroids paper is not applicable – there are so many other unmeasured confounders in that comparison, I have a hard time generalizing those results. And, for a 30-year old with pharyngitis in the ED, even a tiny increase in risk is multiplying zero times another number for those without contraindications.

      It’s easy evidence to go to bat for either side; it’s something I pull out of my hat when necessary, but nothing I do with enthusiasm.

      1. The BMJ paper , well they chose to not give results in absolute risk increase in the abstract. Bad boys. Will have to seek inside, but my question on fracture risk increase was unrelated.

  3. I think it’s overly optimistic to have a primary outcome that’s complete resolution within 24 hours. The patient will usually seek health care when she feels the worst, or in the case of millenials, as soon as they feel uncomfortable. Not many will seek care when they are on the verge of getting symptom free so to choose 24 hours resolution as the primary outcome is in my mind a bit foolish and risky.

    1. I’m sure they had a reasonable debate over the timeframe for the primary outcome. Too early, and it could be overly optimistic regarding the time of exposure to the therapeutic benefit. Too late, however, and you run into issues with the inevitable resolution of symptoms for all. After all, I expect at, say, 96 hours, nearly all patients have had complete resolution of symptoms!

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