Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Abstract

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Sterne reported receiving grants from the UK National Institute for Health Research (NIHR). Dr Murthy reported receiving grants from the Canadian Institutes of Health Research. Dr Slutsky reported being a co-primary investigator of one of the trials that is included in the meta-analysis. Dr Angus reported receiving personal fees from Ferring Pharmaceuticals Inc, Bristol-Myers Squibb, Bayer AG, and Alung Technologies Inc; and having patents pending for Selepressin (compounds, compositions, and methods for treating sepsis) and for proteomic biomarkers of sepsis in elderly patients. Dr Annane reported receiving grants from the French Ministry of Health; and being on the steering committees for 2 of the trials (CAPE COVID and REMAP-CAP) included in this meta-analysis. Dr Azevedo reported receiving grants from Ache Pharma; and receiving personal fees from Pfizer and Halex-Istar. Dr Berwanger reported receiving grants from AstraZeneca, Servier, Novartis, Bayer, Boehringer-Ingelheim, and Amgen. Dr Cavalcanti reported receiving grants from Bayer, Bactiguard, Johnson & Johnson do Brasil, Hemaclear, Hillrom, and Pfizer. Dr Dequin reported receiving grants from the French Ministry of Health, Abionic, Atox Bio, Sphingotec Gmbh, Adrenomed, Medspace, Aridis, Merck, Combioxin, GlaxoSmithKline, Medimmune, Genentech, Revimmune, Faron, Kenta, and Tigenix. Dr Du reported receiving grants from Peking Union Medical College, the Chinese Academy of Medical Sciences, and the Chinese Ministry of Science and Technology. Dr Emberson reported receiving grants from Boehringer Ingelheim. Dr Gordon reported receiving grants from the NIHR; receiving a research professorship from the NIHR; receiving nonfinancial support from the NIHR Clinical Research Network and the NIHR Imperial Biomedical Research Centre; receiving personal fees from GlaxoSmithKline and Bristol-Myers Squibb; and being the UK chief investigator and a member of the international trial steering committee for the REMAP-CAP trial. Dr Granholm reported receiving grants from the Novo Nordisk Foundation, Pfizer, the Rigshospitalet Research Council, Ferring Pharmaceuticals, and Fresenius Kabi; and being a member of the management committee of one of the trials (COVID STEROID) included in this meta-analysis. Dr Jüni reported receiving personal fees from Amgen, Ava, and Fresenius; receiving grants from the Canadian Institutes of Health Research and Appili Therapeutics; and serving as an unpaid member of the steering group of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St Jude Medical, Terumo, and the Medicines Company. Dr Landray reported receiving grants from UK Research and Innovation, the UK NIHR, Health Data Research UK, the NIHR Oxford Biomedical Research Centre, MRC Population Health Research Unit, Merck, Sharp & Dohme, Novartis, Boehringer Ingelheim, the Medicines Company, and UK Biobank Ltd; and receiving nonfinancial support from Roche and AbbVie. Dr Lim reported receiving grants from Pfizer. Dr Machado reported receiving personal fees from ACHE. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Perner reported receiving grants from the Novo Nordisk Foundation and Pfizer. Dr Petersen reported receiving grants from the Novo Nordisk Foundation and Pfizer. Dr Savović reported receiving grants from the UK NIHR. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Marshall reported receiving personal fees from AM Pharma; and serving as co-chair on the WHO Working Group on Clinical Characterization and as management chair for the International Forum for Acute Care Trialists. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram Showing the Identification of Eligible Trials and Participating Trials

Figure 2.. Association Between Corticosteroids and 28-Day All-Cause Mortality in Each Trial, Overall, and According to Corticosteroid Drug

The area of the data marker for each trial is proportional to its weight in the fixed-effect meta-analysis. The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial result is for patients who were receiving invasive mechanical ventilation at randomization. CAPE COVID indicates Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease; CoDEX, COVID-19 Dexamethasone; COVID STEROID, Hydrocortisone for COVID-19 and Severe Hypoxia; DEXA-COVID 19, Efficacy of Dexamethasone Treatment for Patients With ARDS Caused by COVID-19; REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; Steroids-SARI, Glucocorticoid Therapy for COVID-19 Critically Ill Patients With Severe Acute Respiratory Failure. aThe random-effects analysis estimates both the average and variability of effects across studies. The 95% CI for the average effect (shown here) is wide because there is a small number of studies, some of which have very small sample size. The prespecified primary analysis was the fixed-effect analysis, which should be used to guide clinical interpretation of the results.

Figure 3.. Association Between Corticosteroids and 28-Day All-Cause Mortality Within Subgroups Defined by Patient Characteristics at the Time of Randomization

The area of the data markers is proportional to their weight in the meta-analysis. The estimated odds ratios were derived using fixed-effect meta-analyses across all trials for which data on the specified subgroup were available. The results for patients in the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial who required oxygen with or without noninvasive ventilation but were not receiving invasive mechanical ventilation at randomization is shown in a light blue box because these data were not otherwise included in this prospective meta-analysis.

Figure 4.. Association Between Corticosteroids and Serious Adverse Events in Each Trial

The area of the data markers is proportional to the inverse of the variance of the estimated odds ratio. CAPE COVID indicates Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease; CoDEX, COVID-19 Dexamethasone; COVID STEROID, Hydrocortisone for COVID-19 and Severe Hypoxia; DEXA-COVID 19, Efficacy of Dexamethasone Treatment for Patients With ARDS Caused by COVID-19; REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; Steroids-SARI, Glucocorticoid Therapy for COVID-19 Critically Ill Patients With Severe Acute Respiratory Failure. The Steroids-SARI trial recorded adverse events but did not categorize them as serious or nonserious.