Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19

Abstract

IMPORTANCE Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. OBJECTIVE To determine whether hydrocortisone improves outcome for patients with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. INTERVENTIONS The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned-1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). RESULTS After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR,-1 to 15), 0 (IQR,-1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. CONCLUSIONS AND RELEV...

A living WHO guideline on drugs for covid-19

“…This evidence was complemented by new data from six randomised trials of corticosteroids reporting mortality data by subgroup in a prospective meta-analysis of randomised trials for corticosteroid therapy for covid-19 6. The data were made immediately available for the guideline panel, allowing the WHO guidance to be peer reviewed and published simultaneously with the prospective meta-analysis and three of the individual trials 121314…”

High versus standard doses of corticosteroids in severe COVID-19: a retrospective cohort study

“…Dexamethasone at a higher dose (up to 20 mg per day) for critically ill patients was also associated with a positive effect, measured as a composite of days alive and free of MV [32]. Conversely, neither hydrocortisone (up to 200 mg/day) [33,34] nor methylprednisolone (0.5 mg/kg/day) [35] showed a significant difference in their respective primary endpoints compared to placebo or standard care. It is worth to mention the heterogeneity of the study population in the clinical trial with methylprednisolone (ranging from moderate to critically ill COVID-19 patients) [35].…”

“…Despite these limitations, these results could have direct relevance to the evolving management of COVID-19 for treating physicians. In addition to the contribution made by the increasing evidence of corticosteroids at moderate doses for severe COVID-19 [7,[32][33][34][35][36][37], we add robust evidence to prevent from using high doses of corticosteroids for these patients in order to avoid harmful effects.…”

Tocilizumab for Severe Worsening COVID-19 Pneumonia: a Propensity Score Analysis

“…Last, systemic corticosteroids are potent anti-inflammatory drugs and could represent a cheaper alternative than diseasemodifying antirheumatic drugs. Although two randomized failed to evidence a clinical benefit with low-dose hydrocortisone [40,41], a 10-day course of dexamethasone increased the number of ventilator-free days over a 28-day period in a Brazilian randomized controlled trial involving 299 patients [42]. Moreover, with more than 2100 and 4300 patients receiving dexamethasone and standard of care respectively, the RECOVERY trial provides robust evidence demonstrating that dexamethasone (6 mg daily for 10 days) reduces 28-day mortality (age-adjusted rate ratio: 0.83; 95%CI 0.75 to 0.93; p < 0.001) [43], as also evidenced in a recent meta-analysis pooling data from seven randomized trials [44].…”