Pharmacology 101: Dexamethasone for COVID-19: RECOVERY!

Pharmacology 101 is an online column designed to keep EMS providers informed on formularies, dosages, effects, applications, and current research related to medications administered in the prehospital setting. If you have a medication-related question you’d like the author to address, contact editor@emsworld.com.

Author’s note: as our knowledge of COVID-19 continues to grow and evolve, new information is always being added. Every effort has been made to present information that is up to date as of the time of writing; however, readers should always keep abreast of new information that comes to light.

Despite the growing number of studies for COVID-19, there have only been limited data suggesting benefit with any specific treatments. Recently, the hype flared up with hydroxychloroquine, but even then the data were not definitive. Now, the report from the RECOVERY trial is that dexamethasone may be an effective treatment for some patients with COVID-19.

What is dexamethasone?

Dexamethasone is a cheap corticosteroid used to treat a variety of disease states and conditions including asthma, allergies, nausea and vomiting, swelling of the brain and various skin, eye, and ear disorders.¹ It works as a potent anti-inflammatory and is effective for conditions affecting many different organ systems.

What is the RECOVERY trial?

The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial took place in the United Kingdom. The trial took patients with COVID-19 and split them into two groups: patients who received the usual care (control group) and patients who received the usual care plus dexamethasone at a dose of 6 mg daily (either orally or intravenously) for up to 10 days, or until discharge (intervention group).² Then, they investigated whether there was a difference in the number of patients who were alive 28 days later.

This trial was huge. They randomized 6,425 patients in total, of which 4,321 patients were in the control group and 2,104 received dexamethasone (intervention group).

What were the results?

The 28-day mortality rate in the dexamethasone group was lower than in the group of patients who only received usual care: 22.9% vs. 25.7%. This gives an absolute risk reduction of 2.8%. Another way to look at the data would be to state that for every 36 patients treated with dexamethasone, one patient’s life was saved.

One important thing to note is that the patients who benefitted the most were the patients who were intubated on mechanical ventilation at the time they entered the trial—these patients had an incredible 12.1% absolute reduction in mortality. This means that for ventilated patients, one life was saved for every nine patients treated with dexamethasone. Conversely, patients who were not on oxygen supplementation did not benefit from dexamethasone treatment, and even had a trend towards harm.

Are there any concerns with the way the trial was conducted?

This trial had a number of limitations as well as bias, which is defined as “any trend or deviation from the truth in data collection, data analysis, interpretation and publication which can cause false conclusions.”³ For example, the trial was open-label, meaning that everyone knew which group the patients were in. Could knowing that a patient was in the treatment group have influenced other aspects of their care? As some commentators have noted, however, it is difficult to fake being dead, as mortality is an objective outcome.

An early concern was that the complete data were not yet available—only the preliminary preprinted report had been made public, and the manuscript had not been peer-reviewed. Thus, we knew in broad strokes what the results were, but not the finer details. Since then, the preliminary report has been peer-reviewed and published in the New England Journal of Medicine.⁴

The bottom line: should we be using dexamethasone for patients with COVID-19?

Multiple commentators are now recommending dexamethasone for the treatment of patients with COVID-19 who are requiring supplemental oxygen.^5–7 They are basing this on data from the RECOVERY trial which showed benefit among patients meeting these criteria.

The World Health Organization is currently in the process of updating their guidelines.⁸ It seems reasonable to anticipate that they will comment on the data from the RECOVERY trial.

The National Institutes of Health’s COVID-19 treatment guidelines (updated June 25, 2020 at the time of this writing) currently have these statements:

Based on the preliminary, unpublished results of the RECOVERY trial, the Panel recommends dexamethasone 6 mg daily for up to 10 days in patients with COVID-19 who are on mechanical ventilation (AI) or those who require supplemental oxygen but who are not on mechanical ventilation (BI). The Panel recommends against using dexamethasone to treat patients with COVID-19 who do not require supplemental oxygen (AI). The Panel may modify these recommendations based on the final published results of this study and the results of other ongoing studies.⁹

The Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 has been updated as of June 25, 2020, and contains recommendations which are based on the report from the RECOVERY trial:

• Among hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests glucocorticoids rather than no glucocorticoids. (Conditional recommendation, Moderate certainty of evidence)
• *Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.
• Among hospitalized patients with COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, Low certainty of evidence)9

Currently, guideline recommendations are only recommending the use of dexamethasone in specific situations. While the RECOVERY trial’s press release indicated a positive impact on mortality, the full analysis of the study is still ongoing. The National Institutes of Health notes a number of additional considerations to be taken into account with dexamethasone, reflecting the fact that there is still much for us to learn about how we are treating COVID-19.¹⁰

The views and opinions expressed in this article are those of the author and do not necessarily reflect those of people, institutions, or organizations they have been, currently are, or will be affiliated with.

References

1. Micromedex Solutions. Dexamethasone. https://micromedex.com/. Accessed June 25, 2020.

2. RECOVERY Collaborative Group. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1.

3. Šimundić AM. Bias in research. Biochem Medica. 2013;23(1):12-15. doi:10.11613/BM.2013.003

4. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020. doi:10.1056/NEJMoa2021436

5. Farkas J. PulmCrit – Dexamethasone & COVID – a study in immunopathology, evidence-based medicine, and ourselves. https://emcrit.org/pulmcrit/recovery/. Accessed June 25, 2020.

6. Rezaie S. The RECOVERY Trial: Dexamethasone for COVID-19? https://rebelem.com/the-recovery-trial-dexamethasone-for-covid-19/. Accessed June 25, 2020.

7. Morgenstern J. Dexamethasone for COVID: The RECOVERY trial. First10EM blog. https://first10em.com/dexamethasone-for-covid-the-recovery-trial/. Published 2020. Accessed June 25, 2020.

8. World Health Organization. Q&A: Dexamethasone and COVID-19. https://www.who.int/news-room/q-a-detail/q-a-dexamethasone-and-covid-19. Accessed June 25, 2020.

9. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Version 2.1.0. https://www.idsociety.org/COVID19guidelines.

10. National Institutes of Health. Care of Critically Ill Patients with COVID-19. https://www.covid19treatmentguidelines.nih.gov/critical-care/.

Daniel Hu, PharmD, BCCCP, has Doctor of Pharmacy degree and is a critical care and emergency medicine pharmacist. He is a frequent speaker at conferences and has many publications in peer-reviewed journals.