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Systemic Corticosteroids and Mortality in COVID-19 Critically Ill Patients
Quick Takes
- Clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required ventilator support.
- In this prospective meta-analysis of seven randomized trials that included 1,703 patients, administration of systemic corticosteroids, as compared with usual care or placebo, was associated with lower 28-day all-cause mortality in critically ill patients with COVID-19.
Study Questions:
Is administration of systemic corticosteroids associated with reduced 28-day mortality in critically ill patients with coronavirus disease 2019 (COVID-19)?
Methods:
This study was a prospective meta-analysis that pooled data from seven randomized clinical trials conducted in 12 countries that evaluated the efficacy of corticosteroids in 1,703 critically ill patients with COVID-19 from February 26, 2020 to June 9, 2020. Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1,025 patients). The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs).
Results:
A total of 1,703 patients (median age 60 years; 29% women) were included in the analysis. The risk of bias was assessed as “low” for six of the seven mortality results. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1,025 patients randomized to usual care or placebo (summary odds ratio [OR], 0.66; p < 0.001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; p = 0.31 for heterogeneity). The fixed-effect summary OR for the association with mortality was 0.64 for dexamethasone compared with usual care or placebo, the OR was 0.69 for hydrocortisone, and the OR was 0.91 for methylprednisolone.
Conclusions:
In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, as compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
Perspective:
This World Health Organization (WHO)-sponsored prospective meta-analysis is published in this issue of Journal of the American Medical Association, alongside three multicenter randomized controlled trials examining the role of corticosteroids in COVID-19 patients: REMAP-CAP, CoDEX, and CAPE COVID (also included in this meta-analysis). All three randomized controlled trials and the meta-analysis stopped enrollment in June 2020, largely based on the results of the RECOVERY trial (contributing 57% of the weight in the primary meta-analysis). RECOVERY was a large open-label randomized trial enrolling 6,425 patients demonstrating that treatment with dexamethasone reduced mortality by one-third in patients receiving mechanical ventilation and by one-fifth in patients receiving supplemental oxygen as compared with usual care alone. In this meta-analysis, the benefit of systemic corticosteroids appears to be a class effect (as the association between administration of corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone). There was no suggestion of increased risk of serious adverse events. The optimal dose and duration of treatment could not be assessed in this analysis due to imprecise estimates. Overall, the meta-analysis indicates that administration of steroids is clearly associated with benefit among critically ill patients with COVID-19. However, the exact threshold at which a given patient should be administered systemic corticosteroids remains to be determined.
Clinical Topics: COVID-19 Hub, Prevention
Keywords: Coronavirus, Coronavirus Infections, COVID-19, Critical Illness, Dexamethasone, Hydrocortisone, Methylprednisolone, Oxygen Inhalation Therapy, Primary Prevention, Respiration, Artificial, severe acute respiratory syndrome coronavirus 2, Steroids, Treatment Outcome
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