Results of a meta-analysis published in the Journal of the American Medical Association suggest that the use of systemic corticosteroids in critically ill patients with COVID-19 was associated with lower 28-day all-cause mortality compared to usual care or placebo. The study also found that the benefit was the same regardless of age, sex or how long patients had been ill for.
The prospective meta-analysis, performed by Jonathan A. C. Sterne, Bristol Medical School, University of Bristol, Bristol, England, and colleagues, pooled data from 7 randomised trials that evaluated corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries on 5 continents from February 26 to June 9, 2020, with the date of final follow-up on July 6, 2020. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomisation method.
Among the participants, 678 patients had been randomised to receive systemic dexamethasone, hydrocortisone or methylprednisolone, while the remaining 1025 were administered usual care or placebo. The median age was 60 years, and 29% were women. The primary outcome was all-cause mortality up to 30 days after randomisation and was determined before any outcome data were available from any of the studies. In this analysis, the authors noted that 5 trials evaluated mortality at 28 days, therefore the primary outcome is reported here as 28-day all-cause mortality, while 1 trial reported mortality at 21 days, and 1 trial at 30 days.
Researchers found there were 222 deaths among the corticosteroid-treated patients and 425 deaths among those given usual care or placebo, for a 0.66 summary odds ratio (OR) (95% confidence interval [CI], 0.53-0.82; P < .001 based on a fixed-effect meta-analysis). The authors noted that this corresponds to an absolute mortality risk of 32% with corticosteroids compared with an assumed mortality risk of 40% with usual care or placebo. Further, there was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity), and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on a random-effects meta-analysis.
Meanwhile, the fixed-effect summary OR was 0.64 (95% CI, 0.50-0.82; P < .001) for trials of dexamethasone (3 trials, 1282 patients, and 527 deaths; corresponding absolute risk of 30% for dexamethasone vs an assumed risk of 40% for usual care or placebo), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths; corresponding absolute risk of 32% for hydrocortisone vs an assumed risk of 40% for usual care or placebo) and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths).
Further, the overall fixed-effect OR was 0.69 (95% CI, 0.55-0.86) among patients who were receiving invasive mechanical ventilation at randomisation (corresponding to an absolute risk of 30% for corticosteroids vs 38% for usual care or placebo) and 0.41 (95% CI, 0.19-0.88) for patients not receiving invasive mechanical ventilation (corresponding to an absolute risk of 23% for corticosteroids vs 42% for usual care or placebo). Meanwhile, the OR was 1.05 (95% CI, 0.65-1.69) among patients who were administered vasoactive agents at randomisation (an absolute risk of 48% for corticosteroids vs 47% for usual care or placebo) and 0.55 (95% CI, 0.34-0.88) for those not receiving such drugs (an absolute risk of 24% for corticosteroids vs 37% for usual care or placebo).
When looking at the data in terms of age group, sex and duration of symptoms, the OR was 0.69 (95% CI, 0.51-0.93) among patients over 60 years versus 0.67 (95% CI, 0.48-0.94) for those 60 years or younger (ratio of ORs, 1.02 [95% CI, 0.63-1.65], P = .94). Further, the OR was 0.66 (95% CI, 0.51-0.84) among men, and 0.66 (95% CI, 0.43-0.99) among women (ratio of ORs, 1.07 [95% CI, 0.58-1.98], P = .84). Among patients who were symptomatic for more than 7 days prior to randomisation, the OR was 0.64 (95% CI, 0.49-0.83), while the OR was 0.63 (95% CI, 0.39-1.04) among patients who were symptomatic for 7 days or less (ratio of ORs, 1.07 [95% CI, 0.40-2.81], P = .90).
Meanwhile, among the six trials that reported serious adverse events, 64 events occurred among 354 patients randomised to corticosteroids and 80 events occurred among 342 patients randomised to usual care or placebo. “Adverse events varied across trials, but there was no suggestion that the risk of serious adverse events was higher in patients assigned to corticosteroids except for the two smallest trials, in which the total number of serious adverse events was 1 and 3,” the authors noted.
“The findings from this prospective meta-analysis provide evidence that treatment with corticosteroids is associated with reduced mortality for critically ill patients with COVID-19. The findings contrast with outcomes reported for the administration of corticosteroids among patients with influenza, for whom mortality and hospital-acquired infections may be increased by the administration of corticosteroids,” the authors concluded. “The ORs for the association between corticosteroids and mortality appeared similar for older and younger individuals, men and women, and for longer and shorter durations of symptoms before randomisation,” they added.
“This analysis was expedited because of the release of results from the RECOVERY trial, which found that the absolute risk of death was reduced by 12.1% among those assigned to low-dose dexamethasone who were receiving invasive mechanical ventilation at randomisation,” the authors wrote. “These trial results from diverse clinical and geographic settings suggest that in the absence of compelling contraindications, a corticosteroid regimen should be a component of standard care for critically ill patients with COVID-19,” they added.
Nonetheless, the authors noted that the optimal dose and duration of treatment could not be assessed in this analysis, adding that “there was no evidence suggesting that a higher dose of corticosteroids was associated with greater benefit than a lower dose.”