COVID STEROID 2 and the non-statistically significant result

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:

Pocock SJ, Stone GW. The Primary Outcome Fails – What Next? N Engl J Med. 2016 Sep 1;375(9):861-70. doi: 10.1056/NEJMra1510064. PMID: 27579636. [article]

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

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

One comment

  1. I reply as a patient:
    Yes, those differences between the scores might be statistically insignificant, but then so are the small dots of light seen in the night sky. As a patient, though, I am not concerned about statistical significance; My concern is whether I am in the tiny percentage who live! If I would have been in the thirty-eight percent who died on the small dose then being outside the high-dose thirty-five percent group would be VERY significant for me!

    I once, about seventeen years ago, had a doctor tell me, “You have only a seven percent chance of dying.” I replied, “As an engineer, I find a seven percent failure rate to be unacceptable!” My unexpected response made him think about what he had said.

    For the past three years, I have been doing my damnedest to regain the strength I had before my life-path sent me to hell. I was seeing a therapist, to whom I had made it quite clear that my work was having basically no effect, and that the situation was likely to end in me ending my life. As time went on, my anger increased, then became rage. COVID made me delay the decision another year. My GP read her reports. Had anyone bothered to order a hormone panel, it would have been seen that SHBG was too high, T was too low—but no one did.
    June fourth, I asked my GP for a thyroid panel and a T lab test, the latter for curiosity. What I got back was a testosterone LCMSMS panel revealing the mentioned problem. Only now, has an endocrinologist seen the various labs, July sixteen, late September. He, and some other doctors, are now doing what should have been done three years ago. At age sixty-seven, I consider those three years to have been something valuable thrown down the drain. My current endo is a very intelligent man who intends to correct the problem.

    Something unrelated to doctors: I have to take copies of my labs to each doctor, to have copies made, because the lab will not send the results to any doctor but the one who sent in the lab order! Really, folks!

    From what I have seen at https://www.npr.org/2021/10/26/1046432435/ers-are-now-swamped-with-seriously-ill-patients-but-most-dont-even-have-covid?utm_source=pocket-newtab, especially, and read, and seen in real life, the medical community are overworked and underpaid—especially GPs. How can we expect them to do their best work?
    I am abnormally intelligent, speak clearly, say exactly what needs to be said, and can deal with things not being what I expected. How does a normal person, and the doctor, deal with the typical poor communication? Why do we (the U.S.) have doctors wasting their time on paperwork?

    I apologize for the rant. Sorry.

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