Objective. To assess the association between administration of systemic corticosteroids, compared with usual care or placebo, and 28-day all-cause mortality in critically ill patients with coronavirus disease 2019 (COVID-19).
Design. Prospective meta-analysis with data from 7 randomized clinical trials conducted in 12 countries.
Setting and participants. This prospective meta-analysis included randomized clinical trials conducted between February 26, 2020, and June 9, 2020, that examined the clinical efficacy of administration of corticosteroids in hospitalized COVID-19 patients who were critically ill. Trials were systematically identified from ClinicalTrials.gov, the Chinese Clinical Trial Registry, and the EU Clinical Trials Register, using the search terms COVID-19, corticosteroids, and steroids. Additional trials were identified by experts from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Senior investigators of these identified trials were asked to participate in weekly calls to develop a protocol for the prospective meta-analysis.1 Subsequently, trials that had randomly assigned critically ill patients to receive corticosteroids versus usual care or placebo were invited to participate in this meta-analysis. Data were pooled from patients recruited to the participating trials through June 9, 2020, and aggregated in overall and in predefined subgroups.
Main outcome measures. The primary outcome was all-cause mortality up to 30 days after randomization. Because 5 of the included trials reported mortality at 28 days after randomization, the primary outcome was reported as 28-day all-cause mortality. The secondary outcome was serious adverse events (SAEs). The authors also gathered data on the demographic and clinical characteristics of patients, the number of patients lost to follow-up, and outcomes according to intervention group, overall, and in subgroups (ie, patients receiving invasive mechanical ventilation or vasoactive medication; age ≤ 60 years or > 60 years [the median across trials]; sex [male or female]; and the duration patients were symptomatic [≤ 7 days or > 7 days]). For each trial, the risk of bias was assessed independently by 4 investigators using the Cochrane Risk of Bias Assessment Tool for the overall effects of corticosteroids on mortality and SAEs and the effect of assignment and allocated interventions. Inconsistency between trial results was evaluated using the I2 statistic. The trials were classified according to the corticosteroids used in the intervention group and the dose administered using a priori-defined cutoffs (15 mg/day of dexamethasone, 400 mg/day of hydrocortisone, and 1 mg/kg/day of methylprednisolone). The primary analysis utilized was an inverse variance-weighted fixed-effect meta-analysis of odds ratios (ORs) for overall mortality. Random-effects meta-analyses with Paule-Mandel estimate of heterogeneity were also performed.
Main results. Seven trials (DEXA-COVID 19, CoDEX, RECOVERY, CAPE COVID, COVID STEROID, REMAP-CAP, and Steroids-SARI) were included in the final meta-analysis. The enrolled patients were from Australia, Brazil, Canada, China, Denmark, France, Ireland, the Netherlands, New Zealand, Spain, the United Kingdom, and the United States. The date of final follow-up was July 6, 2020. The corticosteroids groups included dexamethasone at low (6 mg/day orally or intravenously [IV]) and high (20 mg/day IV) doses; low-dose hydrocortisone (200 mg/day IV or 50 mg every 6 hr IV); and high-dose methylprednisolone (40 mg every 12 hr IV). In total, 1703 patients were randomized, with 678 assigned to the corticosteroids group and 1025 to the usual-care or placebo group. The median age of patients was 60 years (interquartile range, 52-68 years), and 29% were women. The larger number of patients in the usual-care/placebo group was a result of the 1:2 randomization (corticosteroids versus usual care or placebo) in the RECOVERY trial, which contributed 59.1% of patients included in this prospective meta-analysis. The majority of patients were receiving invasive mechanical ventilation at randomization (1559 patients). The administration of adjunctive treatments, such as azithromycin or antiviral agents, varied among the trials. The risk of bias was determined as low for 6 of the 7 mortality results.
A total of 222 of 678 patients in the corticosteroids group died, and 425 of 1025 patients in the usual care or placebo group died. The summary OR was 0.66 (95% confidence interval [CI], 0.53-0.82; P < 0.001) based on a fixed-effect meta-analysis, and 0.70 (95% CI, 0.48-1.01; P = 0.053) based on the random-effects meta-analysis, for 28-day all-cause mortality comparing all corticosteroids with usual care or placebo. There was little inconsistency between trial results (I2 = 15.6%; P = 0.31). The fixed-effect summary OR for the association with 28-day all-cause mortality was 0.64 (95% CI, 0.50-0.82; P < 0.001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths); the OR was 0.69 (95% CI, 0.43-1.12; P = 0.13) for hydrocortisone (3 trials, 374 patients, and 94 deaths); and the OR was 0.91 (95% CI, 0.29-2.87; P = 0.87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Moreover, in trials that administered low-dose corticosteroids, the overall fixed-effect OR for 28-day all-cause mortality was 0.61 (95% CI, 0.48-0.78; P < 0.001). In the subgroup analysis, the overall fixed-effect OR was 0.69 (95% CI, 0.55-0.86) in patients who were receiving invasive mechanical ventilation at randomization, and the OR was 0.41 (95% CI, 0.19-0.88) in patients who were not receiving invasive mechanical ventilation at randomization.
Six trials (all except the RECOVERY trial) reported SAEs, with 64 events occurring among 354 patients assigned to the corticosteroids group and 80 SAEs occurring among 342 patients assigned to the usual-care or placebo group. There was no suggestion that the risk of SAEs was higher in patients who were administered corticosteroids.
Conclusion. The administration of systemic corticosteroids was associated with a lower 28-day all-cause mortality in critically ill patients with COVID-19 compared to those who received usual care or placebo.