Concise Critical Appraisal: Dexamethasone Use in the Treatment of COVID-19

In the search for treatment options for COVID-19, antibiotics and immunosuppressive drugs such as azithromycin and hydroxychloroquine have yielded disappointing results in high-quality randomized studies (Cavalcanti et al. N Engl J Med. 2020. Online ahead of print). Remdesivir may be helpful, but any benefit seems marginal (Beigel et al. N Engl J Med. 2020. Online ahead of print). Glucocorticoids, however, have previously shown benefit in community-acquired pneumonia and acute respiratory distress syndrome (ARDS) (Siemieniuk et al. Ann Intern Med. 2015;163:519-528; Villar et al. Lancet Respir Med. 2020;8:267-276) and may be of benefit in a primarily respiratory viral disease such as COVID-19.
 
The RECOVERY trial was published in the New England Journal of Medicine on July 17, 2020, a mere four months after beginning enrollment (RECOVERY collaborative group et al. N Engl J Med. 2020. Online ahead of print.). This randomized, controlled, open-label study compared the effects on mortality of dexamethasone versus usual care. Conducted in the United Kingdom’s National Health Service, 6425 hospitalized patients were randomized 1:2 to receive dexamethasone, 6 mg once daily for up to 10 days, or usual care. The primary outcome was all-cause mortality within 28 days after randomization. Prespecified analyses were performed on the primary outcome for five subgroups, including level of respiratory support and days since symptom onset.
 
The results demonstrated a statistically significant improvement in mortality in those who received dexamethasone with a rate ratio (RR) of 0.83 (95% CI, 0.75-0.93). Furthermore, subgroup analysis showed the largest mortality benefit in those undergoing invasive mechanical ventilation (RR 0.64; 95% CI, 0.51-0.81). There was no mortality benefit with steroids in patients who did not require oxygen therapy, and there may have been a signal of harm although it was not statistically significant. Digging deeper into the supplementary data, subgroups with symptoms lasting longer than seven days and age younger than 70 years seemed to benefit the most from dexamethasone.
 
The biggest limitation to this study is its nonblinded design. Eighty-nine percent of patients had SARS-CoV-2 confirmed by laboratory testing. While some may perceive this as a limitation, compared to other critical care trials this represents excellent homogeneity of the study population. Twenty-four percent of patients included were hospitalized but did not require oxygen therapy, which raises concerns over whether they were ill enough to be included in a study along with those requiring mechanical ventilation.
 
This is the highest-quality positive trial for a COVID-19 treatment to date. While we await the results of the complete data set, these preliminary results are promising. Critically Ill COVID-19 patients with hypoxemic respiratory failure have high mortality. Combining the findings of the RECOVERY trial with the cost-effectiveness and established safety profile of dexamethasone in other similar respiratory illnesses and ARDS should cause clinicians to consider administering glucocorticoids in many COVID-19 patients with hypoxic respiratory failure.
 
Coauthors of this installment of Concise Critical Appraisal:
 
Garrett Ghent, MD, is a clinical instructor in Emergency Medicine and an Advanced Resuscitation Fellow in the Department of Emergency Medicine at Stony Brook Medicine.
 
Brian J. Wright, MD, MPH, is a clinical associate professor and the program director for the Advanced Resuscitation Training Program in the Department of Emergency Medicine at Stony Brook Medicine. Dr. Wright is an editor of Concise Critical Appraisal.

References

1. Cavalcanti AB, Zampieri FG, Rosa RG, et al; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020 Jul 23;NEJMoa2019014. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32706953/
2. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19: preliminary report. N Engl J Med. 2020 May 22; 23;NEJMoa2007764. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32445440/
3. Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015 Oct 6;163(7):519-528. https://pubmed.ncbi.nlm.nih.gov/26258555/
4. Villar J, Ferrando C , Martinez D, et al; Dexamethasone in ARDS Network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267-276. https://pubmed.ncbi.nlm.nih.gov/32043986/
5. RECOVERY Collaborative Group; Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19: preliminary report. N Engl J Med. 2020 Jul 17; NEJMoa2021436. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32678530/