Objective To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.
Design, Setting, and Participants Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. 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). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios.
Exposures Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).
Main Outcomes and Measures The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.
Results A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). 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 the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .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 = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.
Conclusions and Relevance In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
In this prospective meta-analysis of 7 randomized clinical trials that included 1703 critically ill patients with COVID-19 recruited from countries on 5 continents, administration of corticosteroids was associated with lower all-cause mortality at 28 days after randomization. There was no suggestion of an increased risk of serious of adverse events. The ORs for the association between corticosteroids and mortality were similar for dexamethasone and hydrocortisone. The comparison of the association between low-dose corticosteroids and mortality and the association between high-dose corticosteroids and mortality was imprecisely estimated.
Corticosteroids were associated with lower mortality among critically ill patients who were and were not receiving invasive mechanical ventilation at randomization, as well as in patients from the RECOVERY trial who required oxygen with or without noninvasive ventilation but were not receiving invasive mechanical ventilation at randomization. These results were consistent with the subgroup analysis suggesting that the association between corticosteroids and lower mortality was stronger in patients who were not receiving vasoactive medication at randomization than in those who were receiving vasoactive medication at randomization. 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 randomization.
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 randomization. Most ongoing trials of corticosteroids in critically ill patients with COVID-19 suspended enrollment after these results became publicly available because equipoise for withholding corticosteroids was no longer present. 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.
The optimal dose and duration of treatment could not be assessed in this analysis, but there was no evidence suggesting that a higher dose of corticosteroids was associated with greater benefit than a lower dose of corticosteroids. Inclusion of data from the Metcovid trial did not materially change the results other than reducing the inconsistency among the trials. Data from the Metcovid trial were not included in the primary meta-analysis because this trial was registered after the searches of the trial registries were conducted.
All subgroup analyses other than that comparing longer with shorter duration of symptoms at randomization were prespecified. Although the benefit associated with corticosteroids appeared greater in critically ill patients who were not receiving invasive mechanical ventilation at randomization, this comparison was based on only 4 trials and 144 patients who were not receiving invasive mechanical ventilation at randomization, of whom 42 died. Corticosteroids were associated with lower mortality in critically ill patients who were and were not receiving invasive mechanical ventilation at randomization, as well as in patients in the RECOVERY trial who required oxygen with or without noninvasive ventilation but were not receiving invasive mechanical ventilation at randomization.7 It was not possible to classify this latter group according to whether they were critically ill at the time of randomization. These patients represented a spectrum of illness from patients receiving supplemental oxygen by nasal prongs to those receiving noninvasive ventilatory support in the form of high-flow oxygen or positive pressure by mask. Nonetheless, the substantial risk of death in these patients (682/2604 [26.1%] in the control group) is consistent with mortality in critically ill patients with COVID-19.
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.26 In the current study, potential corticosteroid–induced complications could not be analyzed reliably because of limitations of the available data (serious adverse events were reported by only 6 of the 7 trials, and their definitions and methods of assessment varied among trials). However, serious adverse events were generally less likely in patients randomized to corticosteroids than to usual care or placebo.
This prospective meta-analysis was based on a relatively large number of critically ill patients with COVID-19 from geographically diverse sites who were randomized to receive corticosteroids or to receive usual care or placebo. The protocol and analysis plan, including specification of subgroup analyses, was registered and made publicly available on the PROSPERO database prior to data analysis or receipt of outcome data. The protocol also has been published along with a structured abstract.8 Provision of pooled data in prespecified subgroups facilitated rapid analysis and dissemination because a need for multiple data-sharing agreements was avoided. As is standard in meta-analyses, patients were compared only with other patients randomized in the same trial. Therefore, observed associations support a causal relationship between the administration of corticosteroids, compared with usual care or placebo, and reduced mortality.
Limitations
This study has several limitations. First, the prospective nature of this meta-analysis implies that there is little risk of selective reporting or of publication bias,6 but it is possible that lack of participation by some investigators of ongoing trials was based on their knowledge of their trial results. Nonetheless, the number of patients randomized in eligible trials who did not participate is likely to be smaller than the number of patients included in this meta-analysis.
Second, all but 1 of the included trials was assessed as “low risk” of bias for the effect of assignment to the intervention. The trial for which the risk of bias was assessed as “some concerns” (Steroids-SARI; NCT04244591) was relatively small (47 patients and 26 deaths) and contributed only 3.5% of the weight in the primary meta-analysis. It was the only trial that assessed the effect of methylprednisolone.
Third, there were only limited missing outcome data, but in many trials, follow-up was censored when participants were discharged from the hospital. We are aware of no reason that the effect of corticosteroids on postdischarge 28-day mortality would differ from that on predischarge mortality, but it will be important to report on longer-term mortality, including postdischarge mortality, in future analyses.
Fourth, the definitions and reporting of serious adverse events were not consistent across the trials and therefore a meta-analysis for this secondary end point was not conducted. Fifth, the trials only recruited adults, and the effect of corticosteroids on children remains unclear. Similarly, the trials were mainly conducted in high-income settings.Sixth, 1 trial reported mortality at 21 days and 1 trial reported mortality at 30 days after randomization, potentially leading to inconsistency between trial results. Seventh, the RECOVERY trial contributed 57% of the weight in the primary meta-analysis of 28-day all-cause mortality, although there was little inconsistency between the effects of corticosteroids on 28-day mortality estimated by the different trials.
Conclusions
In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality
Reference & Source information: https://jamanetwork.com/
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