Clinical Question: Is a single dose of dexamethasone not inferior to 5 days of prednisolone to treat mild to moderate asthma exacerbation in adults?
Authors: Rehrer, M.W. et al
Published: Annals of Emergency Medicine, Nov 2016
Population: Adults 18-55yrs requiring nebulisers in ED but able to be discharged home (with exclusions)
Intervention: 12mg dexamethasone in ED and 4 additional placebo capsules
Comparator: 60mg prednisolone OD for 5 days
Outcome: Relapse within 14 days
Summary: This is a single centre study. The authors hypothesised that because there is an association between poor adherence and poor outcomes in asthma, a dose of dexamethasone, known to have a duration of action of 72 hours, could improve outcomes compared to normal standard of care, which requires 5 days of adherence.
The ED staff, patients, and analysers were all blinded to treatment allocation. Anyone who received a nebuliser was screened for possible eligibility. Relapse was detected by telephone follow-up at 2 weeks.
The authors chose a noninferiority margin on 8%. This is because national records and previous studies find a 16% relapse rate for normal standard of care, and a 33% relapse rate for placebo. They state that 50% of the difference between these two relapse rates is 8%. Choosing 8% as a non-inferiority margin also ensures the intervention is >50% superior to placebo.
This study included 376 adults, 173 in dexamethasone group and 203 in prednisolone controls. Relapse occurred for 12.1% taking dexamethasone, and 9.8% taking prednisolone. 95% confidence interval -4.1% to 8.6%. They state that because this is very slightly greater than their pre-planned noninferiority margin of 8%, a single dose of dexamethasone does not demonstrate noninferiority to prednisolone for 5 days.
Strengths, weaknesses, and clinical relevance
I think the paper is very clearly written and methods thoroughly described.
This study relies on noninferiority methodology. They are testing that the new intervention is ‘not unacceptably worse’ than current care, by an arbitrarily chosen margin. By falling outside of their planned margin, the authors can only say that statistically dexamethasone is “not ‘not unacceptably worse'” than prednisolone.
The authors do not describe their local population. It could be presumed that in a context where patients are less likely to engage with counting out 8 x 5mg prednisolone tablets for 5 days, there would be higher rate of relapse in the control group.
The confidence interval crosses 0 so ignoring the non-inferiority margin it could be considered that there is statistically no difference between the two groups.
The sample size was recalculated when the interim analysis found an overall relapse rate of 11%. The authors do not offer a breakdown of this between the two groups. They did not go on to redefine their noninferiority margin based on a greater difference between this relapse rate and historical placebo relapse rate, because this would have meant changing their outcomes mid-trial; however, should they have done so the noninferiority margin would have been ((33-11)/2=) 11% which would have meant their overall result of 8.6% would have demonstrated noninferiority.
Could the results be different in a UK context prescribing 30-40mg prednisolone instead of 60mg OD?
Is this relevant for the COPD population as well?
Could or should this study change practice here?