The COVID STEROID 2 trial was recently published in JAMA. The study compared different dexamethasone doses (12mg versus 6mg daily) for the treatment of COVID19 respiratory disease requiring high levels of oxygen support (>10L/min) or mechanical ventilation. The primary outcome did not show a statistically significant difference. However, an argument can be made that the study supports the use of 12mg dexamethasone. An important caveat is that this study did not include many patients receiving other immunomodulators, such as IL-6 receptor antagonists (only about 10% of patients). You can read the article here:
COVID STEROID 2 Trial Group. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial. JAMA. 2021 Oct 21. doi: 10.1001/jama.2021.18295. Epub ahead of print. PMID: 34673895. [article]
It is also accompanied by a succinct, balanced editorial:
Webb SA, Higgins AM, McArthur CJ. Glucocorticoid Dose in COVID-19: Lessons for Clinical Trials During a Pandemic. JAMA. Published online October 21, 2021. doi:10.1001/jama.2021.16438. [article]
One of the senior authors of the COVID STEROID 2 trial, Prof Anders Perner (@AndersPerner), shared his interpretation of the trial in a tweetorial re-posted with permission below:
As highlighted in the last tweet, we have previously discussed when non-statistically significant trial results might be considered practice changing in a JAMA editorial:
Young PJ, Nickson CP, Perner A. When Should Clinicians Act on Non-Statistically Significant Results From Clinical Trials? JAMA. 2020 Jun 9;323(22):2256-2257. doi: 10.1001/jama.2020.3508. PMID: 32383733. [article]
Another useful article to help us interpret this study is:
Other useful summaries of the COVID STEROID 2 trial can be found here:
Critical Care Reviews also recently hosted a virtual meeting involving experts from around the world to discuss the interpretation of the COVID STEROID 2 – the videos are highly recommended. Prof Marion Campbell’s editorial, and the panel response, is packed with astute insights including:
- the ceiling effect – a large number of patients got the best possible outcome, survival at 28 days – seen in the primary outcome makes analysis difficult. This is often a challenge in ICU trials as to achieve a sufficient sample size there is a tendency to recruit patients at the milder (likely to survive regardless of therapy) and/or more severe (more likely to die regardless of therapy) ends of the disease spectrum. In theory, this phenomenon dilutes out the patients whose course of illness can be changed by therapy and weakens the power of the study despite an apparently adequate sample size.
- separation between the two groups may have been decreased by prior dexamethasone use, especially affecting the 6mg arm.
- only 3 patients would have needed different results to make the study “positive” (kind of a reverse Fragility Index), which is less than the number lost to follow up.
- the signal for benefit appears stronger in the trial patients in the European healthcare systems compared with the Indian health system, for unclear reasons.
- This trial is remarkable among pandemic trials for having a blinded intervention and for following patients beyond 28 days to 90 days.
- no dose-related safety issues were found in this study, though differences in rarer side-effects cannot be excluded.
- lots of questions remain – especially as this trial does not address the appropriateness of higher dose dexamethasone in conjunction with other immunomodulators.
What’s your take on this trial and how to interpret the findings?
novel coronavirus of COVID-19